Modern fluoroscopes pose a challenge for the clinical physicist for annual testing and continued upkeep. These fluoroscopes are critical to providing care to patients for complex interventions, and continue to evolve in automated image quality adjustments. Few tools in software or hardware currently exist to assist the physicist or technologist in gauging fluoroscope constancy or readiness for procedures. Many modalities such as mammography, computed tomography or even magnetic resonance imaging are much more evolved with respect to testing or quality control. In this work we sought to provide simple reproducible tools and methods for spot evaluating or continued quality testing of interventional fluoroscopes. Quality control (QC) is a necessary and appropriate activity to gauge the readiness of the fluoroscopes used in these procedures. The American College of Radiology (ACR) as well as the American Association of Physicists in Medicine recommend a QC program for these devices to ensure accurate and consistent patient care.Signal to noise ratio (SNR) and contrast to noise ratio (CNR) are widely used in other x‐ray imaging modalities such as computed tomography (CT) and mammography as QC standards. In CT, CNR is used as a pass/fail criterion for ACR CT accreditation.We begin an initial endeavor into continuous monitoring of image quality in fluoroscopy, via the use of SNR and CNR as metrics for QC and operational readiness, as part of an ongoing in‐house QC program. Technologists perform daily QC using a customized phantom, and after months of data collection, we begin to investigate pass/fail criteria for SNR and CNR. The benefits of such a program include engagement of the technologists, in concert with the physicist, in the quality program, as well as aiding the staff in operational readiness of the fluoroscope.22.1Quality control and testing was performed in two high‐patient‐volume interventional departments at our institution. The Interventional Radiology (IR) department specializes in peripheral angiography and has five Siemens fluoroscopes ; one Artis Zeego, two Axiom Artis, and two Artis Q single plane systems. The Interventional Neuroradiology (INR) department has two Siemens Artis Zee Bi‐plane systems, which are predominantly used for neurovascular work. All rooms in both departments have the ability to “Store Fluoro,” which is a feature used to save the last fluoro scene as a series or loop that would otherwise not be captured. To achieve steady state dosimetric parameters , the stored fluoro loops were only saved after multiple activations of the fluoro pedal, a method often described as “double clutching,” to allow a possible spectral filter or other parameters to change if necessary due to increased or different load via our phantoms. Lastly, all fluoro loops were acquired for 5 s, to acquire enough frames for an average to be determined, as well as to allow the system kV or mA to reach steady state within the loop. Three separate and unique phantoms were used for testing based on availability and ease of use. Each is described in more detail to follow.The first phantom, called the slab phantom, consisted of 35.5 cm × 43.2 cm × 2.54 cm polymethyl methacrylate (PMMA) sheets that can be stacked at various thicknesses on the patient couch representing varying patient sizes, similar to the method described in TG‐125.The second phantom used for testing was a 25.4 cm × 25.4 cm × 7.62 cm custom‐built patient equivalent Contrast‐Detail (CD) phantom consisting of 1.59 mm sheet of copper with a 6.35 mm aluminum sheet sandwiched in additional sheets of PMMA  in a ROI, and σBG is the standard deviation in the same background ROI.Initial testing with the slab phantom was performed in one of the IR rooms. The For Presentation DICOM fluoro loops were exported off‐line to a Personal Computer (PC). A custom program written in IDL  was used to perform analysis on all frames from the acquired loops. To determine both SNR and CNR, a 40 mm Region of Interest (ROI) was manually placed in the center of the tin swatch. An ROI of the same size was automatically placed with an offset from the tin swatch to provide a background mean value and standard deviation. Figure f is the frame average CNR, X¯BG is the average background signal in an ROI, and σBG is the standard deviation in the same background ROI and S¯ is the mean average signal in the swatch or contrast object.The CNR for each frame in the loop was determined via eq. :(2)CNRf=It was observed that the fluoroscope output rises for the first several frames and eventually stabilizes according to the dose program's automatic dose rate image quality (ADRIQ) logic system settings.2.3Having established automated analysis of image quality metrics, daily QC was performed for nearly 8 months in the IR department using the previously described CD phantom. In order to provide reproducible and consistent settings, a standard clinical fluoro program was duplicated on each fluoroscope. The program was set to default to 7.5 pulses per second (pps), and named “QC” so it would not be used clinically. The stored For Presentation DICOM loop was sent via standard DICOM networking to a QC‐Track  server where a custom program performed automated SNR analysis, and catalogued the data for each respective fluoroscope. The workflow on the QC‐Track system processed each loop, analyzing only the last two seconds. To reduce the noise, the images were initially smoothed using a Gaussian filter. A Kirsch filter was then applied to find the edges of the contrast holes and an erosion filter was then applied to reduce edge noise. Using a priori knowledge of the contrast hole objects, the largest contrast hole was found using a circle detection algorithm. The 12 mm center ROI was then geometrically placed based from the center of the largest contrast hole. The analysis was repeated for each of the last 15 valid frames of fluoroscopy data, similar to the method used for the slab phantom analysis. The ROI in the center of the phantom was used to determine a frame SNR, and then repeated over all frames and averaged to yield one representative SNR for the entire loop.Daily QC was also performed over a 5 month period in the INR department using the previously described CNR phantom. As was done in the IR department, the dedicated QC program was built on each fluoroscope. The fluoroscopy loops were acquired in the same way as above with the CD phantom, by technologists pressing the pedal for five seconds using the same setup and dose program. Similar to the SNR measurements, to reduce the noise, the images were initially smoothed using a Gaussian filter. Then a simple thresholding algorithm was used to detect the tin swatch in the center of the phantom. The 30 mm contrast ROI was placed in the centroid of the tin swatch and the 30 mm signal ROIs were geometrically placed around the contrast ROI in the center of the phantom. Data from the ROIs was used to determine a frame CNR by comparing the mean signal value in the central ROI to an averaged signal and standard deviation in the background taken from four ROIs drawn above, below, right, and left of the tin swatch. Multiple background ROIs were used since the detector orientation is not fixed with respect to the phantom. SNR and CNR were then determined for each of the 15 frames and used to yield an average SNR and CNR for each loop. Figure The circle in the center of the tin swatch Fig. , Right r33.1Figures 3.2Figure Initially, the daily QC data for CNR for each frame of the fluoro loop were only determined from the ROIs in the center circle Fig. , Right aCoefficient of variation (CV) was again used as a measure of % error for both SNR and CNR. Values of CV for the SNR for both units and all planes ranged from a maximum of 3.6%  to a minimum of 1.9% for both Neuro Lab‐1 and − 2, Lat and AP planes, respectively. However, in comparison, even though the standard deviations for the SNR were higher than the CNR, the low mean values of the CNR elevated the CV values, and in all cases were more than double the CV of the corresponding SNR CV.Figure 4In section 3.A, we showed both temporal response, and fidelity of SNR and CNR using a single fluoroscope. In section 3.A Figs. Section 3.A also showed the relationship between SNR and CNR with respect to a surrogate patient load (PMMA). Figure The CNR results presented in Fig. Figure Figure Figure Now that baselines for SNR and possibly CNR have been established, limits can be placed within QC‐Track prompting the technologist to repeat the QC if it fails. Also, QC on the data acquisition itself could also improve the process. For example, if QC loops were acquired with too few frames to allow adequate analysis feedback to the technologist, it could indicate that the test needs to be repeated. Furthermore, sensitivity of the SNR/CNR measurements needs to be more thoroughly investigated with respect to clinical decisions to fail a fluoroscope. As a simple check of our three standard deviation criterion robustness, we removed the anti‐scatter grid prior to performing QC to simulate a nonready fluoroscope. The CNR value for this test fell below three standard deviations, however the SNR was within three standard deviations of the mean. In this singular simulation, the mA value for the loop dropped 2.4 % from the mean, indicating that there may be a need to programmatically examine multiple DICOM header values  as well as calculated SNR/CNR before making a QC failure decision.The limitations of this study are that there was only one fluoroscope vendor available for these tests, and a small sample of models from that vendor. Future work will include at least two more vendors and several more models to fully understand SNR and CNR utility and clinical impact in fluoroscopy. Automated and observer‐independent QC of units used during FGIs was performed in high‐patient volume IR and INR departments. Minimal technologist effort and change in workflow were needed to regularly monitor system performance and readiness of the system for the day. These data allow for room‐specific SNR thresholds to be established and used as a criterion for providing immediate feedback on whether the system is operating at an expected level.5With the ever increasing complexity of fluoroscopes, coupled with proprietary dose and image quality software algorithms from the vendors, robust and straightforward methods for QC and image quality metrics are needed. We have shown the utility in simple SNR and CNR metrics and how they can be used during fluoroscopy daily QC or during performance testing with very simple patient equivalent phantoms.The authors have no relevant conflict of interest.


