This article deals with the study of the utilisation of irradiated HDPE products after their end-of-life cycle. Today, polymer waste processing is a matter of evermore intensive discussion. Common thermoplastic waste recycling—especially in the case of wastes with a defined composition—is generally well-known—and frequently used. On the contrary, processing cross-linked plastics is impossible to do in the same way as with virgin thermoplastics—mainly due to the impossibility of remelting them. The possibility of using waste in the form of grit or a powder, made from cross-linked High Density PolyEthylene (rHDPEx) products, after their end-of-life cycle, as a filler for virgin Low Density PolyEthylene (LDPE) was tested in a matrix. It was found that both the mechanical behaviour and processability of new composites with an LDPE matrix, with rHDPEx as a filler, depend—to a high degree—on the amount of the filler. The composite can be processed up to 60% of the filler content. The Polymer Mixture Fluidity dropped significantly, in line with the amount of filler, while the mechanical properties, on the other hand, predominantly grew with the increasing amount of rHDPEx. The plastics industry plays a very important role in the global economy. In the last few years, polymers have become one of the most important materials. Polymers are used in a wide range of applications—e.g., packaging, household applications, sport and leisure time accessories. Plastic materials play a very important role in the design of electrical and electronic products, medical applications and automotive, aircraft and aerospace industry components. In co-dependence with the growth of the plastics industry, the amount of generated waste of both types of plastic parts in the end-of-life cycle and post industrial waste phases is also increasing. Research works concerning real time prediction of some types of polyolefin or biodegradable polymer films were also carried out ,2. The qThe reduction of plastic waste and the discovery of effective ways to recycle plastics is the greatest challenge for scientists, producers and users of polymer parts in the future. Today, the most common plastic waste processing method is mechanical recycling, which includes various steps leading to the conversion of the waste into a useful material. These steps cover the collection, sorting, washing/cleaning, and grinding of the waste. The crushed material can be used directly as an addition to a virgin polymer and could be re-granulated in the next possible step ,9,10,11.Over the last few decades, the industrial use of radiation cross-linking for standard as well as engineering polymers has increased rapidly. The cross-linking process enables one to change the properties of plastics, and especially, to improve their mechanical, chemical and thermal properties ,24,25,26This article describes one of the possible ways of processing recycled cross-linked High Density Polyethylene (rHDPEx), originally used for the production of underfloor heating systems. There is a huge amount of waste from this production to dispose of, and millions of kilometres of heating pipes are installed in buildings. It is therefore necessary to think about what will be done with this material/processing waste or waste at the end of such productts’ lifetimes.Crushed cross-linked rHDPEx from underfloor heating pipes as the filler added to the LDPE matrix was used in this study. Granulate of virgin LDPE as a matrix, and recycled irradiated rHDPEx, were used for the preparation of two types of mixtures.The wide availability of rHDPEx was the main reason for the use of this polymer in the research presented herein. This material was supplied in the form of heating pipes used for underfloor heating systems. The pipes were crushed using the low-speed knife mill, type MASKIN AB RAPIS S-33010, screen size 5 mm and ground using the toothed disc mill, type Condux. To obtain crushed or powdered material for further processing, the particles with dimension higher than 1 mm were separated from the powder using screen 1 mm. The pipes were originally irradiated by beta (electron) radiation, with an energy of 10 MeV, and irradiation dose of 165 kGy. Low Density PolyEthylene  was chosen as the polymer matrix regarding their ease of processability, low price and wide availability. LDPE granulate was used as the polymer matrix and rHDPEx in grit or powder states were used as the filler.Irradiation of used HDPE pipes originally determined for use in underfloor heating systems was originally carried out at the premises of BGS Beta-Gama-Servise Company , Germany. Electron beam radiation, with the dose of 165 kGy, and energy of 10 MeV, was used for their irradiation. The cross-linking of used HDPE was realized without the use of a cross-linking agent. Gel Content Measurement and a Dosimeter were used to determine and find proof of correctness. The correct radiation dose was checked by a Nylon FTN 60-00 dosimeter; and the analysis using a Genessis  5 spectrophotometer in correspondence with the ASTM 51261 standard . Gel conFrom crushed and powdered material, two types of mixtures, which differ from each other by filler state , were prepared: Mixture A (LDPE granulate + rHDPEx grit) and Mixture B (LDPE granulate + rHDPEx powder). Crushed (particle size of 1–5 mm) or powdered rHDPEx was mixed together with virgin LDPE granulate in a laboratory fluid mixer. A size analysis was performed using Retsch AS 200 Basic equipment  for