Deep brain stimulation (DBS) is an established therapy for movement disorders such as essential tremor (ET). Positioning of the DBS lead in the patient’s brain is crucial for effective treatment. Extensive evaluations of improvement and adverse effects of stimulation at different positions for various current amplitudes are performed intraoperatively. However, to choose the optimal position of the lead, the information has to be “mentally” visualized and analyzed. This paper introduces a new technique called “stimulation maps,” which summarizes and visualizes the high amount of relevant data with the aim to assist in identifying the optimal DBS lead position. It combines three methods: outlines of the relevant anatomical structures, quantitative symptom evaluation, and patient-specific electric field simulations. Through this combination, each voxel in the stimulation region is assigned one value of symptom improvement, resulting in the division of stimulation region into areas with different improvement levels. This technique was applied retrospectively to five ET patients in the University Hospital in Clermont-Ferrand, France. Apart from identifying the optimal implant position, the resultant nine maps show that the highest improvement region is frequently in the posterior subthalamic area. The results demonstrate the utility of the stimulation maps in identifying the optimal implant position. Deep brain stimulation (DBS) is a neurosurgical treatment for movement disorders like essential tremor (ET). Patients undergo a complex surgical procedure to implant leads in the brain, which are continuously stimulated through a subcutaneously implanted pulse generator (IPG). The outcome significantly depends on the location of the DBS lead in the brain. Over the years of DBS usage, clinicians have established few specific, disease-dependent target regions, e.g., the ventro-intermedius nucleus (VIM) of the thalamus for ET. However, as these targets have a size in the range of millimeters and as the exact mechanisms behind the functioning of DBS are still incompletely known , most clBefore the actual surgery, clinicians perform planning using specially designed software to identify the target structure on the patient’s anatomical images and the best path to reach it from an entry point in the skull. During the surgery, one or more parallel test electrodes are inserted along the planned path and neuronal recording and stimulation tests are performed at pre-determined positions. Therapeutic and adverse effects are evaluated at these stimulation test positions. The details of the surgical procedure may vary between centers, but certain limitations are observed in all centers: the therapeutic effects of stimulation tests, for example, are evaluated visually or through passive movements using subjective clinical scales –5. FurthWe have previously published a method  using acIn comparison to collective data analysis in our previous studies, we propose in the current paper a method to visually analyze the high amount of data that is generated per patient. The aim is to combine the patient-specific electric field simulations with tremor improvement quantified through accelerometry as well as stimulation-induced adverse effects, and to visually present them in the form of so-called stimulation maps superimposed to the patient-specific anatomy to assist in surgical decision making, i.e., choosing the optimal implant position for the chronic DBS lead for the given patient. This stimulation map approach has been applied retrospectively to 9 DBS lead implantations from Clermont-Ferrand University Hospital in France to illustrate its advantage over current methods.The routine surgical procedure at the University Hospital in Clermont-Ferrand began with a meticulous pre-surgical planning. A brief description of the procedure is given here while a complete description can be found elsewhere . A stereDuring surgery, the stereotactic co-ordinates of the planned trajectories obtained from the planning software were set up on the Leksell Stereotactic System  using the repositioning kit. Two intraoperative exploratory electrodes were inserted along the previously identified trajectories. Micro-electrode recording (MER) was performed at all the planned test-stimulation positions along both trajectories simultaneously to confirm the location of the trajectories in relation to the surrounding anatomical structures . StimulaLow therapeutic stimulation current amplitudeHigh threshold for stimulation-induced adverse effectsNeighboring test positions having relatively low therapeutic stimulation current amplitudesAnatomical positionAfter completion of stimulation tests for one brain hemisphere, the surgical team compared the results (current amplitudes improving tremor and/or inducing adverse effect) and mentally visualized the information in relation to the patient’s anatomy. The DBS lead  was implanted at a position along one of the tested trajectories fulfilling the following conditions:The changes in tremor during surgery were evaluated applying a previously published method using an accelerometer . In shorPost-operative analysis of the data using Matlab consisted of calculating and filtering the magnitude of acceleration. Outcome measures  which have been shown to correlate with clinical changes  were extThe effects of electrical stimulation in the brain are not confined to the location of the electrode, but spread farther into the brain in all directions depending on the stimulation parameters and the brain tissue surrounding the contact. To understand these spatial effects of the stimulation, an established patient-specific FEM-modeling technique for DBS leads , 4, 49 wA model of the microelectrode  used in Clermont-Ferrand University Hospital was developed with its specific dimensions. As electrophysiological evaluations were performed through two parallel electrodes, a second model of the MER-electrode was positioned at a distance of 2 mm. The ends of the grounded guide tubes were fixed at 12 mm above the target point. In consequence, the distance (d) between the guide tube and the middle of the stimulating contact decreased or increased respectively when the simulation site was before or after the target (12 mm ± d) along the trajectory.Patient-specific brain models , 5 were highest change in tremor  and converted to the co-ordinate system of the brain model using Matlab. The target co-ordinates and the trajectory angles were used to calculate and to place the stimulating contact and the parallel electrode in the brain model for the different stimulation test positions. The stimulation current amplitude applied intraoperatively was used to simulate the EF. In order to keep the simulation time reasonable, we decided to simulate for each stimulation test position the EF distribution for the current amplitudes with (1) the first appearance of The spatial distribution of EF was simulated by using the equation of continuity for steady state current:In addition to the planned trajectory and target information, the manually outlined anatomical structures were extracted from the iPlan software via a specifically designed interface based on VVLink and VTK . In order to reduce error sources, only the CT data set was used as reference for the outlined anatomical structures and the target co-ordinates. In consequence, the structures initially outlined on the WAIR-weighted sequence were resampled in iPlan to the stereotactic CT data set providing a higher resolution and minimal distortion of the stereotactic reference system.A clinical study was undertaken at the University Hospital in Clermont-Ferrand, France , and 5 patients who were treated for ET using DBS were included for the current work  scripts in the following order: (1) the T1 MR and the WAIR MR image data sets were imported and cropped to the region of interest. (2) The csv files containing the co-ordinates of the thalamic nuclei  using Python  were performed based on these stimulation tests and summarized in 9 stimulation maps. These maps vary from patient to patient depending on the planned trajectory and the test stimulation positions along it.Figure The procedure described above was applied to all the 9 implantations and the results were summarized. The interactions between the anatomical structures and the highest improvement region and the adverse effect threshold outline respectively are listed in Table In the 9 stimulation maps, seven anatomical structures were identified that interacted with the highest improvement region: INL, VO, VIM, PLR, VCL, VCM, and LaCM. The VIM, the planned target for all the patients, occurs the most frequently. It appears in 8 out of the 9 maps, with a complete coverage in 4 cases. In 6 of the 9 stimulation maps, the highest improvement region encompassed the posterior subthalamic area (PSA) inferior to the VIM which includes the PLR and the zona incerta (ZI). This area was not explored in the other three maps as adverse effects were observed in this position at low stimulation current amplitudes. In addition, the anterolateral part of the LaCM was partially enclosed in 6 maps, lateral parts of the ventrocaudal medial nucleus (VCM) in 5 maps, the VO was encompassed in 4 maps , the inferomedial part of the VCL in 4 maps, and the inferior part of intermediolateral nucleus (InL) was partially included in 3 maps.Three different types of adverse effects were observed during 6 out of the 9 implantations as described in Table This paper describes a new digital approach to assist the clinicians in identifying the optimal region to implant the chronic DBS lead after intraoperative stimulation tests: a task currently performed by evaluating handwritten notes taken during surgery. The approach combines the outline of the relevant anatomical structures with a novel technique to quantitatively evaluate the therapeutic effects and a patient-specific method to estimate the spatial effects of stimulation. This combination creates stimulation maps, i.e., 3D visualization of the intraoperative stimulation test results with therapeutic areas, adverse effect areas, and anatomical structures in the stimulation test region. Nine stimulation maps were generated after applying this approach to 5 ET patients who underwent DBS surgery. In comparison to the current practice of handwritten notes, the interactivity and visualization of maps significantly simplifies the discussion within the surgical team to determine the optimal implant position of the DBS lead. The added information about spatial effect of stimulation with sub-millimeter resolution presented in the stimulation maps enables the implantation of the lead at locations in between the ones that are tested along the trajectory during the surgery.Visualization of intraoperative DBS data has been previously proposed. D’Albis et al.  developeIn the present study, we describe a specific case of improvement maps where each voxel in the stimulation test