The Fabry-Pérot interferometer is used in a variety of high-precision optical interferometry applications, such as gravitational wave detection. It is also used in various types of laser resonators to act as a narrow band filter. In addition, ultra-compact Fabry-Pérot interferometers are used in the optical resonators of semiconductor lasers and fiber-optic systems. In this work, we developed a micro-scale Fabry-Pérot interferometer that was constructed within the Rayleigh range of the optical focusing system. The high precision that is conventionally required for the optical parallelism and the surface accuracy of the mirrors was not so critical for this type of Fabry-Pérot interferometer. The interferometer was constructed using a gold-coated silicon microcantilever with reflectivity of 92% and a dielectric multilayer flat mirror with reflectivity of 85%. The focal spot size of the laser beam is 20 μm and the cavity length is approximately 20 μm. The finesse was measured to be approximately 25. The interferometric characteristics of the device were consistent with the theoretically calculated performance. The developed micro Fabry-Pérot interferometer has the potential to make a marked contribution to advances in optical measurements in various micro sensing system. To date, there have been many studies of normal-sized FP interferometers3, but only a few studies have addressed smaller types of FP interferometers5.In this work, we have developed a micro Fabry-Pérot (FP) interferometer with high sensitivity to realize high-performance feedback damping of the thermal vibration of a silicon microcantilever that is intended for use in an atomic force microscope (AFM). FP interferometers have been used in various high-precision optical interferometry applications, such as gravitational wave detection13. Recent studies found that the measured signal-to-noise ratio determines the limits of the feedback cooling performance12. We used an FP interferometer rather than a Michelson interferometer to improve the measurement sensitivity and thus increase the signal-to-noise ratio. In conventional FP interferometers, the polished end faces of optical fibers11 and micro mirrors from the surface of a multilayer dielectric mirror13 formed by focused ion beam microfabrication have been used as cavity mirrors. However, use of these methods for the mirror has led to issues such as low finesse due to optical diffraction from the fiber output aperture and problems with the parallelism of the optical alignment and the interferometer, along with difficulties in the microfabrication process. In addition, these methods do not use the merits of the Rayleigh range. In this work, we have developed a micro FP interferometer that uses the optical merits of the Rayleigh range of the focal system to simplify the optical system and improve the interferometric performance. The interferometric characteristics of this FP interferometer show good agreement with the theoretically calculated performance.There have been several studies of feedback cooling of the thermal vibration of micro cantileversFigure Figure The other side of the FP interferometer is formed by the dielectric multilayer flat mirror. The optical flatness and reflectance of this mirror were λ/10 and 85%, respectively. The diameter and thickness of the mirror were 30 mm and 1 mm, respectively.A laser beam with a diameter of 4 mm was focused using a spherical lens, which has a focal length of 80 mm and an F number of 20. The focal spot size was estimated to be approximately 16 μm under the assumption of the diffraction limit. The Rayleigh range was estimated to be approximately 250 μm, and the cavity length was approximately 20 μm.−3 Pa. The interferometric signal was separated using a beam splitter and measured using an avalanche photodiode. The microcantilever was driven using a lead zirconate titanate (PZT) piezoelectric actuator. The signal was measured using an oscilloscope and a fast Fourier transform (FFT) analyzer. The vacuum circumstance was not essential for this experiment. It was only for obtaining a clear thermal vibration signal of the micro cantilever. The same optical characteristics of it were also obtained in the atmospheric pressure.The optical system was set in a vacuum chamber at a pressure of approximately 4 × 10R was calculated to beR1 and R2 are the reflectances of the multilayer mirror and of the microcantilever, respectively14. δ is the phase shift of each transmitted light wave due to the change in the cavity length LC and is given by The reflectance values of the microcantilever and the dielectric multilayer mirror were 92% and 85%, respectively. The reflectance of the microcantilever differs from that of the dielectric mirror. For the FP interferometer that was constructed using a pair of mirrors with different reflectances, the theoretical interferometric reflectance R as a function of the cavity length, as calculated using eq. . For the various values of R2, the maximum value of the sensitivity for R2 differed from that for R1 and was located between R2 and 1. The open circle in Fig. R2 = 0.85).Figure R1 and R2 were 0.85 and 0.92, respectively. The FP interferometric characteristics were measured by varying the cavity length using the PZT actuator. The gray solid line indicates the theoretical calculation results obtained using eq. . It is the reason why flat mirrors can be used as the reflectors of the FP interferometer placed in the focusing optical system.The Rayleigh length Figure The demand for optical flatness in the micro FP interferometer is also much weaker when compared with that for the normal-type FP interferometer because of the reduced cross-sectional area of the laser beam. The optical flatness of the reflection mirror were only λ/10, by which we cannot obtained the fines of 25 in case of the normal type FP interferometer.Another characteristic of the micro FP interferometer is that it has a large free spectral range because of its short cavity length.For the practical fabrication of this type of FP interferometer, we think that it is one of the method to contact a small dielectric multilayer mirror to the basement of the microcantilever with a thin spacer using the optical contact bonding.We have developed a micro Fabry-Pérot interferometer that is constructed within the Rayleigh range of the optical focusing system and demonstrated that the interferometric characteristics of this interferometer were consistent with the theoretically calculated characteristics. The conventional high precision required for the optical parallelism and the surface flatness of the mirrors was not so essential for the micro FP interferometer. We believe that the proposed micro FP interferometer has the potential to make a marked contribution to advances in optical measurements in various micro sensing system.


For this purpose they have devised a description of the parenchyma incorporating perivascular spaces. Their simulations show that superficial flow velocities of about 50 µm min−1 are needed to produce changes in TMA+ fluxes comparable to those accounted for by diffusion. In the glymphatic hypothesis the proposed flow through the parenchyma can be estimated from the clearance of solutes that are present in the perivenous outflow at the same concentration as in the interstitial fluid of the parenchyma. Reported clearances are approximately 1 µL min−1 g−1. This flow can be converted to a superficial flow velocity using the area available for the flow, which can be estimated using Ray et al.’s description of the tissue as 40 cm2 g−1. The best available estimate of the flow velocity is thus 0.25 µm min−1 which is 200 times smaller than the flow that produces effects comparable to diffusion for TMA+. Thus it follows in Ray et al.’s description of the parenchyma that diffusion rather than flow accounts for TMA+ movements. Because the diffusion constant depends only weakly on molecular weight the same is expected to apply even for solutes somewhat larger than serum albumin.Solutes can enter and leave gray matter in the brain by perivascular routes. The glymphatic hypothesis supposes that these movements are a consequence of inward flow along periarterial spaces and an equal outward flow along perivenous spaces. The flow through the parenchyma between periarterial and perivenous spaces is the same as the inflow and the outflow. Ray et al. (Fluids Barriers CNS 16:6,  There is general agreement that solutes can enter and leave gray matter in the brain parenchyma via perivascular spaces, and that the rates of movement through these spaces are too fast to be mediated by diffusion alone , injected into the parenchyma via iontophoresis  there is a substantial variation between the maximum concentrations that are measured in repeated experiments, and (b) it is difficult to assess the effects that flow might have using a theory that assumes there are none.In a welcome and important advance Ray et al.  have invsis see –8). The . The +),−1 altered the simulated concentrations by about ± 10% relative to the concentrations predicted with no flow .(Technical note: There is no direct way to calculate the flow from a volume average of the superficial flow velocity. Because the velocity is a vector quantity that can point in opposite directions at different locations within a region, the average of the velocity over that region can be zero even though the flow from sources to sinks within it is not. By contrast, the flow from the sources, i.e. the periarterial spaces, to the sinks, i.e. the perivascular spaces, can be calculated as a vector surface integral of the superficial flow velocity over surfaces that enclose each of the sources once while excluding the sinks. For the present model this calculation is particularly simple as the midplane between the arterioles and venules separates the sources from the sinks, and the superficial velocity at this surface is perpendicular to it and always pointing away from the layer of periarterial spaces. Thus for the conditions portrayed in Figures 6a and 4b of , the sur+ in the parenchyma is more than 200 times larger that the average velocity across the mid-plane that accounts for the clearance of solutes in the glymphatic hypothesis. To the extent that their model is an adequate description of the parenchyma there are two important consequences. Firstly it is unlikely that flow through the parenchyma as envisaged in the glymphatic hypothesis is an important part of the explanation of the variation in results between RTI experiments. Secondly, and much more importantly, because the simulations show that the flows which might exist in the parenchyma produce negligible changes in the concentrations and hence fluxes of tetramethylammonium ions, they provide further support for the commonly held view that extracellular solute movements in gray matter occur by diffusion. Because the diffusion constants for solutes vary only weakly with molecular weight (compare Tables 2 and 3 in [The average superficial velocity over the mid-plane between the arterioles and venules that was found in Ray et al.’s simulations to produce clear effects on the movement of TMAand 3 in  and discIt is important to note that the calculations in this commentary do not say anything useful about the processes moving solutes along perivascular routes.