deteTen samples were prepared for each testing method and statistical evaluation was realized in programmes TestXpert II , MS Excel 2016  and MiniTab . In all figures, arithmetic mean and standard deviation are used.A Type LMI 4003Dynisco Kayeness Melt-flow Indexer was used to measure the Melt Flow Index (MFI). The measurements were performed according to ISO 1133 standard , and a lA Modified Spiral Test was performed using a spiral cavity mould , with a A ZWICK 1456 tensile machine  was used for the estimation of tensile behaviour. Measurements were carried out according to the ISO 527 standard  at ambieAn OMAG AFFRI ART 13 Shore D hardness tester  was used for hardness testing in accordance with the ISO 868 standard , therefoMicro-indentation tests were performed using a CSM Instruments Micro Combi tester , according to the ISO 14577 standard . A VickeThe Charpy impact test was carried out on Zwick HIT50P equipment  at an ambient temperature of 23 standard . In thisA LEICA RM2255 microtome  was used for the preparation of samples —which represents a nearly double higher elastic modulus in comparison with virgin LDPE. It is possible to observe the same tendency in the elastic modulus results of Mixture B . Differe∘C , at the Ultimate Tensile Strength increases continually with the amount of filler content and, at the concentration of 60% of rHDPEx in the LDPE matrix, the increase is about 40% . That coA dramatic drop in strain at break was observed—even at the lowest filling concentration . The addperature . Just asShore D Hardness is in line with the increase of rHDPEx in the LDPE matrix. The ShD hardness continually rises to nearly 20% above the hardness of virgin LDPE with the highest filler content. There is only an insignificant difference in hardness when comparing Mixtures A and B ; the meagin LDPE .The impact properties of Mixtures A and B are strongly influenced by the concentration of the rHDPEx filler. By the addition of 10% of filler in Mixture A, the changes in Charpy Notched Impact Strength are negligible, but further increases led to considerable decreases in the impact properties. The difference in the impact strength of virgin LDPE and a composite with the addition of 60 wt. % rHDPEx grit is 54%. The addition of rHDPEx filler in the form of a powder (Mixture B) causes significant changes in impact toughness. This is already detectable from the smallest content of the powdered filler. At the rHDPEx powder concentration of 10%, the impact toughness dropped by up to 45% of the value of the virgin LDPE. With further increases in filler content, impact toughness continually decreased, down to 17% that of the virgin LDPE . From thThe basic processing parameter is represented by the MFI, which is a standard polymer flow behaviour test. Due to the crushed particles’ dimensions—and the impossibility of melting rHDPEx—it was impossible to make MFI measurements for Mixture A (LDPE + rHDPEx grit), so measurement was performed only for Mixture B. With an increasing dose of rHDPEx, the viscosity of Mixture B melts, with a MFI decrease to a minimum at a filler content of 60 wt. % . The melAlthough the MFI results and the Modified Spiral Test cannot be fully compared, both tests showed that the content and particle size of the filler significantly affect the flow properties of the LDPE + rHDPEx mixtures.To be able to evaluate the structure of the mixtures, Microtome Cuts method and SEM Fracture Microscopy  were useIt is visible from the structure of the mixtures, as shown in Results presented in this article show that there is potential to use rHDPEx as a filler up to 60 wt. %. Mechanical properties of the mixtures are influenced by the content of the fillers: use of rHDPEx brings improvement of E-moduli, Tensile strength, shore D, and micro-hardness to Mixtures A and B when compared with virgin LDPE, while the impact toughness, strain and fluidity all show decreases. Flow properties are also influenced by the size of rHDPEx particles. In The aim of this paper was to show the results obtained from the utilization of recycled irradiated High Density PolyEthylene (rHDPEx). Underfloor heating pipe waste, made from HDPEx, was used for this study. The idea of using this material as a filler was studied with the aim of investigating the influence of the filler on the mechanical properties and processability of the mixture. The results show that this technology, in few steps—such as cleaning (if necessary), crushing/grinding of the product from irradiated polymer, and the addition of grit or powder as a filler to the origin polymer matrix, in the concentration up to 60 wt. %—could be very successfully implemented in the waste-processing field. The utilization of crushed/ground rHDPEx as a filler for virgin LDPE matrix seems to be the easiest—and most efficient way—to perform this form of waste processing. It is also possible to take further steps—e.g., the re-granulation of the prepared mixture—but this leads to a rise in production costs. This research paper offers answers to the problem of the re-utilization of irradiated high density polyethylene. Other materials are under research today, with the aim of making a general statement on the utilization of products made from irradiated polymers. The idea presented herein is very simple, and could be, without need for huge investments, used in practice to transform today’s unused waste into the required raw material for the production of a huge amount of useful products.