region is assigned with the maximum value of improvement as measured by the quantitative technique. To the best of our knowledge, no such patient-specific intraoperative approach has been proposed in the literature before. In general, however, the structure of the improvement maps, i.e., the different therapeutic regions and their location, is significantly affected by the choice of the improvement value assigned to a voxel. Theoretically, this choice can be made using computationally simple functions like mean, maximum, etc. or complex functions based on fuzzy logic, weighting function based on distance from trajectory, etc. Importantly though, to the best of our knowledge, there are no methods available that would enable validation of these functions for assigning the improvement values. Therefore, the practical implications of this choice have to be considered. For this study, we aimed at identifying the optimal position to implant the permanent electrode. In consequence, it is necessary to identify the highest improvement region with the least amount of current (less battery consumption), justifying our choice of assigning the maximum improvement to each voxel. Furthermore, the use of maximum function also mimics the current clinical procedure of choosing the smallest current resulting in the highest improvement, which makes it intuitive for a clinician to understand. In addition to the choice of improvement value assigned to a voxel, the input stimulation current amplitude used for the EF simulations also affects the improvement maps. Both these choices depend heavily on the goal set forth before the start of data analysis.The application of the stimulation map approach to five patients showed how it could assist in choosing the depth for the permanent implantation of the DBS lead Table . In addiIn its current form described in this study, the procedure of creating the stimulation maps is very specific to the type of data available from the University Hospital in Clermont-Ferrand. In general, however, the technique is very adaptable to the type of data available. In the absence of pre-operative anatomical outline, the patient images can be co-registered to digitized atlases using open-source software like 3D Slicer  and segmThe primary focus of this paper is to describe the method of generating the stimulation maps and to apply it to 9 implantations. Nevertheless, to draw statistically significant conclusions, the approach has to be applied to a larger number of patients. Moreover, in order to establish that the implant position of the lead based on the stimulation maps is optimal, a larger control group study must be performed comparing lead implant position choices made using conventional methods with those made based on the stimulation maps. In terms of drawbacks of individual datasets, the reconstruction of the outline of anatomical structures is limited by the voxel dimension, which can only be improved by using imaging systems with better resolution. Any caveats associated with the quantitative tremor evaluation and EF simulation techniques also affect the stimulation maps. Our previous research has shown that the quantitative tremor evaluation depends on proper acquisition of baseline data before every stimulation test . In the The stimulation maps presented here were generated and analyzed post-operatively. Steps to generate the stimulation maps in real-time have been identified. The time between pre-surgical tasks  and the actual surgery needs to be utilized for all preparatory steps . The accelerometer-based symptom evaluation system has already been enhanced to analyze data in real-time. Additional provisions have to be made to establish communication between the accelerometer recording software and the simulation software to simulate EF in real-time. The algorithms that generate the stimulation maps from the EF simulation files take a maximum of 5 min and can be executed once stimulation tests are completed during the surgery. Once these steps are realized, a larger clinical study will be conducted to confirm the advantages of stimulation maps highlighted in the current paper and to make them available during surgical decision-making after the intraoperative stimulation tests.A likely long-term application of stimulation maps would be to facilitate the use of directional DBS leads to steer the effects of stimulation in a certain direction. Schüpbach et al. , 39, 40 This paper describes a new technique to generate stimulation maps to summarize and visually analyze data from intraoperative stimulation tests for deep brain stimulation surgery. Data collected from 9 implantations were analyzed with the aim to identify the optimal site to implant the chronic DBS lead. Clinicians found the visualizations intuitive and easy to interpret and to identify the region resulting in highest improvement in tremor. In 7 of the 9 stimulation maps, the highest improvement region was found to be in the PSA in agreement with the scientific consensus. This method has the potential to simplify the surgical team’s task in identifying the ideal implant location of the chronic DBS lead and to facilitate and expedite the use of directional leads in DBS.


Trypanosoma cruzi infections, continues to be a health concern mainly in Latin American countries where the parasite is endemic. The laboratory diagnosis of a chronic infection is determined through serological assays for antibodies against T. cruzi and several tests are available that differ in key components, formats and methodologies. To date, no single test meets the criteria of a gold standard. The situation is further complicated by the difficulties associated with performance comparisons between different immunoassays or methodologies executed at different times and geographical areas. Chagas disease, resulting from T. cruzi: NIBSC 09/186 and NIBSC 09/188 that respectively represent geographical regions with the highest prevalence of TcII and TcI lineages of the parasite. To improve the diagnosis of Chagas disease, the WHO coordinated the development of two International Biological Reference Standards for antibodies against anti-T. cruzi antibodies. The principle goal of this study was to verify the behavior of these standards when assayed by several commercially available serological tests that employ different methods to capture and detect human anti- The results reinforce the recommendation that these standards be considered for performance evaluations of commercialised immunoassays and should be an integral step in the development of new test components or assay paradigms. Trypanosoma cruzi, the etiological agent. First described by Carlos Chagas in 1909,,,,Human Chagas disease is caused by an infection of the protozoa T. cruzi infections through laboratory tests for the administration of the best course of patient treatment to curb disease progression and the prevention of disease transmission. Parasitological tests for T. cruzi infections can directly observe parasites in blood smears,,,T. cruzi genome circulating in blood is also possible through molecular biology techniques.,,,,,,,,,It is of fundamental importance to accurately diagnosis T. cruzi antibodies. A variety of diagnostic tests have been developed and described in the literature and several of them have been commercialised.,,For the chronic phase, when parasitaemia is at its lowest level, serological assays offer an alternative diagnostic method by the detection of anti-T. cruzi at a scale that could be used as a reference to evaluate the performance of existing serological tests as well as the development of new tests. As a result, two regionally distinct samples were generated, defibrinated, aliquoted and lyophilised. After an extensive evaluation for their anti-T. cruzi antibody content, in 2011, these samples were established as WHO International Reference Standards or Biological References for the serological diagnosis of Chagas disease.T cruzi antibodies within a single laboratory setting; a relevant assessment at the moment when, for the first time, Chagas disease immunoassays have been included in the WHO Model List of Essential In Vitro Diagnostics.In 2007, the WHO organised a research group to develop biological resources representing the sera of individuals infected by Biological references standard - The WHO 1st International Reference Standards for Chagas disease antibody in Human PlasmaT. cruzi I (TcI) antibodies regionally collected from individuals living in Mexico. NIBSC code 09/186 contains anti-T. cruzi II  antibodies regionally collected from individuals living in Brazil and Chile. Each standard was prepared and diluted as recommended using 0.5 mL distilled water to provide a 1:1 stock solution. A two-fold serial dilution series was generated from 1:2 to 1:64.Serological diagnostic kits - Eight serological tests were included in the evaluation and each was conducted before their expiration dates . For measurement of optical densities, a Sunrise™ ELISA reader was used (TECAN). For the chemiluminescent magnetic immunoassay, an Architect i2000  was employed.Statistical analysis - The statistical analyses consisted of a Two-Way ANOVA Without Replication that was defined using as the variation factors the degree of dilution and the manufacturer of the test.,,T. cruzi antibodies, NIBSC 09/186 and NIBSC 09/188, was evaluated by the ability of a set of commercially available assays, which are approved by multiple regulatory agencies for the diagnosis of chronic Chagas disease, to detect and measure their respective pool of T. cruzi specific antibodies  of specific protein bands in the range of 120 kDa to 200 kDa. The TESA blot showed the expected bands, although at a lower dilution than the commercial kits that is consistent with the lower sensitivity of this assay .T. cruzi in the diagnosis of chronic Chagas disease. The results of the comparative performance of various assays currently commercialised using the biological references supports the recommendation for their consideration in the evaluation of tests as well as for the testing of prototypes under development.In the last decade, for the first time the WHO coordinated the development of biological references for use in immunoassays to detect antibodies against In serological tests, the objective is for the final result, represented here as the ratio of the measurement of the signal intensity to cutoff, to strictly relate to the diagnostic status of the patient. However, the diverse elements that comprise an assay also contribute to the final result. These factors include the design of the assay, the target antigens, the platform, instrumentation and accessory components such as anti-human secondary antibodies, their conjugated enzymes, enzyme substrates and buffers. With all of these contributing variables, the final value does not exclusively correspond to the actual concentration of the antibodies under analysis in the sample. This limits serological