An anatomically realistic two-dimensional image-based multilayer finite element model of human skin was used to simulate the sliding of rigid indenters of various sizes over the skin surface. A corresponding structurally idealised multilayer skin model was also built for comparison purposes. Microscopic friction specified at skin asperity or microrelief level was an input to the finite element computations. From the contact reaction force measured at the sliding indenter, a homogenised (or apparent) macroscopic friction was calculated. Results demonstrated that the naturally complex geometry of the skin microstructure and surface topography alone can play as significant role in modulating the deformation component of macroscopic friction and can significantly increase it. This effect is further amplified as the ground-state Young’s modulus of the stratum corneum is increased . In these conditions, the skin microstructure is a dominant factor in the deformation component of macroscopic friction, regardless of indenter size or specified local friction properties. When the skin is assumed to be an assembly of nominally flat layers, the resulting global coefficient of friction is reduced with respect to the local one. This seemingly counter-intuitive effect had already been demonstrated in a recent computational study found in the literature. Results also suggest that care should be taken when assigning a coefficient of friction in computer simulations, as it might not reflect the conditions of microscopic and macroscopic friction one intends to represent. The modelling methodology and simulation tools developed in this study go beyond what current analytical models of skin friction can offer: the ability to accommodate arbitrary kinematics (i.e. finite deformations), nonlinear constitutive properties and the complex geometry of the skin microstructural constituents. It was demonstrated how this approach offered a new level of mechanistic insight into plausible friction mechanisms associated with purely structural effects operating at the microscopic scale; the methodology should be viewed as complementary to physical experimental protocols characterising skin friction as it may facilitate the interpretation of observations and measurements and/or could also assist in the design of new experimental quantitative assays.Due to its multifactorial nature, skin friction remains a multiphysics and multiscale phenomenon poorly understood despite its relevance for many biomedical and engineering applications . For example, it is unclear whether, and in which measure, the skin microscopic surface topography, internal microstructure and associated nonlinear mechanics can condition and modulate skin friction. This study addressed this question through the development of a parametric finite element contact homogenisation procedure which was used to study and quantify the effect of the skin microstructure on the The online version of this article (doi:10.1007/s11249-016-0794-4) contains supplementary material, which is available to authorized users. Besides its multiple physiological functions as the largest organ of the human body , the skiSkin friction, which is manifested as forces resisting the motion of skin relative to other surfaces, is a complex phenomenon which conditions and, at the same time, is part of this load transmission process. Understanding the physical mechanisms that give rise to skin friction is therefore essential in furthering our knowledge of it and in developing novel solutions and improved products that are optimally designed to interact with the skin. The corollary aspect of discomfort and pain which are evolutionary survival mechanisms is that excessive mechanical loading can lead to damage, and, eventually, to loss of structural integrity of the skin . Evidence suggests that friction mechanisms are the key in these damage processes –11.Although in the last decade skin friction has attracted a significant interest and a large body of work , 12–36, stratum corneum—the outermost layer of the skin consisting of a 15–20-cell-thick self-renewable layer of keratinised epithelial cells  could not converge before completion of the whole sliding distance. In order to estimate the global coefficient of friction that could not be calculated from the finite element results, a quadratic regression of the form μg(μl) = a * μl2 + μl was established from the results of fully converged simulations featuring the same combination of ESC and R1. A regression equation exhibiting a coefficient of determination R2 = 0.9946 was obtained for a = −0.02926. A summary of the sliding distances and global friction results is provided in Table The simulation featuring the following combination of parameters [stratum corneum stiffness (ESC = 0.6 MPa and ESC = 370 MPa), for each of the specified local friction conditions and for both idealised and anatomical models. In these results, the difference between the global and local coefficients of friction is clearly evidenced in most of the non-frictionless cases. For the idealised skin model, the global friction coefficient appears to be a fraction of the applied local friction coefficient, whereas this trend is reversed for the anatomical skin model. In that case, global friction is larger than local friction. There is also a clear correlation between indenter size and global friction coefficient. The analysis showed that the global coefficient of friction can be estimated with a regression model of the form:δ = R1/2, and where the constants {ci, i = 1.0.7} are dependent upon the type of model and the stiffness of the stratum corneum. This model provided a high correlation with the calculated global coefficients of friction, with a coefficient of determination R2 > 0.997 for the different sets of results, for each type of model and stratum corneum stiffness , in which a higher pressure was exerted by the largest indenter. In the idealised model simulations, the level of contact pressure was maintained constant during each sliding simulations. The indentation conditions of the anatomical model simulations were equivalent to those of the idealised model, under the assumption of a nominally flat surface. The trend was that with a smaller indenter radius, the global friction increased, and even though a larger pressure was applied to the skin surface by the R1 = 0.50 mm indenter, the simulations with the larger indenter led to a global coefficient of friction closer to the assigned local one.This nonlinear trend between the indenter size (i.e. indenting conditions) and the relative difference between the global and local friction coefficients is linked to the pressure distribution for each of the indenting conditions  and hard (ESC = 370 MPa) stratum corneum.In the frictionless cases, the idealised skin model, as expected, showed no resistance to motion with no amplification or reduction in the coefficient of friction from the microscopic to the macroscopic scale. In contrast, even for frictionless conditions, the anatomical model results indicated that the skin topography and its deformation were sufficient to induce macroscopic friction: stratum corneum (ESC = 0.6 MPa to ESC = 370 MPa) lead to an additional increase in the global coefficient of friction: 3.4% for the idealised model and 5.2% for the anatomical one. For both skin models and for the smallest indenter, a larger difference between the global and local coefficient of friction was found , where y = 0 mm represents the mean height of the skin model, in order to identify the simultaneous effects of the skin topographic features and indenter radius on the global coefficient of friction.The cumulative evolution of the local coefficient of friction along the sliding path using the integration procedure described in Sect. R1 = 0.1 mm), which despite being subjected to lower indentation depth, was more susceptible to interlocking with the skin microasperities. On the contrary, the global friction curve was smoother for the larger indenters as less interlocking took place. The relation between the skin topography and the global friction is evident in both models (ESC = 0.6 MPa to ESC = 370 MPa) cases, as the cumulative global coefficient of friction increases significantly when the indenter faces the highly protruding crests at sliding distance x = 0.1 mm, x = 0.6 mm and x = 1.1 mm.It was observed that the cumulative (and not instantaneous) global coefficient of friction increased when in contact with the skin topographic protrusions. Such an increase was more significant for the simulations with the indenter of smallest radius  coefficient of friction were set to represent different levels of local adhesion, as an interplay between humidity and surface energy of the contacting material [nanoscopic asperities averaged at the flat external surface of each finite elements forming the outer surface of the stratum corneum layer in our model.As relative humidity increases, the stiffness of the agnitude , 39. In material , as wellstratum corneum layer was less than 10 µm thick, variation of its in stiffness had a visible effect on the skin global friction response  stratum corneum while typically, skin friction tests report higher coefficients of friction with larger contact areas as higher adhesion resultant forces are produced [Even though the nse Fig. . As expeproduced .i.e. decrease in the macroscopic coefficient of friction). It is believed that this effect is due to the way the idealised geometries of the skin layers deform in combination with the displacement-controlled sliding motion of the indenter. In frictionless conditions, this deformation is symmetrical so the forces experienced ahead and behind the indenter centre of mass balance each other, resulting in an effective frictionless global response. However, the local friction influences the drag and relative motion of the contacting surfaces: the surface of the skin tends to bend and “sinks in” vertically so to minimise the formation of a bow wave resisting lateral displacement. This effectively disrupts the balance of contact forces ahead and behind the indenter, resulting in a “push forward” effect that reduces the global coefficient of friction with respect to the local one.Computational analyses showed that for the idealised skin model, the global coefficient of friction was smaller than the local one. This would suggest that the normal component of the reaction force at the indenter becomes dominant over the tangential component (i.e. larger contact area), the resistance provided by the skin topographic and interfacial shear strength (provided by μl > 0.0). In frictionless contact, a global coefficient of friction of 0.004 and 0.001  was obtained from the resistance provided by the skin topography only. These results provide a quantitative indication of the contribution of microasperity contact to the skin global friction and how the mechanical properties of the skin outer layer can influence these results. The disparity between the idealised and anatomical results provides insights into how topographic features of the skin can amplify the skin friction response, regardless of the local friction conditions.In the anatomical skin model, the global friction measured resulted from the combined effects provided by the compliance of the contact  can modify the physico-chemical properties of the contact interface and lead to higher friction force via alteration of the interfacial shear strength [stratum corneum intercellular space, increasing the thickness of this outer layer up to three times for a 4-h water exposure [stratum corneum thickness, shear modulus and coefficient of friction at the skin–support interface on the shear stress distribution within the skin layers. In their study, they showed how these parameters can increase or reduce the risk of potential damage within the skin. Swelling of the stratum corneum would modify the skin microstructure, smoothing out skin crests and superficial furrows, and closing up the deeper furrows. Furthermore, the thickness of this outer layer would modify the overall skin elastic response as discussed earlier. So, it is likely that, if one takes into account the structural changes humidity causes in the stratum corneum, these changes could also significantly influence the global skin friction response. In Figs. stratum corneum stiffness is minimal.Apart from the Young’s modulus of the strength  rather texposure . Sopher exposure  implemenstratum corneum layer coupled to an increase in adhesive forces at the local level would likely lead to even larger increase in microscopic friction. The hypothesis that this could therefore be a plausible mechanism for the prevalence of skin tears in the elderly population [In reality, the water-induced volume changes in the pulation  should bfμ:fμdef and fμadh are, respectively, the deformation-induced and adhesive component of friction force. Here, it is relevant to point out that Eq.  is thought to provide only a minor contribution , 22, 65.ncoupled . This asA is the contact area and τ the interfacial