Exoskeleton devices for upper limb neurorehabilitation are one of the most exploited solutions for the recovery of lost motor functions. By providing weight support, passively compensated exoskeletons allow patients to experience upper limb training. Transparency is a desirable feature of exoskeletons that describes how the device alters free movements or interferes with spontaneous muscle patterns. A pilot study on healthy subjects was conducted to evaluate the feasibility of assessing transparency in the framework of muscle synergies. For such purpose, the LIGHTarm exoskeleton prototype was used. LIGHTarm provides gravity support to the upper limb during the execution of movements in the tridimensional workspace. Surface electromyography was acquired during the execution of three daily life movements  in three different conditions: free movement, exoskeleton-assisted (without gravity compensation), and exoskeleton-assisted (with gravity compensation) on healthy people. Preliminary results suggest that the muscle synergy framework may provide valuable assessment of user transparency and weight support features of devices aimed at rehabilitation. About 15 millions of people experience a stroke every year worldwide –4. ThereOne of the main advantages of exoskeleton devices is the possibility to move freely in the workspace and, at the same time, to allow reaching and manipulating objects with the hand. Some studies underlined the importance of exploration of the workspace as a key factor for functional recovery . For thiT that a human must apply to the robotic joint in order to perform a user-driven movement. Perfect backdrivability is achieved if T = 0 in all conditions [Besides gravity support, another desired feature for exoskeletons is transparency, or backdrivability. The backdriving torque can be defined as the amount of torque nditions ; in suchnditions , 20, 21.nditions . Howevernditions –25.The framework analysis based on muscle synergies might be a valuable tool for investigating how, and at which extent, the device alters motor modules and affects transparency. Muscle synergies are defined as a spatial-coordinated recruitment of a group of muscles elicited by a shared neural command or specific activation waveforms . The musMuscle synergies have been widely employed in studies on healthy people to investigate motor control during ADL such as upper-limb reaching or walking –31. WhilIn previous works, the LIGHTarm exoskeleton device was presented  and charThree healthy subjects were enrolled in this study . SubjectThe LIGHTarm device  consistsThe experimenters measured subjects' anthropometry of the arm and the forearm and tuned the LIGHTarm so that the shoulder and the elbow of the subjects were aligned with the exoskeleton joints. Then, a proper counterweight was added so that the weight of the device (without limb) was compensated. In this way, the weight of the links anterior to the parallelogram did not influence the execution of movements. After the tuning procedure, the subject was fastened with the strap pads. The arm compensation was chosen as the amount of weight required to maintain the arm raised in the position depicted in EMG signals were recorded at a sample frequency = 1000 Hz, with an 8-channel EMG acquisition system  to evaluate muscular activation patterns of the following muscles: deltoids anterior, middle, and posterior, upper trapezius, pectoralis major, triceps lateral head, biceps brachii caput longum, and brachioradialis of the right limb. Such muscles were chosen since they are mainly involved in upper limb tasks with focus on exploration of the workspace.Kinematics of the right limb was recorded with a 6-TVC marker-based motion capture system . Markers were positioned on C7 and D5 vertebras, acromion, right epicondyle of the elbow, and styloid process of the ulna . The elbReaching against gravity RCH, : from thHand-to-mouth HTM, : from thHand-to-nape HTN, : from thThe tasks selected to evaluate the LIGHTarm were functional movements usually performed in everyday life. The starting position was the same for every movement; the subject was seated on a chair with the hand lying on a cushion positioned on the thigh. The subject performed 12 repetitions of each task at a self-selected speed without pauses between one repetition and the following. The three movements proposed are listed below:The three tasks were executed in three different conditions: free movement without the exoskeleton (free), with the exoskeleton without arm weight compensation (not compensated), and with the exoskeleton with arm weight compensation (compensated).EMG and kinematic data were recorded during each set of 12 repetitions. Then, the first and the last movements were discarded, and only the forward phase of each repetition was considered for synergy extraction. Movement phases were detected through kinematic analysis, applying an automatic phase detector algorithm based on the velocity of vertical coordinate of the wrist marker as a reference for RCH and HTM movements and on the velocity of vertical coordinate of the elbow marker as a reference for the HTN movement. If the elbow marker tracking was not available due to exoskeleton obstruction, the lost frames were reconstructed through the four-marker cluster. Data from retroreflective markers were filtered with a low-pass, 3rd-order Butterworth filter, with cut-off frequency set at 6 Hz.wi), and the second one representing time-variant activation commands for each synergy (ci) [t) represents the EMG data at time t and N is the total number of extracted synergies.EMG signals of the eight muscles in the forward phase were filtered (high-pass filtering (50 Hz), full-wave rectification, FIR low-pass filtering (cut-off frequency = 20 Hz) ) in obtargy (ci) , as in tThe procedure of synergy extraction was performed by pooling together the EMG envelope matrix of each acquisition, including ten repetitions of the motor task for each experimental condition (3 subjects × 3 motor tasks).r was chosen increasingly from 1 to 8 . For each r, the NMF algorithm was applied 100 times in order to avoid local minima, and the repetition accounting for the higher variance of the signal was chosen as the representative of order r. The number of synergies was chosen as the minimum r explaining at least 0.75 of the total variance of the signal [The order of the factorization e signal .For representation purposes, authors ordered synergy datasets by matching synergies that have a similar functional role within a specific gesture. For such reasons, synergy datasets were matched at best by considering the Pearson correlation coefficient of the temporal components. After the matching procedure, extracted synergies are naturally matched so that they are at best comparable between experimental conditions.Then, the dataset of extracted spatial synergies was split into three subdatasets: the first one comprehended the synergies extracted from free movements, the second one including synergies extracted from noncompensated assisted movements, and the third one including compensated movements. A k-means cluster analysis was conducted on each of the three datasets, to identify mean spatial synergies (centroids) for each of the experimental conditions. The order of each clustering was selected by considering a tradeoff between accuracy and synthesis, pondering indexes related to clustering quality such as silhouette and Euclidean distance of synergies from their reference centroid. Finally, each temporal component was coupled to its mean spatial synergy.user transparency is here introduced. User transparency may be defined as the alteration of motor modules (here modelled as muscle synergies) due to the interaction with an exoskeleton. Alterations may be due to device encumbrance, singular configurations, mechanical locks or couplings, or weight support features. In this paper, it is proposed that user transparency can be assessed in the framework of muscle synergies. For a device that is aimed at producing weight