tests to being qualitative assays where the measured intensity can only indicate the presence or absence of reactive antibodies. The qualitative nature of serological testes makes it is very difficult to compare the results obtained with kits of different origins and/or methodologies.In the study originally describing the International Biological References Standards,To remove any contribution of the laboratory setting to the final result, a set of commercial tests were executed in a single laboratory using the biological reference standards. For the ELISA tests executed here, the relative strengths for NIBSC 09/186 were observed to be between 8 and 16 with only one showing a relative strength of 32, which was obtained with the CMIA format. In comparison, a higher reactivity was measured for each assay over the dilution series of NIBSC 09/188 with four test kits showing a relative strength of 32, including the CMIA format. Overall, each of the tests showed a fairly linear relationship between the dilution value and reactivity, which suggested good consistency between each measurement.T. cruzi antibodies; the diversity in the geographical distribution of parasite lineages and the corresponding immunological response. Only one immunoassay displayed reactivity for NIBSC 09/186 at a dilution of 1/32 whereas four immunoassays showed reactivity at this dilution for NIBSC 09/188. No assays showed reactivity at the highest suggested dilution of 1/64. As the reactivity of each test is statistically significant to the result and their relative strength differed between the standards, it strongly suggests that NIBSC 09/186 and 09/188 have a different composition of anti-T. cruzi antibodies.The difference in the relative strengths of each test to the two different standards highlights a major difficulty associated with the development of a gold standard test for detecting T. cruzi polymorphism, seven distinct lineages, called Discrete Typing Units (DTU), TcI to TcVI and Tcbat have since been defined.,,,,,,,,,T. cruzi, irrespective of their distribution between the two and the relative concentration of antibodies to common epitopes should be nearly equivalent. Unless there is a diminished immunological reaction against infections by TcII-TcVI than TcI that would reduce the antibody titer in NIBSC 09/186 compared to NIBSC 09/188, the difference in the results would suggest that the antigenic compositions in the different assays are more representative of TcI than TcII-TcVI.At the time that the sera used to generate the biological references was collected, there were only two recognised lineages, TcI and TcII, which were used to define the geographical regions used to differentiate the two biological references NIBSC 09/188 and 09/186, respectively. Due to the high degree of intraspecific This difference in antigen composition is supported by the results with the CMIA platform that appeared to be equally sensitive to the two regionally representative biological standards, although the result with NIBSC 09/186 at the 1/32 dilution was close to being defined as non-reactive. Its higher sensitivity was evident by the consistently higher values observed for the CMIA-based assay throughout the serial dilution compared to the other tests. The results suggest that the CMIA assay can serve as a blood screening platform with the lowest possible rate of false negative results, which is a public health objective that drove its development.The TESA blot showed the lowest sensitivity for both biological references with reactivity observed only up to the 1/8 dilution. Considering that the TESA blot is primarily a complementary test for specificity to a previously reactive test, the lower sensitivity can be accounted for during execution. Unlike the ELISA formats, the western blot format of the TESA blot did not show a difference in sensitivity to NIBSC 09/186 & 09/188 suggesting that its application in the diagnosis of Chagas disease can be universal.Regardless of the serological panels used or the populations studied, we believe that it is essential to have a mechanism to be able to compare the results obtained with different immunoassays and methodologies. The WHO International Biological References Standards can serve this mechanism to evaluate the performance of all commercialised immunoassays and prototypes under development to meet the ongoing need for a gold standard test to diagnose human Chagas disease.


Multi-under-actuated unmanned surface vehicles (USV) path tracking control is studied and decoupled by virtue of decentralized control. First, an improved integral line-of-sight guidance strategy is put forward and combined with feedback control to design the path tracking controller and realize the single USV path tracking in the horizontal plane. Second, graph theory is utilized to design the decentralized velocity coordination controller for USV formation, so that multiple USVs could consistently realize the specified formation to the position and velocity of the expected path. Third, cascade system theory and Lyapunov stability are used to respectively prove the uniform semi-global exponential stability of single USV path tracking control system and the global asymptotic stability and uniform local exponential stability of coordinated formation system. At last, simulation and field experiment are conducted to analyze and verify the advancement and effectiveness of the proposed algorithms in this paper. Unmanned surface vehicle (USV) is a small intelligent mission platform on the water surface, and has such advantages as small size, low cost, high speed, intelligence, small radar cross section, and no personal injury or death . In the The study of USV coordinated formation control started quite late, but has great potential for actual application. In the civil domain, it could be performed to not only coordinate the hydrologic and topographic surveys in a large sea area, but also complete the pavement and patrol of subsea pipeline. In the military domain, it could be conducted for large minefield detection and clearing, and tactical formation could be employed to block the enemy warship or port, and enhance the combat efficiency and the success rate of enemy target strike. Therefore, it is of great significance.With regard to USV path tracking control, Børhaug et al. 2011) put forward the integral line-of-sight (ILOS) guidance control law as a compensation for the environmental disturbance, and demonstrated the stability of system . John et put forwAt present, most USV path tracking algorithms including those used in the above references are designed with simplified system and numerical analysis. In their design, it is assumed that USV is longitudinally and laterally symmetrical. All the models are strictly diagonal, and employ inertial coefficient matrix and damping coefficient matrix. However, USV often has a structure of lateral symmetry but longitudinal asymmetry. Therefore, modeling results in very large errors. Algorithms are designed with known disturbance, so that the disturbance caused by ocean current to the USV kinematic model is overlooked in most references, but regarded as the disturbance to the USV kinetic model together with wind, wave and un-modelled dynamics. As a matter of fact, ocean current exerts only kinematic effects on the USV maneuvering motion, and causes USV drifting to change its velocity and position and make it deviate from the planned route and heading. In the meanwhile, some references rely on much prior knowledge of single structure, so that the models are less adaptive to environment. Error direct feedback disturbance observer is used in the design to observe disturbance in a real-time manner, which sacrifices the controllability of system.With regard to USV formation control, Shojaei et al. 2015) studied the under-actuated USV formation control under external disturbance and model parameter perturbation. After firstly designing a formation coordination controller based on the leader-follower mode, they utilized state feedback in the design of single USV tracking controller and introduced generalized saturation function to effectively prevent the possible oversaturation caused by actuating mechanism. After that, neural network was utilized to online approach the uncertain terms caused by external disturbance, and eventually Lyapunov stability theory was employed to prove the uniform semi-global stability of closed-loop control system. However, leader’s breakdown may lead to the collapse of the formation so that the leader-follower mode is not applicable to practical engineering applications . In 2016 studied Generally, formation control is often achieved using leader-follower method , behavioIn the abovementioned formation control methods, coordination control law is designed only to realize the relative position or distance of USVs as expected and maintain a specific formation for mission execution, but no restriction is imposed on the motion track of each USV. In most references, the design of formation controller does not include external disturbance and uncertainties in USV mathematical model. Most references describe the verification of algorithm only by virtue of simulation, but rarely put it into the actual cruising test of USV coordinated formation.This paper focuses on formation path tracking in the problem of formation control, and addresses the problem of coordinated path tracking for multiple under-actuated USVs subject to external disturbance. With the decentralized control strategy, the problem of multi-USV coordinated path tracking is decoupled into the design of single USV path tracking controller and multi-USV coordination controller. In this way, each USV is controlled to overcome the influence of external disturbance and realize accurate path tracking while maintaining the expected formation. Hence, this approach is suitable for some engineering applications with higher requirements for the USV formation path tracking accuracy.Based on Reference , this paSecond, integral line-of-sight guidance is mainly employed as a strategy to address the problem of single USV control. The strategy is further improved by changing the fixed headway range to the time-variant adaptive headway range. Time-variant headway range allows more flexible motion of USV. When USV is very far away from the expected path, tracking error is large, but headway range is small, making USV approach the expected path fast. When USV is close to the expected path, tracking error is small, but headway range is large, which could effectively reduce the position error overshoot. Meanwhile, the influence of USV under-actuation, uncertainty and external disturbance is taken into account comprehensively to design the heading and velocity controller of single USV based on the idea of feedback control. In this way, the expected heading given by the guidance system is tracked so that USV could maintain the accurate and stable tracking of the expected