shear strength. In human skin, the interfacial shear strength is dependent on the applied contact pressure [μl, but this parameter was set constant and independent of A. Consequently, the effect of reduction in global friction with larger contact area observed in our results is derived purely from deformation.In the analytical model developed by Wolfram , the adhmentclasspt{minimafμdef was related to the level of deformation and viscoelastic dissipation effects (hysteresis) induced under the sliding indenter. In this model, hysteresis losses are derived from the elastic work required to move the indenter forward in a rolling motion. In the case of a sliding motion, additional work is provided by shearing losses. It must be emphasised that although Adams et al. [In the analytical model of Greenwood and Tabor , widely s et al.  interpres et al.  and of ts et al. . This wai.e. neo-Hookean elasticity), it is relevant to point out that the dissipative Newmark scheme was implemented to provide dynamic stabilisation to the highly nonlinear contact procedure. The effects of this procedure were sufficiently small to have a negligible effect on the solutions so that deformations of the skin could be considered fully recoverable.Although the constitutive model used for the skin layers was that of a conservative material  can provide a significant contribution to friction forces measured at a higher length scale. Moreover, it is clear that, for a given local friction value, the resulting global friction can be significantly different . This finding is of particular relevance to the modelling of contact interactions where global (i.e. macroscopic) coefficients of friction are often applied to systems featuring microscale interactions. For example, this was the case of a microneedle penetration model by Kong et al. [The computational study presented in this paper demonstrated that local deformations of the skin microrelief and internal microstructure  which might alter the skin global friction response so that anisotropic friction is produced. Within a 3D modelling environment, more realistic aspects of skin micromechanics can be taken into account such as skin collagen fibre architecture and anisotropic elasticity which are likely to produce more complex strain and stress distributions.In the present model, the skin layers were modelled as isotropic neo-Hookean hyperelastic materials. One of the principal mechanical characteristics of skin is its anisotropy and stiffening behaviour in tension. Lanir and Fung  documenti.e. viscoelasticity) would allow to extend computational analyses to account for the effects that sliding velocity and material dissipative processes have on the global friction response of skin. Persson [Furthermore, incorporation of skin time-dependent behaviour , nonlinear constitutive properties and the complex geometry of the skin layers. It was demonstrated that this approach offered a new level of mechanistic understanding into how local skin deformations in combination with alterations in the mechanical properties of the The global coefficient of friction can be significantly different to the local coefficient of friction. The difference between the micro- and macroscopic friction is dependent on the microscopic geometry of both contacting surfaces, i.e. skin and rigid counterpart, as well as the mechanical properties and geometry of the skin layers.The global coefficient of friction is lower than the local one when the skin is assumed to be flat. Although this effect seems to be counter-intuitive, it was already observed in previous works, e.g. .The global coefficient of (deformation-induced) friction is magnified by the structural effects engendered by the geometry of skin microasperities. The presence and deformations of these asperities lead to interlocking with the rough contacting surface.stratum corneum can considerably modify the global friction response by influencing the local skin deformation at the contact area and providing stiffer asperities that increase resistance to motion, and therefore, the global friction response.The mechanical properties of the From this study, it is concluded that in the deformation component of skin friction :The modelling approach proposed here should be viewed as complementary to physical experimental protocols characterising skin friction as it may facilitate the interpretation of observations and measurements and/or could also assist in the design of new experimental quantitative assays. These results also suggest that care should be taken when assigning a coefficient of friction in computer simulations, as it might not reflect the conditions of macroscopic friction one intend to represent. The findings of this computational study could be significant for a wide range of applications where skin friction is relevant, from superficial pressure ulcers, through male/female shaving and cosmetics to automotive safety.Supplementary material 1 (DOCX 650 kb)Below is the link to the electronic supplementary material.


Ligand efficiency is a widely used design parameter in drug discovery. It is calculated by scaling affinity by molecular size and has a nontrivial dependency on the concentration unit used to express affinity that stems from the inability of the logarithm function to take dimensioned arguments. Consequently, perception of efficiency varies with the choice of concentration unit and it is argued that the ligand efficiency metric is not physically meaningful nor should it be considered to be a metric. The dependence of ligand efficiency on the concentration unit can be eliminated by defining efficiency in terms of sensitivity of affinity to molecular size and this is illustrated with reference to fragment-to-lead optimizations. Group efficiency and fit quality are also examined in detail from a physicochemical perspective. The importance of examining relationships between affinity and molecular size directly is stressed throughout this study and an alternative to ligand efficiency for normalization of affinity with respect to molecular size is presented. Your job is to lead us in prayers, and from now on you’re going to lead us in a prayer for more ligand efficiency in every project. Is that clear? I think more ligand efficiency is something really worth praying for”.Adapted from Joseph Heller, Catch 22“a useful metric for lead selection”, has been discussed at length in reviews  can be considered to be a composite transformation consisting of both chloro-substitution and chiral resolution. The (ΔpIC50/ΔNnH) value of 0.37 per non-hydrogen atom for [3 → 6] would place it on the Q3 reference line for the F2L optimizations surveyed in Johnson et al.  would place it in the top quartile of the F2L optimizations surveyed in Johnson et al.  transformation. A significant portion  of the residual for 5 can probably be explained by its racemic nature. Had the more active enantiomer of 5 been used in the analysis, the GE value for the chloro-substitution might have been 1.2 kcal/mol per non-hydrogen atom rather than 1.6 kcal/mol per non-hydrogen atom as reported in Saxty et al. [6 and the GE value for the [5 → 6] transformation highlight the importance of the chloro substituent as a molecular recognition element in this system. Given that the pyrazole ring is present in all structures, it is not possible to draw any inference about the contribution of this molecular recognition element to affinity although the excellent linear fit to the data shown in Fig. Once it has been established that the pyrazole substructure is important for affinity, the non-pyrazole les Fig. b. The rey et al. . Both thAnalyzing affinity data in this manner effectively partitions MSE for a compound into a term that characterizes the steepness of response of affinity to molecular size for the particular selection of compounds and a residual term that quantifies the extent to which the affinity of a compound beats (or is beaten by) the trend in the data. The residuals are invariant with respect to change in C° so there is no change in perception if affinity is expressed using a different concentration unit. Although residuals cannot be used to define efficiency in an absolute sense, compounds can still be ranked and there is no requirement, as is the case for analysis based on GE , 86, thaD value of 1 M [Drug discovery scientists typically need be able to address a range of questions when interrogating project data. For example, it may be useful to focus analysis on the most active compounds in an optimization project. It is important to stress that residuals are not generated in isolation and they result from analysis that, arguably, should be performed anyway. The line fit to a plot of affinity against molecular size is likely to be a better predictor of outcome than a line that has been artificially forced to intercept the affinity axis at a point corresponding to a Ke of 1 M . The strLE has been discussed in depth from a physicochemical perspective in this study and the difficulty of interpreting affinity in terms of molecular interactions was highlighted. The nontrivial dependency of LE on the concentration unit in which affinity is expressed means that LE has no physical significance and, strictly, should not even be considered to be a metric. As such, LE is unsuitable for ranking compounds, setting acceptability thresholds for affinity and modeling relationships between affinity and molecular size. While it does not appear to be possible to quantify absolute efficiency of binding for compounds in an objective manner, efficiency can still be defined in a relative manner by scaling affinity differences by the corresponding molecular size differences.


The metamaterial electromagnetic response is controlled via a low-frequency or dc magnetic flux bias, and we present a control line architecture that is capable of applying sufficient magnetic flux bias with minimal parasitic coupling. Together this design allows for an in-situ tunable cavity which enables low-temperature quantum control applications.Here we consider a tunable superconducting cavity that can be used either as a tunable coupler to a qubit inside the cavity or as a tunable low noise, low temperature, RF filter. Our design consists of an array of radio-frequency superconducting quantum interference devices (rf SQUIDs) inside a superconducting cavity. This forms a tunable metamaterial structure which couples to the cavity through its magnetic plasma frequency. By tuning the resonant frequency of the metamaterial through an applied magnetic flux, one can tune the cavity mode profile. This allows us to detune the cavity initially centered at 5.593 GHz by over 200 MHz. The maximum quality factor approaches that of the empty cavity, which is 4.5 × 10 These all have various tradeoffs in terms of switching speed, power handling, tuning range, susceptibility to vibration/noise, and other factors4. However, none of these systems are capable of operating at low temperatures. In order to overcome these limitations and create a device useful for cavity control in cryogenic systems, we have designed an electronically tuned cavity that can be rapidly switched between states and is compatible with cryogenic temperatures. This will enable novel cryogenic tunable filters as well as unique cavities that enable coupling control to and between superconducting qubits.Waveguide cavities provide a simple resonant system with their fundamental mode set by the speed of propagation in the cavity and the size of the cavity itself. Tuning cavities is traditionally accomplished by physically changing the size of the cavity, which although effective, results in slow and bulky devices. Other methods of tuning include electronic tuning through varactor diodes6. In particular, people have used the nonlinearity of superconductors and Josephson Junctions (JJs) to design tunable superconducting metamaterials. The tuning is provided by either temperature or dc magnetic field and is capable of tuning the resonant frequency or of controlling the electromagnetic transparency15. Related to these superconducting metamaterials are SQUID metamaterials9, which rely not on the properties of just superconductors or JJs, but on superconducting SQUIDs made from JJs. Due to the SQUID’s interaction with a magnetic field, they possess an effective uniaxial magnetic permeability that can be dynamically controlled via an applied magnetic flux. In this paper, we use a SQUID metamaterial to design and computationally model a tunable superconducting cavity that demonstrates the high level of control and the compatibility inherent within our proposed design.In order to accomplish this tunability in a manner that can operate below 4 K, we use metamaterial rf SQUID arrays inside the cavity to perturb the cavity modes. Metamaterials are artificially designed materials that consist of sub-wavelength unit cells, or meta-atoms, and achieve effective electromagnetic properties that are not available in naturally-occurring materials. We use superconducting metamaterials in order to take advantage of their