support, transparency may be “decomposed” into two main contributions. At first, a desirable transparency term is related to weight support. As a consequence of LIGHTarm support, the magnitude of temporal components should be reduced, because of the less effort needed to elevate the limb. A second term, instead, deals with the modifications of the spatial synergy composition. It investigates how the motor modules are modified due to the interaction with the device. Since the weight support action should not alter the spatial composition of motor modules underlying movement, preservation of muscle patterns in assisted movements in respect to free ones is considered as an index of the effect of the exoskeleton to preserve unaltered physiological patterns and not interfere with spontaneous EMG activity.While several definitions of transparency are given in the literature , 25, forIn summary, coordinated muscle patterns can be evaluated by considering the difference in the composition of spatial muscle synergies, while weight support features can be analyzed by considering the magnitude of the temporal component associated to each synergy.Mean spatial synergy similarity, investigating if LIGHTarm alters muscle patterns during dynamic motion.Weight support features, investigating if LIGHTarm is effectively reducing the magnitude of the temporal components related to spatial synergies.Consequently, in this work, the evaluation of user transparency is split into two components:In order to quantify pattern alteration, the similarity of mean spatial synergies is considered. The metrics chosen for detecting similarity among mean spatial synergies (centroids) were the dot product, which was already used in previous studies as an indicator of synergy similarity –41. A hiFor the evaluation of the weight support features, the integral of each mean temporal component (mtc) was calculated as a representative of the magnitude of the activation of each spatial synergy. A reduction in the integral value is evidence of less muscular effort needed to perform the movement. The mtc were calculated for each mean temporal component as follows:Spatial synergy compositions, matched by correlation of temporal components, for each of the considered tasks and subjects, are shown in Mean spatial synergies, computed with the clustering k-means algorithm, are shown in Pairwise dot products relative to mean spatial synergy compositions are shown in Dot products between free, not compensated, and compensated movements are always >0.80 for all the pairwise matched mean spatial synergies, indicating that the basic muscle patterns underlying movements are not consistently altered. All the values found are above the range of baseline dot products identified in previous studies in the literature to quantify similarity , and theFor each mean spatial synergy, the higher mtc value is found in free movements . The mtc in movements performed with LIGHTarm in not compensated set-up indicate that there is a tendency toward a slight reduction of muscle activity. When LIGHTarm was used in the compensated set-up, the mtc decreases consistently.A detailed review of the insights provided by muscle synergies for the assessment of user transparency is presented in the following sections.In comparison to traditional methods for EMG analysis, muscle synergies capture spatial and temporal features that are shared by groups of coactivating muscles, which, according to this framework, are controlled as groups rather than autonomous entities. Consequently, the muscle synergy approach is particularly suited for evaluating pattern alterations induced at the neural level when interacting with a device.Referring to In fact, loss of transparency might be observed in the emergency of new motor modules (centroid 4). While the main modules are in general preserved, all subjects had to rely on some trials on an additional synergy, characterized by abnormal triceps activation. This result can be interpreted in an excessive gravity compensation imposed on the upper limb, as at the end of the range of motion the device was still providing support on the arm, slightly pushing it upwards. Probably, this effect induced triceps compensation, needed to slow the shoulder flexion effect exerted by the exoskeleton. These observations might be valuable for further tuning of the device or for its partial redesign.While the sample of subjects is too low for proposing statistical analysis for the specific case of LIGHTarm, the explained methodology proposes valuable insights on muscle coordination while interacting with a device and may help in deducing if a generic exoskeleton may induce modifications to the motor modules underlying movement. In hypothesizing to have a wider sample of subjects, the muscle synergy analysis might provide such valuable insights with statistical confirmation—or denial—of the results.For a device like LIGHTarm which is aimed at supporting the weight of the limb, the weight support features are a needed “loss of transparency”; the magnitude of temporal components should be reduced to allow elevating the limb against gravity with less effort. Weight support features can be evaluated by considering the magnitude of the activation profile of each synergy. In the muscle synergy framework, the reduction of magnitude of a module is seen as the reduction of activity of a whole set of muscles responsible for a specific kinematic movement. In case of a decrease of the temporal component integrals, the device is inducing an effect of reduced effort, allowing the subject to elevate the arm with less EMG activity. In the specific case of LIGHTarm, a reduced magnitude is always shown between the not compensated and the compensated configurations. A magnitude difference can also be noticed between the free and not compensated configurations, with decrement of the integral values in most of the trials. Despite the counterweight was specifically set only for the compensation of the weight of the exoskeleton, wearing the device induced an effect on the amount of muscle activation needed to complete the movements. This could be interpreted with a nonhomogenous support in the workspace, with a slight overcompensation of the shoulder when over 90° of shoulder flexion as seen in the RCH and HTN and a little resistance contribution in the lower part of the workspace that require more muscle activation to achieve the target, as seen in HTM.All the reported results are preliminary and, due to the low number of subjects, are not statistically significant. However, they show how the muscle synergy framework might be valuable for assessing the weight support features of an exoskeleton device.As proposed in many papers , 23, traThis study has several limitations. At first, the number of enrolled subjects is low and does not allow providing statistical conclusions over LIGHTarm transparency. However, several aspects that might be observed in the framework of muscle synergies have been considered, and their applicability to other devices has been discussed. Furthermore, authors acknowledge that many features of muscle synergies could be examined in more detail. A study design including a comprehensive exploration of the workspace would elicit a higher variety of motor modules, allowing a detailed mapping of motor module alterations. This would allow providing a more refined mapping of the repertoire of upper limb motor modules when in interaction with the device, rather than simple, task-specific patterns.Lastly, a new, refined version of LIGHTarm is about to be released and will be tested in future studies, including a larger number of subjects.In this work, the concept of transparency was assessed in relation to the interaction with passive exoskeleton devices for rehabilitation. Preliminary assessments were proposed, suggesting the potential of the muscle synergy-based approach for the evaluation of transparency. Such method might lead to the definition of the alteration induced by the device and its weight support features.