path, which resolves the problem of lower path tracking accuracy caused by time-variant disturbance in the traditional ILOS algorithm. As for multi-USV coordination control system, this paper utilizes the graph theory to design the decentralized velocity coordination controller for USV formation. Therefore, each single USV could accurately track the expected path, while the velocity of each USV is controlled in a decentralized manner to quickly realize the USV formation and maintain it in a coordinated and consistent way.Subsequently, Lyapunov theory is employed to verify the uniform semi-global exponential stability of single path tracking control system, while guidance system and heading and velocity control system are constructed into a cascade system. The theory of cascade system is utilized to prove the global asymptotic stability and uniform local exponential stability of multi-USV coordinated formation control system. Compared with the global K-exponential stability described in most references, this approach offers faster convergence and stronger robustness.At last, comparative simulation experiment and USV maritime test are conducted to analyze and verify the advancement and effectiveness of the proposed algorithm in this paper.This paper is organized as follows: Considering the irrotational flow of seawater in the geodetic coordinate system (hereinafter referred to as  follows :(2)J(ψ)=At present, the nonlinear mathematical model of USV with 3 degrees of freedom (DOF) is employed nearly in all references available at home and abroad, so that this model could accurately present the motion of USV in the horizontal plane. In many other works, this model has been also used, but it is simplified for controller design to different degrees. In this paper, this model is employed but not simplified.The influence of stock torque on the transverse motion of USV makes it difficult to design the heading and velocity controller. To prevent this influence, the center of USV in the After coordinate transformation, Equation (12) shows that The planned path is an expected path formed by a number of track reference points under the geodetic coordinate system The current position of USV in the Equation (19) is differentiated as follows:From Equation (18), we obtain:Based on the geometry in Equations (21) and (22) are substituted into Equation (20) to obtain:The problem of multi-USV formation control could be broken down into the problem of single USV path tracking and the problem of multi-USV coordinated formation. First of all, a path tracking controller is designed for single USV to realize the control objective of spatial motion converging to the expected path. After that, the forward motion velocity of each USV is adjusted considering the USV path tracking velocity and position to realize the control objective of multi-USV coordinated formation.Considering the above analysis of path and model, this paper employs the integral line-of-sight guidance subsystem and the heading control subsystem cascade. Guidance system could be used to determine the heading of under-actuated USV based on the real-time position, attitude information and planned route of under-actuated USV. Heading control subsystem could determine the expected steering gear manipulation signal based on the deviation between expected heading and actual heading of guidance system, so as to control the under-actuated USV and make its path tracking position and heading converge to the equilibrium position. Heading control subsystem controls the velocity of under-actuated USV converging to the expected velocity.Therefore, the expected control objective in this paper could be described as follows:As shown in The USV forward velocity Designing a single USV path tracking controller for USV control to realize the control objective Equations (24) and (25), of position and heading, and move along the Designing a controller for Above all, the problem of multi-USV formation coordination path tracking could be divided into:In the traditional line-of-sight (LOS) algorithm, the current position of USV is projected on the expected route and a tangent is made at the point to define the headway range on the tangent and obtain the virtual target point related to the reference point. The current position of USV and the virtual point are the LOS vectors. The resultant velocity direction of USV is guided to align with the LOS vectors for tracking. The LOS algorithm does not rely on the USV model in principle, so that it is slightly affected by the algorithm. Hence, it does not have very high requirements for parameter design. Additionally, expected heading could be calculated only using the real-time position and expected route of USV. The expected heading could be obtained and output in a real-time manner to the control system. Nevertheless, the traditional LOS algorithm may be affected by time-varying disturbance, so that its accuracy is poor during the tracking process. For this reason, integral term should be introduced to make compensation for disturbance in a real-time manner, so as to realize higher accuracy. The integral LOS (ILOS) guidance strategy under the relative velocity in the traditional algorithm could be expressed as follows:The adaptive headway range r than 0 ; Δmin isIn this section, the feedback linearization design control law is followed to make the USV heading and velocity converge to the expected values.Based on the expected heading ubsystem , EquatioEquation (13) is used to design the velocity control law as follows:The influence of seawater flow on the design of path tracking controller has been taken into account. Therefore, Because of By then, the controller The controller is designed as follows:During the process of USV motion, Assumption 1.Therefore, Equation (23) could be written as:After defining Equation (38) is expanded to obtain:Moreover, there is:Equations (40) and (41) are substituted into Equation (38) to obtain:Obviously, there is Let In other words, there is:The Lyapunov function It is differentiated to obtain:As a result of Therefore, guidance subsystem has uniform global asymptotic stability (UGAS) at the equilibrium point Additionally, there is The formula for dynamic tracking error of heading and velocity control subsystem is as follows: When the system is linear and time-invariant, and l stable ,36, i.e.The position error dynamic equation and heading and velocity error dynamic equation are written in the following cascade:When the system Verification: As a result of Since the systems Equation (36) is substituted into Equation (34) to obtain:Let Equation (57) is transformed in the form of vector Stability analysis is conducted as follows:Theorem 1.Considering the kinematic and kinetic model of USV Equation (1), it is assumed thatis continuously differentiable, and satisfies Equation (35);satisfies; and the communication topographic graph G between USVs has at least one globally reachable point. In the USV formation, the initial position of each USV is random. Under the effect of controller Equations (30), (31), and (32), USVs move at the expected velocity obtained from Equation (36). Eventually, all exponents could converge to the expected path and the expected formation is realized. In other words, control objective Equations (24) and (25) are fulfilled.Theorem 2.Considering that Theorem 1 is justified, and the system in Equation (58) is under the coordination transformation, the following formulas are established:(1), i.e.,(2), whereis globally bounded.(3) There is positive definite and radially unbounded Lyapunov function, which satisfies:The systemhas global asymptotic stability and uniform local exponential stability.Verification: It is assumed that the communication topographic graph Verification 1. There is Verification 2. Equations (58), (62), and (64), are combined as follows:Verification 3. Equation (65) is used to obtain:Considering the Lyapunov function:Let We select After linearization, Equation (66) is changed to:Let Meanwhile,Above all, USV formation system could tend to be stable under the control of the controller Equation (36). Hence, Theorem 1 is verified. The verification of its stability fulfils a control objective The verification ends.To verify the effectiveness of the proposed control approach in this paper, the USV model in Reference  is emploA USV path is straight and curved. In this section, simulation experiment is conducted using the path tracking algorithm with the traditional LOS guidance strategy and the control algorithm with the proposed ILOS guidance strategy in this paper to compare straight and curved paths. Among them, the parameters for heading and velocity subsystem are (1) Straight pathThe expected route of USV is (2) Curved pathThe expected track is a continuous curve generated through approximation by five polynomials, that is, As revealed in As shown in After comprehensively analyzing After comprehensively analyzing To verify the validity and advancement of the USV formation control algorithm proposed in this part (hereinafter referred to as Algorithm 3), a formation of 5 under-actuated USVs is employed for control. Each USV has the same model parameters and single USV path tracking simulation parameters. The software MATLAB is used for comparative simulation experiment. The control group is taken from Reference . In the 1, The parameters of simulation environment are selected as follows: the parameters of heading and velocity subsystems are A triangular formation is made by 5 USVs. Among them, The simulation results are given in As shown in As revealed in As shown in As shown in To verify the engineering effectiveness of the proposed USV formation control algorithm, three ‘Jellyfish’ USVs , calm sea surface, Level 0–1 sea condition, and wave height approx. 0.6 m.During the field test, the parameters of heading and velocity subsystems are The results of USV formation cruising control are shown in As shown in This paper proposes an improved ILOS guidance strategy while considering the influence of USV under-actuation, uncertainty, and external disturbance. A single USV path tracking controller is designed, while the idea of feedback control is followed to complete the stabilization of position error, heading angle, and expected velocity, so as to realize the single USV path tracking control. Based on the graph theory, a decentralized speed coordination controller is designed to realize USV formation tracking and maintain the formation. At last, cascade system theory and Lyapunov stability are utilized to respectively prove the uniform semi-global exponential stability of path tracking control system and the global asymptotic stability and uniform local exponential stability of coordinated formation system. Simulation and field experiment is conducted and analyzed to prove the advancement and effectiveness of path tracking algorithm and coordinated formation control algorithm based on the improved ILOS guidance strategy.