low losses, high nonlinearity, and ability to probe quantum phenomena. There are several reviews of their use as a low temperature metamaterial availableμr = 0. While there have been recent studies on the behavior of epsilon-near-zero (ENZ) materials in quantum physics, there are relatively few studies of the magnetic equivalent17. Our work represents a new and novel system for probing the properties of mu-near-zero materials.Using these SQUID metamaterials inside a cavity, we find that the coupling between the cavity and the metamaterial occurs at the metamaterial’s magnetic plasma frequency, where the effective magnetic permeability 13 and SQUIDs19 have previously been used to build planar tunable superconducting cavities. Additionally, there has been significant progress with regards to controlling planar qubits by using either a tunable coupler20 or cavity22 to mediate coupling with a qubit. Instead of using a physical tunable cavity or coupler, our device provides a new method of controlling this cavity-qubit coupling by tuning the cavity mode itself, allowing for the coupling and isolation of the qubit. This would allow the qubit to be addressed when the resonance is coupled to the qubit and isolated when it is not, allowing processing to occur during the isolation, where the qubit is insulated from outside noise improving its lifetime.Our tunable cavity could also have applications for quantum computing architectures. JJs9.A SQUID metamaterial is composed of rf SQUIDs arranged in a periodic 2D array, each of which function as a meta-atom. These rf SQUIDs are composed of a single JJ in a superconducting loop, and can be effectively modeled as an RLC circuit in series with a variable inductance. We briefly review the rf SQUID model here, but additional details can be found in the literatureIc is the critical current of the junction, and h is Planck’s constant, and e is the elementary charge. The pads of the junction give it a capacitance C, any loss in the circuit can be taken into account by a resistance R, and the overall geometry of the circuit adds an additional inductance L. Hence, the resonant frequency of the SQUID is given byThe Josephson effect produces a current across the JJ, Since the behavior of the JJ is dependent on F is the 2D filling fraction of the meta-atom SQUIDs in the medium and 8. It is important to note that this model does not take into account the coupling between SQUIDs, which may introduce higher-order effects on the behavior of the metamaterial24.In the frequency regime where the size of the meta-atom SQUIDs is sufficiently sub-wavelength, the array of SQUIDs acts like a metamaterial with effective relative permeability6. The upper limit on the Q is the result of the impedance of the waveguide ports in and out of the cavity. We place the metamaterial towards the edges of the cavity and extend it halfway towards the center of the cavity, as shown in Fig. The empty cavity we chose for our simulation has a fundamental resonance at 5.593 GHz see Fig.  and a Q S2,1 parameters for various tunings of the metamaterial, Figure μs is the static magnetic permeability of a Lorentz model fitted to the metamaterial μr (details are outlined in the Methods section). Figure Looking at the eigenmode in Fig. entclass1pt{minimaμr = 0 and magneto-inductive waves can propagate26. Magneto-inductive wave devices have been investigated in waveguide structures28. However, the nature of this interaction has not been previously observed in any cavity system and although not a focus of this study, is an area of interest for further exploration.Although the cavity resonance is at 5.593 GHz, the metamaterial most strongly couples to the cavity when the metamaterial resonance is tuned to 3.95 GHz, so the coupling does not occur at the metamaterial’s resonance. Instead, we observe maximum coupling and modulation in transmission corresponding to the zero crossing of the metamaterial’s frequency-dependent permeability, which happens when 5 down to well below 103 as the coupling between the metamaterial and the cavity increases due to the losses in the SQUID. As we further decouple the metamaterial from the cavity, Q approaches that of the empty cavity.Figure 5), and the metamaterial couples to the cavity only for specific, short operations such as fast qubit reset. Additionally, the ability to modulate Q by such a large factor can be used to tune the ring-up or ring-down time of individual qubits. Thus, this system can act as an isolation switch for a qubit allowing many qubits to be addressed in the same frequency by providing rapid on-off addressing.The tuning of the cavity mode provides a mechanism by which one could potentially isolate a qubit or couple to other mode frequencies by modulating the cavity mode. The losses are not necessarily detrimental to such a qubit control scheme if the qubit is tuned to the cavity’s natural resonance with a high Q , Trepanier et al. determine other SQUID parameters  are uncertain enough to require fitting in order to determine their value. This fitting is accomplished by measuring S2,1 and fitting it to the SQUID models8. In particular, the effective resistance R can only be precisely determined by fitting the width and depth of S2,1. This fit is subject to the largest uncertainty since it is influenced by the fabrication and measurement quality. Measuring a low Q from the S2,1 parameter may predict too small of a value for R, which in turn would lead to predicting a high value for damping factor While several of the SQUID parameters are controlled by its geometry and fabrication . Inductors are placed in series with the port, and physical space between the two arms of the antenna gives rise to capacitance. Thus, we can model the antenna as an RLC circuit whose resonance can be tuned by tuning the inductance. The antenna is placed in the middle of the cavity with the arms aligned along the short dimension of the cavity such that it couples most effectively to the electric field of the cavity’s fundamental mode.S3,3 parameter to see how the qubit couples to the cavity as a function of the cavity mode. The results are shown in Fig. We sweep the metamaterial resonance and measure the fq is the resonance frequency from the S3,3 parameter and We calculate the effective Q of the qubit for a particular tuning of the metamaterial by S3,3 parameter approaches 1 and the qubit does not couple effectively into the cavity. Away from this regime, the metamaterial is decoupled from the cavity and the qubit effective Q increases to >5,000. The qubit-cavity system is isolated so that they do not see losses through the metamaterial or waveguide ports leaving the qubit isolated for information storage.In the regime where the metamaterial is most closely coupled with the cavity, the qubit resonance is detuned by 10 s to 100 s of MHz, and the effective Q of the qubit drops allowing fast coupling in and out of the qubit state. However, in this regime, the 3 for a detuning of 50 MHz, the Q of the detuned cavity can be improved by reducing losses in the SQUIDs.In summary, we have designed and computationally modeled a tunable superconducting cavity architecture using a metamaterial consisting of rf SQUIDs. The metamaterial displays an effective magnetic permeability, which is tuned through an applied magnetic flux. By tuning the metamaterial and coupling the metamaterial with the cavity fundamental mode, the cavity mode frequency can be shifted by 100 s of MHz. While the Q of the cavity drops down to 10et al.8, then the effects are quite large. But for quantum information applications typical temperatures are much lower, 25–50 mK instead of 6.5 K, where SQUID behavior is no longer strongly temperature dependent. For other applications at higher temperatures the tuning range would be lowered and as seen in other experiments..While temperature dependence of material properties is critical in low-temperature physics, we do not expect temperature dependence of SQUID parameters to be relevant to applications of our cavities to quantum information applications. When the temperature of the system is a significant fraction of the critical temperature of the SQUID materials, such as in Trepanier 23.Further study into the effects of inhomogeneity of the control field is required, as the control mechanism proposed here would not bias the metamaterial uniformly. The dominant effects are expected to be broadening of the metamaterial resonance, which would broaden the coupled cavity mode and decrease the level of detuning. Additional engineering of the control loop can reduce this effect. Additionally, engineering of the SQUIDs to increase the coupling between them or decrease their dc flux sensitivity can further reduce the effect of the field inhomogeneityIn order to design the devices we used finite element method (FEM) simulations of the electromagnetic fields in CST Microwave Studio 2016. Our test chamber is a waveguide cavity resonator with perfect electric conductors (PEC) boundaries that represent the superconducting walls. SMA pin connectors are added to couple the microwave signals in and out of the cavity, and CST waveguide ports are set up at the end of the SMA pin connectors to control input signals and calculate the S-parameters. The dimensions of the cavity are shown in Fig. et al.8. They determined SQUID parameters L, Ic, and C from its geometric design, and S2,1. We use similar RLC model parameter values, but adjust them to bring the SQUID resonance frequency close to that of the empty cavity. This ensures that we are modeling realistic devices but in the frequency range of interest. The parameters we use are L = 0.27 nH, C = 2 pF, R = 820 Ω, and Ic = 1.2 μA. The thickness of the metamaterial is taken to be the SQUID-to-SQUID separation distance, 157 µm. The geometry of the rf-SQUID shown in Fig. et al., there are two layers of Nb separated by a 200 nm layer of SiO2. The overlap of the two layers gives the capacitance of the rf-SQUID. A Nb/AlOx/Nb Josephson Junction connects the two layers.A metamaterial is embedded in the cavity such that it couples strongly to the magnetic field of the cavity’s fundamental mode. The details of the metamaterial layout and design are described by Trepanier mentclass2pt{minimfdc = 1, but this is only the case when the mean Figure mentclass2pt{minimsing Eq. . Normallλ/646), so this is a valid approximation in line with effective medium theory. Here we use the Lorentz model for the effective permeability:μs are the infinite and static magnetic permeabilities, respectively, μr to the Lorentz model are shown in Fig. To simplify the simulation, the metamaterial is replaced in CST by a uniform, dispersive material with a uniaxial magnetic permeability and unity relative permittivity. The unit-cell dimension of the SQUIDs is very sub-wavelength (2, giving our device a total of 20,656 SQUIDs.As shown in Fig. R when extracting the effective parameters of the SQUIDs. Additionally, due to the substrate being electrically thin, the permittivity has a negligible effect on the cavity mode and is thus ignored in our model. When modeling the flux tuning of the metamaterial in CST, we assume for simplicity that only μr in Fig. μs do not change significantly for various values of fdc, so our assumption is reasonable. For all of the simulations, we use magnetic permeability parameters μs = 2. Unless otherwise stated, The substrate of the SQUID array is not modeled directly, but the losses from the substrate were taken into account through