Over the past few years, there has been an increasing demand for stretchable electrodes for flexible and soft electronic devices. An electrode in such devices requires special functionalities to be twisted, bent, stretched, and deformed into variable shapes and also will need to have the capacity to be restored to the original state. In this study, we report uni- or bi-axially wrinkled graphene–silver nanowire hybrid electrodes comprised of chemical vapor deposition (CVD)-grown graphene and silver nanowires. A CVD-grown graphene on a Cu-foil was transferred onto a bi-axially pre-strained elastomer substrate and silver nanowires were sprayed on the transferred graphene surface. The pre-strained film was relaxed uni-(or bi-)axially to produce a wrinkled structure. The bi-axially wrinkled graphene and silver nanowires hybrid electrodes were very suitable for high actuating performance of electro-active dielectric elastomers compared with the wrinkle-free case. Present results show that the optical transparency of the highly stretchable electrode can be successfully tuned by modulating input voltages. Smart windows, which can control the level of light transmission, have recently been attracting great interest, because they can be applied to a variety of applications, including vehicle windows, exterior wall windows and skylight windows. Until now, most smart window technology has been based on the redox reaction of a molecular element and a chromic material in response to external stimuli such as light, electricity, or temperature ,2,3,4. HAmong various approaches to smart window technology, there has been recent interest in techniques for modulating transmittance by changing the surface morphology of an elastomer actuator. In order to generate such a morphological change of soft materials, a flexible and stretchable conducting material should be used as compliant electrodes, which can be stretched or shrunk according to the movement of the soft material, such as nanowires, graphene, and hybrid materials ,10,11,12However, since most devices were operated with flat electrodes, the changes in transmittance were not so large, resulting in a limited application. In order to resolve this performance problem, research on smart windows using graphene and silver nanowire hybrid electrodes has been carried out, but a wrinkled structure implemented with stretchable hybrid materials has not been reported yet.In this study, we developed a wrinkled hybrid electrode, comprised of CVD-grown graphene and silver nanowires, and reported a tunable transmittance by applying electrical fields to the dielectric elastomer actuators sandwiched with the wrinkled graphene–silver nanowire hybrid electrodes. A monolayer of graphene grown by CVD on a Cu-foil was transferred onto a bi-axially pre-strained elastomer substrate and silver nanowires were sprayed on the transferred graphene surface. The pre-strained film was released bi-(or uni-)axially to develop a wrinkled structure. The morphological and electrical characteristics of the wrinkled structures with bi-(or uni-)axially compressive strains were investigated using scanning electron microscopy (SEM). Also, the bi-axially wrinkled graphene and silver nanowire hybrid nanostructures were successfully applied to produce high actuating performance compared with the wrinkle-free case. Using the fabricated electrode, we demonstrated a device whose optical transparency was tunable with input voltages.3. The dielectric constant of the VHB 4905 film is 3.21 at 1 kHz. The dissipation factor and dielectric breakdown strength are 0.0214 and 630 V/mm, respectively [VHB 4905 film  is an appropriate material for dielectric elastomer actuators because the film is easy to handle, and both sides of the film are sticky enough for coating with electrode materials such as graphene and silver nanowires. In addition, the VHB 4905 is almost transparent, with a thickness of around 5 mm and a density of 960 kg/mectively ,19.Silver nanowires (AgNWs) are nanostructures, generally with a diameter of ten to several hundred nanometers and lengths of tens of microns. Silver nanowire material is a kind of grayish powder and is often dispersed in solvents, such as water, ethanol, and isopropanol . The silThe fabrication process of the graphene and silver nanowire hybrid electrode with a wrinkled structure is illustrated in The first step is the transfer of the CVD-grown graphene onto the surface of the pre-stretched elastomer film. In this step, the copper layer is removed using a wet-etching process to allow the graphene transfer. In order to maintain electrical conductivity between the graphene islands on the elastomer surface, silver nanowires were sprayed on the wrinkled graphene surface. Then, the pre-stretched elastomer film was released, to prepare a hybrid electrode with a wrinkled structure. In order to fabricate a dielectric elastomer actuator with a wrinkled structure, the electrode formation method described above was also applied to the opposite