Bayesian reasoning is common and critical in everyday life while the performance on Bayesian reasoning is rather poor. Previous studies showed that people could enhance their performance by applying cognitive resources under the natural frequency format condition. Working memory is one of the crucial cognitive resources in the reasoning process. However, the role of working memory on Bayesian reasoning remains unclear. In our study, we verified the effect of working memory on Bayesian reasoning by evaluating the performance of participants with high and low working memory span (WMS); we also investigated if working memory as a kind of cognitive resource can affect Bayesian reasoning performance by manipulating the cognitive load in a dual-task paradigm among participants with no-, low-, and high-loads. We found the following: (1) The Bayesian reasoning performance of high WMS participants was significantly higher than that of low WMS participants. (2) Performance under natural frequency condition was noticeably higher than that in standard probability condition. (3) Interaction between working memory and probability format was significant, and the performance of participants with high-load in natural frequency condition was higher when compared to those of participants with no- and low-load. Therefore, we can conclude that: (1) Working memory resource is a major factor in Bayesian reasoning. The performance of Bayesian reasoning is influenced by working memory span and working memory load. (2) A Bayesian facilitation effect exists, and replacing the standard probability format with a natural frequency format can significantly improve Bayesian performance. (3) Bayesian facilitation occurs only in participants with sufficient working memory resources. In daily life, people often make critical decisions based on conditional probabilities, such as in courts, hospitals and war rooms . AlthougThen we can calculate it as Bayes’ rules:Where, P(h) represents the base rate of 1%, P(d| h) represents the hit rate of 80%, P(d|−h) represents the false alarm rate of 9.5%, and P(h| d) represents the posterior probability.Since There are two influential theories about the natural frequency promotion of Bayesian reasoning. One is the framework of ecological rationality, the other is nested set theory . The ecoTheir study showed that both working memory span and working memory resources were highly positively correlated with reasoning tasks . The theResearchers have explored cognitive processing, such as cognitive reaction ability, to investigate the facilitation effect . Even chTo further research the relationship between working memory and Bayesian reasoning, we expand upon the study of This experiment is aiming to investigate the effect of WMS on Bayesian reasoning and Bayesian facilitation. Based on previous studies, the hypotheses are as follows: (1) working memory span is highly correlated with Bayesian reasoning score, the performance of high WMS group was better than those of low WMS group; (2) there is a natural frequency facilitation effect.This experiment was approved by the Ethics Committee of Hunan Normal University, and written informed consent was obtained from all participants before the experiment was started. The sample size was calculated with a power of 0.8 and the minimum requirement of sample size was 36. 120 college students  participated in this experiment, with ages ranged from 18 to 25 years . All of the subjects volunteered to participate in the experiment and did not learn or understand Bayesian reasoning.This experiment used Operation Span Task designed by The WMS index was represented by the total number of double-character words correctly recalled in the group, with a range from 0 to 60. To ensure the validity of the subjects’ participation in the dual-task, the correct rate of the secondary task  was required to be more than 85% . In the A total of 5 of the 10 Bayesian problems  were extracted from materials developed by Here are two versions of the same Bayesian reasoning question (the Red Nose problem) see :The procedure consisted of an exercise part and a test part. When the subjects familiarized themselves with the probabilistic question of the exercise part, they could start the second part of the formal experiment. The instructions were presented first and then entered the reasoning task. After the reasoning questions were presented, they analyzed and calculated on the paper and input the results into the answer box when they were completed see . At the The results of reasoning score of the 72 subjects were regarded as “correct” when the difference from standard answers was less than 1%; otherwise, they were regarded as “wrong.” Correct answer was scored as 1 while incorrect answer was scored as 0, and the total score was between 0 and 5 points. The SPSS19.0 software was used to analyze the data. The analysis and results are shown in F = 6.967, p < 0.05, η2 = 0.10], that is, the Bayesian reasoning performance of high WMS subjects was significantly higher than that of low WMS subjects. The main effect of data format was significant , indicating that the results of reasoning by means of natural frequencies were significantly better than those of reasoning by means of standard probability. Interaction between WMS and data format was significant .Two-factor ANOVA showed that the main effect of WMS was significant . The results of reasoning in the three working memory load conditions were as follows: the best results were in the no-load condition, the second was in the low-load condition, and the worst was in the high-load condition. The main effect of the data format was significant . The reasoning results of subjects in the natural frequency scenario were significantly better than those of subjects who were in the standard probability scenario. Interaction between working memory load and data format was significant .Two-factor ANOVA showed that the main effect of the working memory load was significant [A further simple effect analysis showed the following:F = 18.49, p < 0.05), which showed that the reasoning results of the subjects in the natural frequency scenario were significantly better than those of subjects in the standard probability scenario.At the no-load level, the data format effect was significant , that is, at the low working memory load level, the reasoning score of the subjects in the natural frequency scenario were significantly better than those of subjects in the standard probability scenario.At the low-load level, the data format effect was significant . At the high-load level, there was no significant difference in reasoning performance between the two data formats.At the high-load level, the data format effect was not significant (The results of experiment 1 showed that the performance of Bayesian reasoning was influenced by the working memory span (WMS). This is consistent with the researches of Bayesian reasoning is a kind of complicated probabilistic reasoning that involves a series of probability information and rules. Individuals with high WMS have more ability and resources to use probability rules, so they could integrate all kinds of explicit information relationships and operate on numbers, and can result in the answer smoothly. However, for individuals with low WMS, it is impossible to integrate and calculate the probability information effectively because the complex cognitive process is far beyond their own WM ability. Therefore, the reason why individuals cannot obtain the correct answer when completing the experimental task is that they guess or input an answer randomly according to their own intuitive judgments, which lead to a reasoning error .The results of experiment 2 showed that WM load can affect Bayesian reasoning. Specifically, the degree of influence increases with WM load. The reasoning performance was best in the no-load condition, second in the low-load condition and the worst in the high-load condition.For each individual, the WM resource remains relatively stable and limited. When a secondary task occupies more WM resources, they have fewer resources to solve the main task . Of the Therefore, two experiments verified the Bayesian facilitation in natural frequency representation. However, the Bayesian facilitation effect did not appear under all conditions, that is, the occurrence of the Bayesian facilitation effect requires certain conditions. The results of experiment 2 verified the facilitation effect. The results showed that the performance in natural frequency format was significantly better than in the standard probability format under low-load and no-load conditions, but the difference between them was not significant under a high-load condition. This indicated that the Bayesian facilitation effect was only reflected in the low-load and no-load conditions, but it was not found in the high-load condition.Working memory resource is a kind of important cognitive resource for reasoning . Under hExperiment 1 found that under the natural frequency condition, the score of the high WMS group was significantly higher than those of low WMS. Experiment 2 also found that under the natural frequency condition, the reasoning results of subjects in low-load and no-load conditions were significantly higher than those under the condition of probability .The ecologically rational framework argues that people perform better at natural numbers because people process natural frequencies better than probability. And the computational requirements for natural frequencies are much simpler than for probabilities. However, the participants couldn’t complete the problems well in high-load conditions. The nested sets theory holds that there is a positive relationship between working memory resources and reasoning performance, especially under the natural frequency condition that nest-set is clear . The resThe nested sets theory is proposed on the basis of the dual-process model, which makes the structure of the problem set clear and triggers the analysis system. The system uses executive cognitive resources to calculate the correct answer. Therefore, the reason why people perform better with natural frequency is that the nest-set is clear by making a collection of “nested” relationship (the larger subset embedded collection) visualization . That isThe results support the effect of working memory on reasoning. If the cognitive process is too complex that it exceeded people’s working memory ability, their reasoning will be wrong. Bayesian reasoning is a very difficult probability reasoning that involves a series of probability rules such as addition, multiplication, division, and a complex cognitive process. The use and storage of the information, rules, and the calculation of the premise and new information are all