Fault diagnostic software is required to respond to faults as early as possible in time-critical applications. However, the existing methods based on early diagnosis are not adequate. First, there is no common standard to quantify the response time of a fault diagnostic software to the fault. Second, none of these methods take into account how the objective to improve the response time may affect the accuracy of the designed fault diagnostic software. In this work, a measure of the response time is provided, which was formulated using the time complexity of the algorithm and the signal acquisition time. Model optimization was built into the designed method. Its objective was to minimize the response time. The constraint of the method is to guarantee diagnostic accuracy to no less than the required accuracy. An improved feature selection method was used to solve the optimization modeling. After that, the design parameter of the optimal quick diagnostic software was obtained. Finally, the parametric design method was evaluated with two sets of experiments based on real-world bearing vibration data. The results demonstrated that optimal quick diagnostic software with a pre-defined accuracy could be obtained through the parametric design method. In time-critical applications, fault diagnostic software is required to respond to a fault as early as possible. Based on the timely diagnostic result, operators can prevent the aggravation of consequences over time, such as the risks associated with crew member exposure to toxic or dangerous chemicals , the wroTo achieve this aim, many methods have been applied to enable diagnostic software to respond to faults as early as possible. Those methods are divided into two categories. The first is based on signal processing technologies such as wavelet transform ,6, empirAnother effective way is to increase the response rate of the diagnostic software by shortening the collection time of signals. Essentially, this kind of method speeds up the process of fault diagnosis in the software. In these methods, time series classification in machine learning is applied to shorten the collection time of signals ,23,24,25As stated previously, although many approaches have been proposed to obtain a response as early as possible, to the best of our knowledge, there is no widely available quantified measure to assess whether the response time is improved by such methods. These approaches assume that the response time obtained by the software can be objectively evaluated without taking into account the effect caused by the hardware. Furthermore, it is assumed that the response time can be quantitatively assessed, which means different approaches can be evaluated against a common standard, and a reference can be provided in software design. On the other hand, a design to respond to faults as early as possible may be achieved at the expense of the accuracy of the fault diagnostic software. As mentioned in , a fault(1)In order to carry out the parametric design of an optimal quick diagnostic software for time-critical applications, a measure of the response time is proposed. By combining the time complexity of the algorithm with the calculation formula of the signal acquisition time, we can quantitatively and rationally evaluate whether the response time is improved.(2)We present a parametric design method for the optimal quick diagnostic software. This method adopts time series classification in machine learning as the diagnostic algorithm. The objective is to minimize the measure of the response time, and the constraint is to guarantee that the accuracy of the diagnostic software is no less than a pre-defined accuracy. An improved wrapper method is used to solve the optimization model in order to acquire the design parameters.The contribution of this paper is two-fold:The remainder of the current paper is organized as follows. The response time is actually the time lag The time of the diagnostic algorithm execution he input . Using tWhen a diagnostic software is in service, the time lag The method adopted in this study involves the following steps: Building the optimization design model, narrowing the solution space through prior knowledge, and solving the model. In the parametric design, a fault diagnostic software is often defined as a tuple In the context of machine learning, the diagnostic algorithm To guarantee the accuracy of the designed diagnostic software to be no less than the required accuracy trapping . The desCombining Equations (1) and (3), the problem in the design of the optimal quick diagnostic system can be formulated as Equation (4). It minimizes the response time The set of natural numbers accuracy ,31,32. OTheoretically, a signal of the length  . The. Them is  A generation procedure to generate the candidate subset of features: The timestamp (2) An evaluation procedure to evaluate the subset: The classifier (3) A judgment procedure to judge the stopping criterion: Steps 1 and 2 are repeated until the maximal In order to solve the optimization problem in this paper, the wrapper method is improved, which is called Algorithm 1. Upon increasing of the sampling number from 1 to Algorithm 1 Algorithm of the optimal solutionStep 1. Determine the dataset Step 2. Initialize Step 3. Execute the iteration below:While     If              For every sample in                take End              Learn the classifier        Estimate        Else:       End while     Step 4. Output the optimal sampling number This paper adopts a dataset of bearing vibration signals from the Case Western Reserve University (CWRU) bearing test data center, and the conditions of data acquisition are given in . The sigAccording to previous research on bearing fault diagnosis based on the CWRU dataset, the signal length of 4096 was used for fault diagnosis [The Naïve Bayes classifier was selected as the diagnostic method umptions . In machTwo experiments, denoted as experimental groups A and B, were conducted. In group A, eight diagnostic software were designed based on the proposed method, and the required accuracies In order to present the results intuitively, the values of In group A, the 200 executions of the algorithm with different accuracy requirements all obtained the optimal sampling number For group B, the overlapping densities plot is presented in In order to evaluate the proposed design method objectively, it was compared with other methods. The methods used for comparison should provide the estimation of the accuracy, and the sampling number and sampling frequency should be known. Based on this, four methods were chosen, as listed in the first column of This study proposed a parametric design method for an optimal quick diagnostic system. Using this method, an optimal quick diagnostic system can be obtained, which has the smallest response time and a pre-defined accuracy. By means of experimental verification, the feasibility of the parametric design method was validated. Contrary to other existing methods, the proposed approach fulfills the following three characteristics:First, the measure of the response time was proposed in this method, which provides a common standard to quantitatively assess the improvement of the response time.Secondly, using the parametric design method proposed in this paper, the designed fault diagnostic software exhibited an obvious improvement in the response time to faults as compared with the response times of traditional methods with the same vibration data. Thirdly, the parametric design method exhibited superiority in the trade-off between the accuracy and the response time.Additionally, the experimental results revealed that the higher the required accuracy is, the less robust the designed diagnostic software is to noise and uncertainty. At the same time, the experimental results demonstrate that serious faults are guaranteed to be diagnosed more quickly by the diagnostic software; although, the more serious the fault is, the more easily the feature will be recognized.


Mechanical properties of the cells are among the most highlighted area of interests among researchers for decades. Not only many of the cells’ crucial functional characteristics such as adherence to the cellular substrate, migration abilities and morphological factors are directly influenced by their mechanical properties but also changes in these traits could have importance in diagnosis and even treatments of some serious diseases. The general mechanical properties of the cells are associated with some intercellular characteristics such as arrangement and organization of the actin fibers and cytoskeleton architecture. Any changes due to pathological conditions in the molecular and cellular processes related to these elements can alter the cells’ mechanical characteristics. In this paper, the viscoelastic properties of diabetic and normal lymphocytes were analyzed and compared by application of the iron nanoparticles attached to the cellular membrane and putting the cells in a magnetic field with certain frequency and intensity. Step force was applied to the normal and diabetic lymphocytes and their membrane displacement was tracked by special software and plotted with respect to time. Fitting the experimental data on theoretical formulation of standard linear viscoelastic model, it was demonstrated that diabetic lymphocytes have significantly different viscoelastic characteristics. The results of this paper can be of importance in assessments of diabetic lymphocytes’ abilities to fulfill their immune surveillance tasks. Cell mechanical properties play pivotal roles in vital characteristics of cells. Many of the biophysical and biological peculiarities are determined by viscoelastic properties of cells . The cell suspensions of two groups were incubated separately in culture medium for 18 h, followed by addition of magnetic FeSince the lymphocytes are characterized as non-adhesive cell types, for test one droplet of the cell suspension was applied to the laboratory neubauer lam. Cells were transferred on neubauer lam and their displacements were recorded after application of the magnetic field under the optical microscope 1600×). For each test, first a single cell has been located and different magnitudes of forces were applied under the effect of different magnetic fields. The displacement of cells under the effect of forces was recorded by a 2 mega pixels 60 frames per second camera. Figure 600×. ForWith the use of a function generator, the desired wave form could be produced and after amplification to 4 A the electrical current was applied to a coil. Magnetic field has the effects on magnetic nanoparticles which are connected to cell membrane. The coil has two cores. The central iron core has the radius of 2.5 cm and the length of 7 cm and the secondary Si core has the length of 2.5 cm and wrapped around the central core. The copper wire of 1.1 mm was twisted 400 times around the cores. A teslameter with the accuracy of 0.001 was located in an appropriate location for determination of the magnitude of magnetic field.The videos are transferred into computer for processing. On the computer, four specific softwares for this purpose have been installed. The function generator software induces the desired wave form to the generator, Teslameter software that shows the magnitude of the magnetic field in micro Tesla in three Cartesian directions, video recording software that is related to the microscope and finally the software of Tracker (version 4.81) analyzing the displacement.Standard linear model was considered for force and displacement relation. This model consists of a spring and a Kelvin model in series. This model is shown in Fig. The relation between stress and strain can be readily obtained as below Eq. . This mop1, q0 and q1 we have Eq. By substituting the coefficients with σ0 for the σ function we will have Eq. And by applying the step function with amplitude of p1, q0 and q1 should be determined in practical experiment. Figure The parameters T test-paired statistical analysis was done for the three constants of the Eq. P value below 0.05 was set as the criterion of significant difference.All the tests were performed three times and in each test at least ten cells from each group were selected. x- and y-direction displacements with time for the membrane have been depicted in Fig. The displacement of the cell membrane in different normal and diabetic groups was analyzed after application of magnetic field. Figure Figure Table The mechanical properties of cells and tissues have attracted many scientists’ and researchers’ attention. It has been demonstrated that changes in mechanical characteristics of cell can be one of the best criteria in early diagnosis of many diseases. In addition, cellular well-functioning is attributed directly to mechanical properties of those cells. Due to these facts, recently some papers have been published on measuring viscoelastic properties of lymphocytes. To the best of our knowledge, this is the first time that the viscoelastic properties of normal and diabetic lymphocytes were measured and analyzed by this approach. While many researchers use micropipette aspiration or AFM method, in this research the viscoelastic properties of normal and diabetic lymphocytes have been investigated by application of magnetic field on iron nanoparticles-loaded cells. In this research, the viscoelastic properties of normal and diabetic lymphocytes were assessed and obtained. Magnetic iron nanoparticles have been added to the culture medium of the lymphocytes with certain concentration and by application of magnetic field in the graph of membrane displacement with respect to the time was plotted. By utilization of standard linear viscoelastic model, the mechanical properties of normal and diabetic lymphocytes were investigated and compared.The results demonstrated that diabetes can change the mechanical properties of lymphocytes. Any physical  which contribute as actors in remodeling of cytoskeleton (Chen et al. In this research, the viscoelastic properties of normal and diabetic lymphocytes have been investigated and significant differences have been identified. It has been understood that the mechanical properties of healthy and diseased lymphocytes are different in terms of their energy storing and dissipating rates. While cellular migration includes continuous membrane bending and deformation, it can be deduced that the diabetic cells have different migration pattern. Finally, while the most important function of the lymphocytes necessitates their facilitated movement, diabetic cells seem to have problems in performing their tasks.