side of the elastomer. Using this method, a wrinkled elastomer actuator whose light transmittance could be controlled was manufactured.To induce the electro-mechanical deformation of the dielectric elastomer actuator, a high input voltage over 1 kV needs to be applied to both electrodes. For this purpose, a high voltage power supply  was connected to both the top and bottom electrodes of the actuator. To connect each compliant electrode to a cable from the power supply, conductive copper tape was used instead of the conventional cable-wires. Actuation testing was performed on an experiment table, and video data was acquired using a complementary metal-oxide-semiconductor (CMOS) image sensor to show the areal expansion of the actuator. To observe the variation in optical transmittance under actuating conditions, we placed the fabricated actuator on the sample holder of a UV-VIS spectroscopy. The optical transmittance was then examined, as input voltages were applied to the actuator.In The working principle of the elastomer actuator is based on an attraction force which is generated between the two electrodes. This force causes an expansion of the electrode area in the in-plane direction. In order to examine the change of the surface in the multilayered elastomer-electrodes according to the pulling forces in the in-plane direction, the surface morphology was examined under tensile conditions, as shown in R/R0) remains stable in the initial section, and as the strain value is increased, the magnitude of the relative resistance value is changed sharply. These results can be explained based on the wrinkled structure of the electrode. As shown in The relative resistance of the electrodes was examined in order to investigate the influence of the wrinkling morphology. Three types of specimens with different compressive strain values were prepared for this experiment. The compressive strain values applied to the specimens were 20%, 33% and 42%, respectively. As shown in The dielectric elastomer actuator has a sandwich structure consisting of an elastomer film with two electrodes on both sides. For application, the elastomer film was fixed in a rigid frame made of polyacetal. A/A0) of 33%. Within 4 kV, the areal change of the actuator is almost similar in both cases, but there is a remarkable maximum difference of about 6% at 6 kV.In order to verify the operating performance of the actuator, we connected the electrode of the actuator to a DC high voltage supply capable of generating 0–10 kV. Then, the applied voltage was gradually increased from 0 to 6 kV, and the change in the area of the actuator was examined. For more precise performance analysis, it is essential to determine the area of the increased actuator under electrical stimuli. For this purpose, the moving images of the actuator were captured frame-by-frame, and analyzed using an image processing program. The actuation of conventional dielectric elastomer actuators using a high input-voltage caused the electrodes to expand with an isotropic areal strain as shown in As the applied voltage increases, the strength of the interaction force in the thickness direction increases in the elastomer actuator. This force has the effect of reducing the thickness of the film and increasing the area of the electrode. At this time, the transmittance of the active area is increased due to the reduced thickness of the film and the change in surface morphology on the surface of the elastomer film. Using the same method as that used for the wrinkle-free sample, the change in active area of the dielectric elastomer actuator with wrinkled graphene–AgNWs hybrid electrodes was measured with respect to the applied voltages. Then, the transmittance change according to area changes was also examined. The wrinkled electrode structure exhibited about a 33% change in area ratio, and a transmittance change of about 15%. That is, although the wrinkled structure showed the same area change rate, it can be confirmed that the transmittance was about twice as large as that in the case of the wrinkle-free sample. When compared with the structure without wrinkles, the cause of this phenomenon is understood to be the difference in transmittance due to the scattering of light.A novel dielectric elastomer actuator with wrinkled graphene and silver nanowire hybrid electrodes was developed in this study. Graphene and silver nanowires were used to realize the highly conductive and compliant electrodes. The developed dielectric elastomer actuator with the wrinkled surfaces exhibited a large in-plane deformation of up to 33%. As compared with wrinkle-free electrodes, the proposed actuator with wrinkled electrodes exhibited a 10% higher areal change rate because of the synergistic effect of the ultrahigh conductivity of the silver nanowires and the remaining capacitance of the graphene under large deformation. This novel elastomer actuator with wrinkled hybrid electrodes may be a candidate to tune the transmittance of a smart window system.