restricted by working memory capacity . For indWorking memory resource is an important factor that influences Bayesian reasoning performance; that is, the quality of Bayesian reasoning results depends on working memory resources. Individuals with high WMS or sufficient resources exhibit better cognitive processing than those with low WMS or insufficient resources. However, this advantage is not always true, and it may not exist when the cognitive task is too hard. A Bayesian facilitation effect exists and replacing standard probabilities with natural frequency can greatly improve Bayesian performance. However, only in individuals with high working memory span or sufficient cognitive resources does this effect occur. The experimental results provide experimental evidence for the effect of working memory on Bayesian reasoning.https://figshare.com/articles/data/11827053.The original contributions presented in the study are publicly available. This data can be found here: This experiment was approved by the Ethics Committee of Hunan Normal University in China, and written informed consent was obtained from all participants prior to the experiment.ZS, LY, and ZL conceived and designed the study. LY and ZL performed the experiments and wrote the manuscript. LY, ZL, and SP analyzed the data. ZS, LY, TT, and YX the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Many articles have been published on scale-down concepts as well as additive manufacturing techniques. However, information is scarce when miniaturization and 3D printing are applied in the fabrication of bioreactor systems. Therefore, garnering information for the interfaces between miniaturization and 3D printing becomes important and essential. The first goal is to examine the miniaturization aspects concerning bioreactor screening systems. The second goal is to review successful modalities of 3D printing and its applications in bioreactor manufacturing. This paper intends to provide information on anaerobic digestion process intensification by fusion of miniaturization technique and 3D printing technology. In particular, it gives a perspective on the challenges of 3D printing and the options of miniature bioreactor systems for process high-throughput screening. The pressure to reduce bioreactor costs and accelerate the bioprocess development in the biotech industry is ongoing and increasing . The ideSimilar to reactor performance in chemical research, in biochemical research, the term bioreactor performance is often used. However, a rapid scan of the literature elucidated that bioreactor performance is a well-known known concept, but it is never thoroughly explained ,7. In prHowever, process performance usually connects to a particular market price of the product. On the other hand, there are also costs involved in the microbial conversion processes. The reduction of costs is often the main objective of biochemical engineering . The bioBioreactors can also be used for the production of cells where batch production is facilitated. The problem is that these batch-wise operated bioreactors have a lower output per volume per hour unit than with continuously operated bioreactors. On the other hand, continuously operated bioreactors have more risk involved, because the impact of the failure is higher. However, if there is a way to reduce the effect of failure in these types of bioreactors, then this can replace the batch-wise operated bioreactor. Lowering the impact of failure can be achieved by spreading the risk. Such an approach implies a system of many continuous bioreactors working independently. Hence, if one or more bioreactor becomes contaminated, it can be shut down, and all other bioreactors remain in operation. The approach in scaling-up by numbers instead of scaling-up by size reduces the risks in fermentation processes but increases the amount of materials needed.Biotechnological applications can differ significantly from each other. Therefore, a suitable process screening system varies per specific application. A flexible and modular system deals with the variation in applications. The 3D printing process helps to quickly manufacture the particular modules that are necessary for the screening. Additive Manufacturing describes the 3D printing process in a larger whole. The 3D printing is a crucial part of Additive Manufacturing as it enables the construction of the design layer-by-layer rather than through molding or subtractive techniques . MoreoveThis paper combines technological perspectives of fusion of miniaturization and 3D printing for the development of multi-parallel bioreactor screening systems. This paper is a short and comprehensive perspective of 3D printing technologies with a selection of references summarizing research progress and challenges in applying miniature bioreactor systems. It reflects not only on miniaturization concepts but also on 3D printing techniques, as well as on the auxiliary equipment that is part of the screening system. According to Latterman and Buchs , the desBiotech enterprises have to compile current research and frontline developments in bioreactors and make endeavors towards the design and application of sustainable principles though process intensification.In the case of an anaerobic fermentation process, small anaerobic digesters (AD) can serve as a screening tool for biogas production. A fermentation screening system using low-volume reactors would be able to operate and control many parallel fermenters. Besides, parallelization of a miniature AD system enables the monitoring of multiple operational parameters allowing detailed process insight . CurrentThe materials employed for the manufacturing of the bioreactors may influence their applicability . The theA continuous mini-bioreactor system may consist of multiple parts and the reactor vessel is one of those parts. When scaling down the bioreactor, three main aspects must be taken into account. These aspects are maintaining the possibility to sterilize the reactor, maintain perfect mixing and options to measure and control, pH, dissolved oxygen (DO), temperature and level. These three aspects have to be reevaluated when designing a continuous miniature bioreactor. Currently, relatively large and expensive bioreactors are used in the laboratory. If cheaper and smaller bioreactors could replace those bioreactors, while still maintaining the same performance, that would be ideal. A morphological overview is depicted in The flow characteristics in a miniaturized bioreactor differ significantly from those in the laboratory scale reactor ,50. At tGathering comprehensive process information concerning the development of a bioprocess requires several simultaneous experiments. Therefore, there is a demand for cost-effective, parallel, and multiparametric systems with a high throughput . ParalleOnline and in real-time monitoring of a bioprocess is inherently complex. However, it ensures the control of the vessel conditions and the optimal use of raw materials. Thus, consistent quality of the final product and a reduction in wastes and process cycle time can be reassured. Besides, the replacement of costly and slow laboratory testing (screening systems) opens up the possibility of bioprocess innovation ,63. WhenThe prospect of fabricating objects with the use of 3D printing has seen increased interest in recent years . AlthougIt is found that different types of applications require different kinds of materials and various kinds of 3D printing techniques. Fused deposition modeling (FDM) is a method that uses a polymer as the main material and builds parts with a layer-by-layer-technique from the bottom to the top, by heating and extruding a thermoplastic filament . BenefitBesides the pros and cons, 3D printing in general has some significant advantages over other conventional constructional methods. The process of designing and fabricating an object overtakes some traditional manufacturing steps, including procurement of individual parts, creation of parts using molds, machining to carve parts from blocks of material, welding metal parts together and assembly . AnotherTo show the increasing interest in 3D printing, an overview of the articles found on this subject is given on the Web of Science (Web of science.2020). The search terms were 3D printing, 3D printing + reactor and 3D printing + materials, and the search was done on the topic of the publications. An overview is given in However, the combination of “3D printing” and “reactor” is still not that common in the scientific literature. The volumes of the 3D printed reactors vary widely: some are about 2.65 μL for the preparation of perovskite nanocrystals , while oWilliams  states tFor this particular research, biocompatibility is described by translating the three goals into specific requirements: (1) the material surface area of the bioreactor has to be inert; (2) must be non-biodegradable; and (3) bacteria must not adhere to the material. All three requirements are important for research reproducibility and research integrity and these requirements should be accurately tested and at all times kept in mind when doing microbial experiments.In the microbial research, upcoming 3D printing techniques show opportunities for biomaterials to fabricate miniature bioreactors. The interactions between microbes and biomaterial influence the functionality of the bioreactors in terms of microbial growth. For the majority, this description can be related to the definition of biocompatibility. Instead of having a local host in the system, the system contains an inoculum or medium in which the microbes interact with the material substrate surface. Now the question remains, is the general definition of biocompatibility limited to the medical point of view and should the definition be overhauled or rephrased, or should another term be used to describe the interactions that happen in microbial research?Pahl and Beitz (2007)  distinguThe economic criteria firstly consider the costs. The costs can be separated into raw material costs, production costs and general overhead costs . AdditioIn this paper, we discussed several important topics on scaling-down and manufacturing of bioreactors. We brought up issues for combining miniaturization and additive manufacturing techniques, culminating in 3D printing, and how this combination can affect the evolution of biotechnology through the fabrication of advanced screening systems. These topics include the future of the 3D printing application in bioprocess technology, potential for bioreactor miniaturization and concurrent development of bioreactor screening systems for optimization studies. These topics are essential for academics, entrepreneurs and policy makers to be aware of and consider as we usher in a new bioprocess renaissance.