FATE (Focus‐Assessed Transthoracic Echo) protocol. The aim of the study was to determine the feasibility and utility of this method FATE protocol teaching.Peyton's four‐step approach is well‐known and commonly used in medical education. It is a practical and useful method which is simple to apply. The study presents the implementation of the modified four‐step approach method to teach how to perform the emergency echocardiographic assessment according to We collected students' feedback relating to perception of this way of teaching. Based on a semistructured interview conducted with the students, as well as an evaluation of the electronic survey, it has been demonstrated that the four‐step method is useful for teaching emergency echocardiographic assessment.One Polish medical school.The classes were run in small groups as part of an elective ultrasound course for the fourth‐ and fifth‐year students of the Faculty of Medicine of the Medical College. Twenty‐two students were trained.FATE protocol, it has been determined that the four‐step method is effective in imaging training. All participants claim that this method is clear and understandable. Advantages of the methodological approach: a slow‐motion demonstration by the instructor, accompanied by the commentary on the activities undertaken and practical exercises performed by the participants, learning through repetition, requirement of constant concentration.Based on the opinions of the participants of the elective course and the teacher conducting the classes, which involved the use of the modified Peyton's four‐step method in teaching echocardiography in emergency cases according to the Peyton's approach allows to use of the class time in maximal extend by consolidating new information and facilitating memorization through adequate instructor guidance and observation of the training of the peer students and repetition of the skills acquired. This study assessed the feasibility and utility of the modified four‐step approach method in teaching of the emergency echocardiographic assessment according to FATE (Focus‐Assessed Transthoracic Echo) protocol. Teaching of the echocardiographic imaging in the small group is the most effective, so the conditions of the course influence on the strength of the study and also on the limitation (a few participants of the study).We analyzed participants' perspectives from only one medical course entitled “Ultrasound imaging in life‐threatening situations” and that limits the generalizability of our findings.1At the Faculty of Medicine of the Medical College, an elective course is organized, entitled “Ultrasound imaging in life‐threatening situations.” This kind of training is addressed to interested students of the fourth year and fifth year of study. The elective class is conducted at the Department of Medical Education of the Medical College by university teachers with practical experience in ultrasound imaging. The aim of the training was to teach emergency patient ultrasound assessment according to FAST (Focused Assessment with Sonography in Trauma), EFAST (Extended Focused Assessment with Sonography in Trauma), BLUE (Bedside Lung Ultrasonography in Emergency), FEEL , and FATE (Focus‐Assessed Transthoracic Echo) protocols.All the aforementioned protocols used in emergency cases are of high practical importance. They shorten the time between the first contact with a patient in life‐threatening conditions and the correct diagnosis followed with the appropriate treatment.This publication concerns the students' perception of the modified Peyton's four‐step method, used during the elective course exclusively to teach echocardiographic imaging according to the FATE protocol. The remaining elements of training included in the framework of the elective course were taught in a traditional manner, involving demonstration by the instructor followed by practical exercises performed by the students, without the use of the four‐step method.1.1The aim of the study was to determine the feasibility of this method in teaching echocardiography in accordance with the FATE protocol and the perception of the method by students.2Over the last 2 years, an elective course was organized for the fourth‐ and fifth‐year medical students to familiarize them with the imaging examination quite frequently performed in life‐threatening cases, often performed in emergency departments or admission room, as well as to allow the students to practice it. During the first half of 2017, a new learning tool was implemented to teach echocardiographic imaging in emergency cases, that is, a modified Peyton's four‐step method, described in the literature in the field of medical didactics as an effective way to teach practical skills.As part of the elective class, 22 students were trained. Three weeks before the planned classes, each of the students was granted access to materials for self‐preparation for classes. The materials included current literature in terms of the course content, as well as videos of pathological ultrasound images. The practical classes were preceded by a precourse test to assess the participant's knowledge at the onset of the course. Subsequently, the students practiced, divided into three groups. The course lasted 30 hours.1st day of the course included lectures and getting to know the equipment. 2nd, 3rd, and 4th day included workshops.Each day: I group trained FATE (Focused Assessed Transthoracic Echo) protocol, II group—BLUE (Bedside Lung Ultrasound in Emergency), and III group FAST (Focused Assessment with Sonography in Trauma). The groups changed the trained protocol (and teacher) each 60 minutes.http://www.fate-protocol.com and are available as a free application for iPhone and Android. While students trained first time the FATE protocol, they focused on basic views:Third‐ and Fourth‐day students practiced also ultrasonographic assessment of main vessels. The students received from the teacher the FATE card that can be requested free of charge at Subcostal four‐chamberApical four‐chamberParasternal long axisParasternal LV short axisThe next day students trained the extended FATE views:Subcostal vena cavaApical two‐chamberApical long axisApical five‐chamberParasternal short‐axis mitral planeParasternal aorta short axisThe next day students repeated basic and extended FATE views. The students were only instructed to take the specifics ultrasound windows and to identify characteristic anatomical structures without taking more complex measurements.The modified Peyton's four‐step method, used during the class on echocardiography in emergency cases according to the FATE protocol, was presented to students at the beginning of the training. Having determined that the participants had actually understood the instructions on how to proceed in Peyton's method, the teacher moved on to practical training.In accordance with the stated objective of this study, it aims at discussing the value and the educational benefits of using the modified four‐step method. Therefore, the actual echocardiogram performed in emergency cases  is discussed only briefly, to make persons without any medical background understand the manner in which the classes are conducted.As part of the elective course, echocardiographic examination was performed according to the FATE protocol on a healthy participant of the course.The echocardiographic imaging according to the selected protocol requires the application of a dedicated probe to the appropriate sites of the body of the person examined. Knowledge of the probe locations  and ability to visualize the heart are essential for proper imaging. Apart from the scheme of the echocardiographic procedure, time needed for proper visualization is crucial, because the right diagnosis and the immediate treatment depend on it. The modified Peyton four‐step method ensures effective use of the course time.2.12.1.1The teacher provides real time presentation of a given procedure, in demonstration quality, without any commentary Students watch the presentation—at this stage, questions are not allowed.2.1.2Second slower presentation of the procedure with a detailed overview. At this stage, students are allowed to ask questions.2.1.3The instructor involves a student, asking him to comment on the actions taken by the teacher during third demonstration. The remaining participants observe it.2.1.4The student, who previously commented on the examination, performs the echocardiographic test in accordance with the FATE protocol by himself, commenting on his actions.After the completion of the above four steps, another series begins, in which the student involved in the two last stages (steps 3 and 4) of the previous series assumes the role of the teacher. Thus, theoretically, every participant of the training could do and comment on the whole procedure.The remaining elements of the imaging  were taught in a standard manner, in which the presentation with a commentary was followed by the participants of the class practicing on one another.To meet the assumptions of this study and determine the significance of the four‐step method in teaching imaging, a semistructured interview and a survey were conducted with the elective course students. This publication takes into account the statements made verbally by the students, as well as the information obtained with the use of an anonymous evaluation questionnaire collected after the end of the course.Semistandardized interview contained two kind questions:Open questionsWhat are your general impressions of the course?What do you think about the usefulness of the modified four‐step approach method in teaching of echocardiographic examination using the FATE protocol?What do you think about learning by observation?What do you think about learning through repetition?What do you think about the instruction in the four‐step method?What do you think about learning by teaching others?Could you give the advantages and disadvantages of the modified Peyton's four‐step method in teaching echocardiography according to the FATE protocol?Close and open questionsAre you satisfied with the course? Why?This method is practical or no in your opinion? Why?Is the modified four‐step approach method understandable?3Twenty‐two students participated in the elective course “Ultrasound imaging in life‐threatening situations”, aged between 23 and 26, 24 years on average, including five men and 17 women. The students eagerly practiced the new method as part of the elective course in echocardiography.The publication shows the advantages of the modified Peyton's four‐step method in teaching echocardiography according to the FATE protocol. Therefore, the comments of the study participants concern exclusively those activities in the class in which the method was used.The students participating in the elective course of emergency imaging had not been familiar with the modified Peyton's four‐step method. They declared that they (quote) “have never heard of it before.” During the partially structured interviews, the elective course participants expressed their positive opinions on the modified Peyton's four‐step method.Quantitative analysis of the semistandardized interviews conducted with the students trained.Topics and categories resulting from the interviews conducted with the students (trainees).3.1Understanding the new didactic method of Peyton's four steps.3.1.1“Easier, because you can learn how to hold the probe and where it should be applied.”“That's the easiest way of learning.”“Multiple repetitions allow you to master the examination technique better and make it easier to remember.”“It allows you to remember the correct order in which the examination is executed and the technique.”“Holding the head appropriately becomes a habit during repeated exercise.”“The one‐time oral instruction was sufficient and allowed me to use the method during the training.”“It was understandable.”“You cannot switch off during lessons.”