Gait festination is one of the most characteristic gait disturbances in patients with Parkinson’s disease or atypical parkinsonism. Although festination is common and disabling, it has received little attention in the literature, and different definitions exist. Here, we argue that there are actually two phenotypes of festination. The first phenotype entails a primary locomotion disturbance, due to the so-called sequence effect: a progressive shortening of step length, accompanied by a compensatory increase in cadence. This phenotype strongly relates to freezing of gait with alternating trembling of the leg. The second phenotype results from a postural control problem (forward leaning of the trunk) combined with a balance control deficit . In this viewpoint, we elaborate on the possible pathophysiological substrate of these two phenotypes of festination and discuss their management in daily clinical practice.The online version of this article (10.1007/s00415-018-9146-7) contains supplementary material, which is available to authorized users. The propensity to lean forward becomes invincible, and the patient is thereby forced to step on the toes and fore part of the feet, whilst the upper part of the body is thrown so far forward as to render it difficult to avoid falling on the face. In some cases, when this state of malady is attained, the patient can no longer exercise himself by walking in his unusual manner, but is thrown on the toes and forepart of the feet; being, at the same time, irresistibly impelled to make much quicker and short steps, and thereby to adopt unwillingly a running pace. In some case it is found necessary entirely to substitute running for walking; since otherwise the patient, on proceeding only a very few paces, would inevitably fall’ [Gait festination is among the most characteristic gait disturbances in patients with Parkinson’s disease (PD) or atypical parkinsonism . Festinaly fall’ .Gait festination is common , and oftfestinare which means to hasten. Over the years, several—partly overlapping—definitions of festination have been proposed. Giladi and co-workers described festination as ‘rapid, small steps, done in an attempt to keep the centre of gravity in between the feet while the trunk leans forward involuntarily and shift the centre of gravity forward’ [The term festination is derived from the Latin word forward’ . In contforward’ .Here, we argue that there is not one, but actually two basic phenotypes of festination Fig. . ImportaThe second phenotype is not a primary locomotion disturbance, but represents a secondary phenomenon, resulting from a combined postural deficit (forward leaning of the trunk) and a balance control deficit . When there is severe forward leaning of the trunk, the centre of gravity will be located in front of the feet, and the patient will fall forward if no compensatory balance-correcting steps are made . In patiThis second phenotype can be seen when observing the response to the retropulsion test: the balance-correcting steps are too small to restore the centre of gravity within the base of support, and patients would continue to step backward if they would not be caught by the examiner . This noFestination is not restricted to gait, and can also be observed during upper and lower limb tapping tasks , 18, or We next elaborate on the possible pathophysiological substrates. The first phenotype of festination is due to progressive shortening steps and acceleration of step frequency. This has been related to defective cue production by the basal ganglia . The basThe second phenotype is the result of combined forward leaning of the trunk and small balance-correcting steps. Forward leaning of the trunk (a stooped posture) is common in parkinsonism, but the degree of anterior flexion of the thoracolumbar spine varies considerably across patients, ranging from a relatively mild stooped posture to pronounced forward bending, which is termed camptocormia . CamptocA relatively mild stooped posture is presumably directly related to nigrostriatal degeneration, as it is often one of the first presenting signs in PD. On the other hand, previous studies failed to identify one single pathological process for camptocormia . The patBecause the first phenotype of festination is so closely related to freezing of gait, we recommend applying the management guidelines for freezing of gait here. A recent viewpoint on the management of freezing  recommenFor the second phenotype, treatment should primarily target the underlying postural control deficits and balance impairment, and not the locomotion disturbance. A mildly stooped posture usually responds to some degree to treatment with levodopa , whereasImportantly, all of these management options are based on personal experience and extrapolation from the field of freezing of gait. Having a clearer definition of festination now opens the possibility for further testing of therapeutic options for festination in better-defined populations.In this viewpoint, we have introduced a framework for the presence of two phenotypes of festination. This framework may explain several findings and discrepancies that were observed in previous studies on festination , 20. HowBelow is the link to the electronic supplementary material.Video 1 First phenotype of festination (example 1) in a patient with Parkinson’s disease (MP4 20140 KB)Video 2 First phenotype of festination (example 3) in a patient with Parkinson’s disease (MP4 7846 KB)Video 3 Second phenotype of festination in a patient with Parkinson’s disease (WMV 1310 KB)


In radiotherapy, cancer stem cells (CSCs) are well recognized as one of the radioresistant cell types. Even in a small subpopulation, CSCs may have an influence on tumor control probability, represented by cell killing after irradiation. However, the relationship between the percentage content of CSCs and the cell survival dose–response curve has not yet been quantitatively clarified. In this study, we developed a cell-killing model for two cell populations (CSCs and progeny cells) to predict the surviving fractions, and compared it with the conventional linear–quadratic (LQ) model. Three prostate cancer cell lines  were exposed to X-rays at doses ranging from 0 to 10 Gy. After the irradiation, we performed clonogenic survival assays to generate the cell survival curves, and carried out flow-cytometric analyses to estimate the percentage content of CSCs for each cell line. The cell survival curves for DU145 cells and PC3 cells seemed not to follow the conventional LQ model in the high dose range (>8 Gy). However, the outputs of the developed model agreed better with the experimental cell survival curves than those of the LQ model. The percentage content of CSCs predicted by the developed model was almost coincident with the measured percentage content for both DU145 cells and PC3 cells. The experiments and model analyses indicate that a small subpopulation of radioresistant CSCs has lower radiosensitivity in the high-dose range, which may lessen the clinical outcome for patients with prostate