Mankind is witnessing economic uncertainty due to a health crisis as never before. In the era of industrializationwhere the emergence of invisible enemies of humans is causing a great death toll, "nothing seems more universalthan health", the old proverb in nearly all human cultures is once again rebirthed by the current COVID-19pandemic. Nevertheless what is distinctive is that the SARS-CoV-2 seems to be unequally targeting a particularsector of the populations with risk factors for preventable diseases. Comorbidities, mainly non-communicablediseases (NCDs), seem to be the primary contributors of the current pandemic and not the SARS-CoV-2 per se.The present letter attempts to underscore the converging pattern of communicable (CDs) and NCDs in humantoll. For the tens of thousands of lives coming to an end since the turn of the year, we are all truly sad, but thankfulto the virus for unearthing the grave need of the mankind to improve his life style and behaviors. It directs us torevisit the values and ultimately save millions of lives in future. The present commentary attempts to underscore the convergingpattern of communicable (CDs) and NCDs in human toll, where only a fewfrequently asked questions are barely answered, even if asked from the most knowledgeablesubject matter experts in the field.In the era of industrialization and globalization where the emergence of invisible enemiesof humans is growing at a speedy pace with inevitable consequences, nothing seems moreuniversal than health The first 5-page situation report of WHO on 21The first United Nation High-Level Meeting (UNHLM) on Health issues was held in 2001 for HIV andyet millions are awaiting a real breakthrough amidtremendous progress in research and management ofAIDS. The second HLM was held in 2011 where theimpact of NCDs on countries economic growth wasbrought to surface. Cost of illness, whether direct orindirect, economic loss of productivity and the value ofstatistical life were the three approaches used to calculatethe burden by a collaboration between WHO and theHarvard School of Public Health in 2011 , simulatth Apr 2020 (JHU corona map) in nearly 4 months, worldwide(healthimpact and the economic turmoil are felt simultaneously.Unhealthiness and death concurrent with economic distress, leading toimmediate unemployment and cash shortages, let aside the health access disparities, travelrestrictions, voluntary quarantines, and forced lock-downs, all occurred in about 2 shortmonths!On the same track, the latest UN HLM was convened in September 2019 on Universal HealthCoverage issue with the objective of achieving and promoting physical and mental health andwell-being of all world inhabitants, leaving no one behind. To cognize the thoughts cloud ofthe participants, a few keywords were searched for in the published list of pre-registeredstatements from multistakeholder constituency/institutions in that convention , includiorldwide. The wororldwide, 8. In aorldwide. The picorldwide and probper se would not bring any change, it needs to be enacted. The number ofpreventable deaths is still on the rise as if the due interventions are themselves sufferingfrom inefficiency and chronicity. The total number of deaths from NCDs between 2007 and 2017increased by 27% and that of total YLDs rose more than 50% (Following the striking report on the burden of NCDs  many couthan 50% . It seemIt was the general belief of the past century that mostinfectious diseases are acute illnesses and chronicdiseases are mostly non-communicable . Howeverperse, it is the comorbidity of the infected that has created all the chaos andconfusion. SARS-CoV-2 does not seem to be as cruel as flu virus. As of to date andaccording to the limited information about its mechanistic path in human body, thecomorbidities are killing the host and NOT the COVID-19. If the poor virus had an officialspeaker and a podium to be questioned by aggressive reporters, it would have pleaded "NOTGUILTY"! Most probably, what the virus is trying to unearth is our vulnerability,predominantly caused by NCDs. It is forcing us to realize that it is our way of livingthat is backfiring. In other words, SARS-CoV-2 is doing a good job of inversing thechronic character of NCDs into an acute picture, visible and experienced by nearly allindividuals across borders.Let us focus on the fact that the COVID-19 is not causing all the problems th century, influenza and measles, as singlepathogen diseases, weredefeated when NCDs were either absent or at their infancy and not hitting all-timerecords. However, COVID-19 has picked a time to spread where NCDs are at their highest andhuman microbiome diversity at their lowest (syndemic, the metaphor of "the blind man and theelephant" may get bridged in order to improve nations’ resilience.In the 20r lowest , 15. DynAs David Jones puts it: "The history of epidemics offersconsiderable advice, but only if people know the historyand respond with wisdom" . Can we


Due to the changes in consumer demand and generational transformations, Kyoto’s traditional craft industry has suffered substantial revenue losses in recent years. This research aimed to characterize Kyoto’s traditional craft industry by analyzing the supplier-customer network involving individual firms within the Kyoto region. In the process, we clarify the community structure, key firms, network topological characteristics, bow-tie structure, robustness, the vulnerability of the supplier-customer network as crucial factors for sustainable growth. The community and bow-tie structure analysis became clear that the traditional craft industry continues to occupy an important position in Kyoto’s industrial network. Furthermore, we clarify the relationship between modern and traditional craft industries’ network characteristics and their relative profitability and productivity. It became evident that the traditional craft industry has a different network structure from the modern consumer games and electric machinery industries. The modern industries have the strongly coupled component, and the attendant firms there create high value-added and play a significant role in driving the entire industry, while more traditional craft industries, such as the Nishijin silk fabrics and Kyoto doll industries, do not have this strongly coupled component. Moreover, the traditional crafts industry does not have a central firm or a dense network for integrating information, which is presumed to be a factor in the decline of the traditional craft industry. In a highly developed industrialized society, mass production is at the center of economic activity. This mass production arguably stands in stark contrast to production methods such as the “flexible division of labor” system  that chaKyoto, the region of interest for this research, has a long history of crafts and is highly representative of Japanese culture as Japan’s long-time capital. The traditional crafts industry in Kyoto produces so-called “Kyoto products,” which are characterized by sophisticated sensibilities grounded in over a thousand years of history and a high-quality build produced through an extreme subdivision of labor system –11, wherHere, we address this by establishing a method for clarifying the supplier-customer network structure among the individual firms within the current traditional craft industry in the Kyoto region. To this end, we regard the production activity in terms of complex networks consisting of firms (as nodes) and transaction relationships (as links). Recently, numerous studies have suggested that analyzing farm-level transaction relationships as a supplier-customer network could prove useful for understanding specific economic issues –18. By tOur main goal is to understand the underlying structures and dynamics to nurture sustainability and ensure the traditional craft industry’s survival within the existing broader and ever-changing market environment. To present a detailed discussion, we examine the traditional craft industry’s problems from the viewpoint of sustainability and survivability of Kyoto’s traditional craft industry using actual data. We assume that a firm’s sustainability is the capability to operate the firm in a healthy state under normal economic conditions, measured by the productivity and profitability of firms. We also assume that the survivability of a firm is the capability to keep the firm functioning under exposure to critical situations, measured by firms’ robustness. Our research questions are 1) to what extent can the supplier-customer network’s characteristics explain productivity, profitability, robustness? 2) what is the difference between traditional craft industries and other industries? More specifically, the aim is to explain the profitability, productivity, and robustness of the industry in terms of the bowtie structure components and various centrality indicators for the traditional craft industry. As a result of our research, we expect to make a valuable contribution toward raising production efficiency while preserving the desired quality in terms of the traditional procedures and products.The paper is organized as follows. In the next sections, we explain the dataset and the method of network analysis used in this paper. Following this, the results section, the main part of the paper, outlines the main characteristics and issues of the supplier-customer network of Kyoto’s traditional craft industry before the last section reviews the results and provides a conclusion.The data analyzed in this paper is a subset of 5,943,072 supply chain transaction relationships among 1,668,567 individual Japanese firms , as investigated by Tokyo Shoko Research, Ltd (TSR) in 2016. From this data, we constructed a supplier-customer network, where each individual firm is a node, and specific links connect pairs of firms with at least one supplier-customer relationship, such that we could construct a directed graph. Due to the dataset limitation, the links have no weights. Focusing on firms in Kyoto and those that have business relationships with firms in the region, our analysis involves 79,678 nodes and 153,684 links.First, we conduct a community analysis to identify representative industrial sectors in Kyoto. The identified industrial sectors are three traditional craft industries and three modern industries.Secondly, in terms of the characterization of the industries identified as communities in the supplier-customer network in Kyoto, we estimate the centrality indices and the site of the Bow-tie structure. We focus on the three centrality indices here. Firms with a high degree centrality are considered advantageous for capturing the consumers’ needs and immediately respond to them in a rapidly changing market. The clustering coefficient is considered as a measure of exchanging information. A higher clustering coefficient means more efficient information exchange. Firms with a high betweenness centrality act as connectors to connect network groups with different economic roles. Strongly coupled component (SCC) in the Bow-tie structure is especially important. Because it is considered that the SCC works a feedback loop for the entire industry. Firms in the SCC create high value-added and play a major role in driving the industry.Thirdly, we estimate the productivity and profitability for each firm as surrogate variables of the firms’ sustainability. Here, profitability and productivity are the ratio of profit to equity (Return on Equity) and the profit per employee, respectively. We note that more appropriate variables are value-added per employee as productivity. However, the value-added was not available in the current dataset used in this study. We also estimate the robustness for each firm as a surrogate variable of the survivability of the firm. The robustness is measured as the removal rate at which a node is removed from the maximum connected component by removing the firm’s links.Finally, we develop an econometric model to explain the profitability, the productivity, and the robustness of firms in terms of sites of the bowtie structure and three centrality indicators for the traditional craft industry. The following questions 1) to what extent can productivity, profitability, robustness be explained by supplier-customer network characteristics? 