“The four‐step method makes you concentrate on the examination.”“Teaching others, we learn ourselves, and we remember for longer.”3.1.2All the trainees decided that the method is (quote) “easy to understand.”The students decided that this was “not only a comprehensible and clear method, but also one which facilitates learning the imaging examination.”One of the participants expressed his opinion in the following fashion:“Echocardiographic imaging (in emergency cases) is hard, but owing to Peyton's four‐step method it is easier to take it in.”Other students expressed their opinions as follows:“The four‐step method allows for understanding and technical mastery of skills.”Quote:“It is worth using, because it may seemingly take up much time, but in reality it allows you to consolidate your knowledge and skills.”Students from all the groups said repeatedly: “It's a good method and it should be used more often.”Another participant of the course expressed his opinion about the new method in the following manner:“On the other hand, the four‐step method is effective, so there is no question of wasting time—it is an effective use of it.”3.1.3“It is great to do the course—no stress at all.”“The course conditions are good and the instructors are very nice.”“The course atmosphere is so much low‐key, one can talk—it's so nice.”3.1.4Students commented positively on the method:“It is great because at the end of the classes I became convinced that I could perform echocardiography on a patient with a severe condition (on my own).”“The training is effective, because the effects can be seen immediately—you can do the imaging by yourself.”“You can see the effects, because everyone immediately performs the test on a colleague by themselves.”“I feel that I am ready to start examining patients.”3.1.5“It is good that we practice in a small group, because five students per an ultrasound machine are enough.”“We can say anything in a small group, there is time to ask.”3.2The purpose of this study was also to obtain information on the defects of the modified Peyton's four‐step method. The students participating in the elective course decided, however, that “it is difficult to find the negative side of this method.”3.2.1One of the students thought that “the four‐step method takes time and it may be more difficult for the instructors because they have to perform the same test many times.”3.2.2One trainee student expressed his doubts as follows: “Why this method anyway?—After all, you can train just as well without it.”Another participant expressed the following opinion, quote:“One can always pick on something and find faults in it, but what can be regarded as a disadvantage is the longer time needed to complete all four stages of the method.”Another student added that the four‐step method “requires constant concentration, which gives headache.”The trainees said: “I liked it.”To the question “Is it worthwhile to apply the four‐step method in training imaging, or is it better to selectively use only the second step  and then to move on smoothly to practical exercises performed by the participants?”, the students responded unanimously that it was worth using.To the next question: “Why? Is it not a waste of time?”, the participants expressed unambiguously positive opinions about the method used and tried to support it with arguments that multiple repetitions allow for better mastery of the technique and easier memorization.The students were asked to express their opinion on whether it is worthwhile to continue teaching imaging, not only echocardiographic one, but also other elements of the course with the use of the modified Peyton's four‐step method. According to the participants of the elective class, the method they have learned should be used in teaching practical skills in general. They pointed to the fact that the four‐step method allows you to memorize the correct order in which the test is performed and its technique. During multiple exercises, adequate holding of the head becomes a habit, which is extremely important in proper imaging.Among the students' opinions, the positive evaluation of Peyton's modified four‐step method was predominant. As it turned out, the time which must be devoted to repeat the examination several times was the only problem. However, according to the students, this was an advantage, because, as the old maxim, well‐known to medical students puts it: “repetitio mater studiorum est”—repetition allows for the consolidation of information and skills.In the course evaluation questionnaire, the participants wrote: “we need more of such classes” because they are practical and useful for the future career of a doctor. One student stated that it would be best if the participants could start using the skills learned immediately, because otherwise they could forget the technique of performing imaging tests. The participants of the training suggested the course was worth repeating in the future, conducted in a similar way. It would be a good reminder immediately before starting actual professional work, in which the ability to perform imaging studies in emergency cases involving a threat to a patient's life is important.Everyone answered to the semistructured interview, but only 9 students filled out the questionnaire Table There were collected three negative comments on open‐ended questions:Two students answered: “The method is time‐consuming”One student answered: “Too many steps”4Quantitative analysis of the semistandardized interviews performed with all of the trainees revealed that learning echocardiographic examination using the FATE protocol in the small group by observation and repetition, learning by teaching and active engagement, and the opportunity for independent performance made the modified Peyton's approach a valuable learning and teaching method.Recent literature in the field of medical education recognizes the four‐step method as a valuable and easy‐to‐use teaching tool. It was also accepted by students.In his study, NikendeiThe trainers and trainees participating in the study were instructed about the stages of Peyton's four‐step method in the following way:The teacher demonstrates the skill at normal pace without comment The teacher repeats the procedure, discussing all its phases A student explains the individual stages of the procedure, performed again by the teacher A student performs the entire task by him/herself Subsequently, the participants of the experiment were to perform the procedure first on a dummy and then on a living patient .Based on the study of Nikendei et al, which was an analysis of partially structured interviews with all the teachers and the students training the insertion of a catheter into a peripheral vein, it has been demonstrated that the modified Peyton's four‐step method is useful and effective. According to the teachers introducing the catheter placement, its advantage lies in the ease of use and the control over the session of intravenous catheter insertion by all students. For students participating in the study, the new method proved to be useful, because according to their statements “they received detailed instructions and were able to repeatedly track the process of the catheter insertion, also in slow motion,” “they weren't annoyed, did not have to ask questions to understand the procedure.”The study of the implementation of the modified Peyton's four‐step method to teach conducting imaging tests as exemplified by the training in echocardiography in emergency cases according to the FATE protocol confirms the usefulness of the new tool. The teacher running the training echocardiography in emergency cases had direct control over the comprehension and correct implementation of the particular stages of the test by all the trainees.The Peyton's four‐step method was also used in another study, when teaching a more complex procedure of gastroscopy. Third‐year medical students performed it on a dummy.According to the participants of the elective course “Ultrasound imaging in life‐threatening situations,” heart imaging with the use of the FATE protocol is highly difficult. The four‐step method may significantly contribute to the memorization and mastering of a large amount of content in a short time. This is a useful method, which can be successfully used in medical didactics, especially in teaching imaging in emergency cases.Scientific research indicates that echocardiogram performed using the FATE protocol in patients with a severe condition (referred to in the publication) is a fast and effective method for confirming or excluding cardiac causes for severe, often even critical, condition of the patient.The students assessed the course and the modified Peyton's method positively.Based on the partially structured interview with the students, clear conclusions were drawn that the method used during the elective course classes aimed at mastering the skill of echocardiography in emergency cases is recommendable. It is worth using in both the opinions of the participants and the teacher conducting the class, as it organizes presented information and facilitates the acquisition of content which is new for the students. Owing to multiple repetitions, the four‐step method allows for better mastering of the skills introduced during the elective course and the memorization of the test procedure.The fact that the method used is not wearisome is important. It allows for maintaining vigilance, as each participant is actively involved. The participants of the elective course, who are passive observers at a given moment, are also trying to intently observe the test performed by other participants, as they are aware that they will soon perform it themselves.The statement “practice makes perfect” is a perfect illustration of the assumptions behind the implementation of the modified four‐step method. After the short course of imaging used in emergency cases, the modified Peyton's four‐step method is proven successful. It makes the course very intense and effective. Students said: “you can't switch off,” “the four‐step method makes you concentrate on the test.”Due to the small size of the group of students practicing during their elective course in imaging in emergency cases, research should be continued to assess the four‐step method application in teaching echocardiography. The usefulness of the four‐step method in teaching imaging according to other protocols should also be assessed, including standard imaging.5Based on the opinions of the participants of the elective course and the teacher conducting the classes, which involved the use of the modified Peyton's four‐step method in teaching echocardiography in emergency cases according to the FATE protocol, it has been determined that the four‐step method is effective in imaging training. It allows for the maximum use of the time assigned to student practice. It consolidates the information and facilitates its memorization through repetition. The authors of the publication decided that it is worthwhile to use the modified four‐step method in teaching imaging, as well as to continue running elective classes in imaging in emergency cases using this method. The study confirms that the modified four‐step method leads to effective learning through observation, the tutor's detailed instruction, several repetitions, and teaching others Table .15None declared.AS contributed to study conception and design. MN supervised the study. AS and TG contributed to data entry. PK, MP, KJ, MSz, and GC helped data analysis and interpretation. AS drafted the manuscript. AS contributed to discussion and manuscript revision. All the coauthors approved the final version of the manuscript.The Ethics Committee of the Jagiellonian University accepted the study protocol (No 1072.6120.164.2017).Not commissioned; externally peer reviewed.agnieszka.skrzypek@gmail.com) on request.A fully anonymous data set is available from the authors (