2) what is the difference between traditional craft industries and other industries? will be answered based on the results of econometric analysis.L in the community division M that divides the network into C is defined byq⤼ is the probability that a random walker moves to another community, H(Q) is the average description length of the community index codewords given by the Shannon entropy, i will stay in the same community in the next step, H(Pi) is the entropy of the codewords in the module codebook i, and c is the number of communities.Community analysis divides the network into closely related groups, and we used this method to distinguish the traditional craft industry network from the supplier-customer network in Kyoto. The most popular method for community detection is the modularity maximization approach . HoweverWe explain topological characteristics and centrality briefly to analyze the structure and the dynamics of each industry’s supplier-customer network.R is defined by dij is the average shortest path length between nodes i and j, and N is the number of nodes in the network.The average shortest path length is given by the average number of the shortest paths for all possible pairs of nodes in the network. Given that the larger the average shortest path length is, the more firms are involved in manufacturing. The average shortest path length i defined by ci = Li/ki(ki − 1). Here ki(ki − 1) is total number of possible connections between the neighbors of node i, and Li is the actual number of links among the neighbors of node i. The clustering coefficient C of an entire network is the average of the clustering coefficient of all nodes i, defined by The clustering coefficient is used to measure how connected a node’s neighbors are to one another . The cluAssortativity indicates the similarity among the connections in the graph concerning the node degree. If a node is connected to nodes with degree values similar to its own, the network is assortative, and its assortativity is close to 1, while if the opposite is the case, the network is disassortative, and its assortativity is close to -1. It is well known that biological networks tend to be disassortative, while social networks tend to be assortative. In the case of an assortative network, the damage to the network due to the removal of the hub node will be small, but in the case of a disassortative network, removing the hub node may cause significant damage to the network .D of a network is defined by D = M/N(N − 1). Here M is the actual number of links in a graph.The density is calculated according to the proportion of the actual number of links in a graph within the maximum possible number of links and indicates how closely the entire network is connected. The density N − 1). The degree centrality of a node i is defined by xi = ki/2(N − 1). Here ki is the number of degrees of node i.Degree centrality is a measure according to the number of links on each node . Firms wi is defined by njk is the number of shortest paths between nodes j and k, and njk(i) is the number of paths that pass through node i among the shortest paths between nodes j and k. This was normalized by dividing the maximum number of pairs of nodes, excluding the node itself.Betweenness centrality is a measure according to the number of shortest paths passing through a node . Firms wG, we first referred to the undirected graph obtained by G without the direction of its links. Assuming this graph is G*, all nodes in G are classified as one of the following components:Bow-tie decomposition is widely used to understand the flow structure of various complex networks, such as hyperlink networks on the web  and metaG.SCC: nodes in the largest strongly connected component of IN: nodes reachable to SCC, but not from SCC.OUT: nodes reachable from SCC, but not to SCC.TENDRIL: nodes not in the previous categories, reachable to OUT (OUT TENDRIL), or reachable to IN (IN TENDRIL), but not both.TUBE: nodes reachable from IN and to OUT, but not SCC.G*OTHER: nodes not connected to Each component makes different contributions to the network in terms of economic activity, while the SCC plays a central role here. All industries in the specific economy are closely connected, and the growth of the core industries may have greater significance for the economy’s growth compared with that of the peripheral industries .To measure network robustness, we applied the percolation theory to the supplier-customer network concept. Percolation theory informs us how many nodes or links must be removed for breaking down the network into isolated elements and is used to describe the stability of a system in terms of disturbances . In the γin = 2.34 and γout = 2.38 respectively. The power-law tail of the degree distribution is also presented in the past research of the empirical supply chain network [First, we calculated the degree distribution to better understand the trends of the Kyoto supplier-customer network. As shown in  network , 31.Following this, we identified the supplier-customer network communities in Kyoto’s traditional craft industry using a map equation and subsequently, the 79,678 firms related to Kyoto into 1,212 communities. Each community has a hierarchical structure, which consists of subcommunities in a lower hierarchical layer. Here subcommunity a-b means that community a includes subcommunity b. By identifying the nodes that play a central role in the network, we could clarify the key firms in each of the selected industries’ supplier-customer networks as detected as subcommunities. Figs The profitability and productivity of each bow-tie component of the selected industries are shown in Figs The robustness of the network is an extremely important factor for the traditional craft industries, where the number of firms is declining rapidly. Figs The division of labor, manufacturing equipment, know-how, and skilled workers of the traditional craft industry in Kyoto has not allowed the industry to respond to market structure changes or technological innovation. We designated Kyoto’s traditional crafts industry as a supplier-customer network formed by interfirm transaction relations to elucidate its characteristics and the reasons behind the industry’s decline from a network theory perspective.The extensive dataset of interfirm supplier-customer relations related to Kyoto allowed us to analyze the traditional craft industry structure concerning those of other industries. Specifically, we focused on the community structure, the bow-tie structure, the robustness, and the supplier-customer network’s vulnerability as key factors for sustainable growth. From the community analysis and the bow-tie structure analysis, it became clear that the traditional craft industry continues to play an important role in Kyoto’s supplier-customer network.Rlr, Dlr, Blr are average link removal rates when each node is out of the largest connected component for 1000 samples in random link removal, link removal proportional to the degree, link removal proportional to the betweenness centrality, respectively. The profit to equity (Return on Equity) and the profit per employee are used as surrogate variables of the profitability and productivity, respectively.We constructed econometric models that consider the various structural characteristics variables simultaneously to realize the inter-dependencies among the structural characteristics, robustness, profitability, and productivity. The robustness Rlr, Dlr, Blr, the profitability, and the productivity was conducted using the explanatory variables: degree centrality, betweenness centrality, clustering coefficient, and part of bow-tie structure . For the modern industry sectors, the results of the regression analyses of Rlr, Dlr, Blr, the profitability, and the productivity are shown in Tables Rlr, Dlr, Blr, the profitability, and the productivity are shown in Tables The regression analyses of the robustness R2 of the robustness Rlr, Dlr, Blr are high, but the profitability and the productivity are low for both the modern industry sectors and the traditional craft industry sectors. The statistically significant explanatory variables of the robustness in the modern industry sectors are Degree (positive), Betweenness (positive), Clustering (positive), Profitability (negative), Productivity (positive), and SCC (positive), where the directions of effect are shown in parentheses. The robustness of the electric machinery industry is higher than the consumer game industry and civil engineering industry. The statistically significant explanatory variables of the robustness in the traditional craft industry sectors are Degree (positive), Betweenness (positive), and Clustering (positive). In addition to these variables, the part of the bow-tie structure is significant; OUT (negative) for Rlr, and SCC (positive) for Blr. For Rlr and Blr, the Kyoto doll industry is higher than in other industries. For Dlr, the Kyoyuzen dyeing industry is higher than in other industries. The statistically significant explanatory variables of the profitability and the productivity in the modern industry sectors are the part of the bow-tie structure; IN (negative) for profitability and productivity, and SCC (negative) for productivity. The statistically significant explanatory variables of the profitability in the traditional craft industry sectors are OUT (positive). The profitability of the Kyoto doll industry is higher than in other traditional craft industries. The statistically significant explanatory variables of the productivity in the traditional craft industry sectors are Dlr (positive) and Blr (positive). The productivity of the Kyoyuzen dyeing industry is lower than other traditional craft industries.The values of Based on the network and econometric analyses, it was clarified that the traditional craft industry has a markedly different network characteristics to more modern industries such as the consumer games and electric machinery industries. According to the centrality analysis, the consumer games and electrical machinery industries, which are the leading industries in Kyoto, have established a central production structure in which a single manufacturer has an unparalleled centrality. Such a structure is considered an advantageous structure for responding to a rapidly changing market because one firm has a consensus on manufacturing and manages every aspect from production to sales, enabling the manufacturers to directly capture the consumers’ needs and immediately respond to them. In contrast, the traditional craft industry has a clear division of labor throughout the process, where wholesale firms continue to play a central role. Such a structure is regarded as having been formed in an age in which good-quality products always sold out. On examining the results related to the network topology characteristics, it became clear that the traditional craft communities have low clustering coefficients than networks with degree-preserving randomization. The traditional craft industry also has issues in exchanging information, while the modern industry has a dense structure with a high clustering coefficient . FurtherThis research aimed to characterize Kyoto’s traditional craft industry by analyzing the supplier-customer network involving individual firms within the Kyoto region. It became evident that the traditional craft industry has a different network structure from the modern consumer games and electric machinery industries. The modern industries have the strongly coupled component, and the attendant firms there create high value-added and play a significant role in driving the entire industry, while more traditional craft industries, such as the Nishijin silk fabrics and Kyoto doll industries, do not have this strongly coupled component. We constructed econometric models that simultaneously consider the various structural characteristics variables to realize the inter-dependencies among structural characteristics, robustness, profitability, and productivity. The mode revealed that the statistically significant explanatory variables of the robustness, the profitability, the productivity differ in the traditional craft industry and the modern industry. Moreover, the traditional crafts industry does not have a central firm or a dense network for integrating information, which is presumed to be a factor in the decline of the traditional craft industry. The results of this analysis suggest that the main issue lies in the fact that the traditional craft industry in Kyoto does not have a structure to integrate information that will allow it to respond to the markets. In order to take advantage of the strength of a region-based industry, Kyoto’s traditional craft industry must create a production system that accurately reflects the consumer’s voice and carries out it’s manufacturing in close collaboration with the industry as a whole.S1 Appendix(PDF)Click here for additional data file.