cancer after high-dose radiation therapy. In the application of radiotherapy, such as intensity-modulated radiation therapy, cancer cells with radioresistance can allow relapse or distant metastasis, and a poor prognosis , 2. A smin vitro experiments. So, a biologically mechanistic cell-killing model adaptable for radiotherapy is necessary for providing an analysis tool for CSCs in radiation biology and for precision of tumour control probability in radiation therapy.The linear–quadratic (LQ) model, which quantitatively describes the relationship between absorbed dose and fraction of cells surviving, is widely used for determining the treatment planning in multifractionated radiotherapy . Althougin vitro experiments, the clonogenicity of the three types of prostate cancer (PCa) cell lines  after exposure to the high dose of 10 Gy exhibited lower radiosensitivity than predicted for low-dose cell survival by using the LQ model . Due to the unexpected radioresistance in the high dose range, the accuracy of fitting the model predictions to experimental data is sometimes poor. Regarding recent reports on the CSCs  and D2 [Gy2], respectively, which represent the target activation probabilities for the cells hit by the radiation releasing cell-killing signals [ST is the surviving fraction for the DNA-TEs, which is given by Eq. For the LNCaP cells, there was a large discrepancy between the model results and the experimental results. Focusing on the comparison of the CSC fractions, the dominant factor to induce the sigmoid curve might not be the existence of a subpopulation of CSCs. So here we added the IMK model analysis in consideration of both the DNA-TEs and the non-targeted effects (NTEs), because of higher radiosensitivity in the low dose range <4 Gy. The cell survival formula for the NTEs according to the IMK model  is given signals . Thus, tThe previous study showed that prostatospheres with a high level of CD133 expression have a highly efficient DNA repair function and resistance to damage induction by reactive oxygen species (ROS) . The ROSIn this study, the model prediction Fig.  shows thin vitro experiments and the IMK model study provide a more precise dose–response curve as a function of absorbed dose and the contents of CSCs. The CSC marker might be useful as one indicator to quantify the degree of modification of the cell survival curve and the BED for PCs and CSCs, and treatment planning in radiotherapy can be improved by using the developed cell-killing model, which takes the CSC fraction into account. The findings in this study contribute to an increased understanding of the relationship between the fraction of CSCs and radioresistance in radiation therapy for prostate cancer.In conclusion, the


To use and test a new method of inducing endogenously generated pupillary oscillations (POs) in patients with unilateral optic neuritis (ON), to describe a signal analysis approach quantifying pupil activity and to evaluate the extent to which POs permit to discriminate patients from control participants.Pupil size was recorded with an eye-tracker and converted in real time to modulate the luminance of a stimulus (a 20° disk) presented in front of participants. With this biofeedback setting, an increasing pupil size transforms into a high luminance, entraining a pupil constriction that in turn decreases the stimulus luminance, and so on, resulting in endogenously generated POs. POs were recorded for 30 seconds in the affected eye, in the fellow eye and in binocular conditions with 22 patients having a history of unilateral ON within a period of 5 years, and with 22 control participants. Different signal analysis methods were used to quantify the power and frequency of POs.On average, pupil size oscillated at around 1 Hz. The amplitude of POs appears not to be a reliable marker of ON. In contrast, the frequency of POs was significantly lower, and was more variable over time, in the patients’ affected eye, as compared to their fellow eye and to the binocular condition. No such differences were found in control participants. Receiver operating characteristic analyses based on the frequency and the variability of POs to classify patients and control participants gave an area under the curve of 0.82, a sensitivity of 82% (95%CI: 60%-95%) and a specificity of 77% (95%CI: 55%-92%).The new method used to induce POs allowed characterizing the visual afferent pathway defect in ON patients with encouraging accuracy. The method was fast, easy to use, only requiring that participants look ahead, and allows testing many stimulus parameters . The pupil regulating the quantity of light entering the eyes is controlled by dedicated circuits. Pupil constriction is mediated the parasympathetic pathway which originates from melanopsin-containing, intrinsically photosensitive, retinal ganglion cells (ipRGCs), a special class of RGC that do not project to the LGN but to the pretectal olivary nucleus (PON). Neurons from the PON project to the Edinger–Westphal nucleus (EW) that then innervate the ciliary ganglions driving the sphincter muscle that constricts the iris. –5 Pupil Pupillary responses have long been studied to determine the extent to which they provide reliable markers of optic neuropathies and retinopathies. AbnormalAnother approach developed by Miller and Thomson investigated the characteristics of the pupil cycle time (PCT) to seek whether it provides a quantitative marker of ON.,19 In thMeasuring the peak-to-peak time between oscillations revealed that the PCT is stable, repeatable and is significantly longer for patients with ON. Although Miller and Thompson,19 and fPCT measures require a good practice to master the slit-lamp positioning, and any eye or head movement of the participant may disrupt the pupil cycling,The slit-lamp stimulus can only be easily applied to the iris margin; hence, it cannot be used to test specific foveal or other retinal regions, or to investigate different stimulus characteristics ,Recording pupil activity allows quantitative off-line analyses to characterize the time and variability of pupil oscillations. The development of graphics displays and of video based eye-tracking devices open the way to a thorough characterization of pupil activity over time. Recording pupil oscillations with an eye-tracker permit off-line analyses to compute many variables , and to remove blinks or saccade that could alter pupil activity. Importantly, it also permits simultaneous measures both pupils.In the clinic, pupil reactivity to light (PLR) and the relative afferent pupillary reflex (RAPD) are used to detect lesions of the optic nerve with standardized available devices. The RAPD allows detecting asymmetrical amplitude of pupil constriction in response to alternating light stimulation of each eye, only allowing intra-individual assessment of pupil reactivity, and being useless whenever both optic nerves are symmetrically affected. Here, we present a simple and novel method to induce endogenous pupil oscillations (POs) that avoids some of the above-mentioned caveats, and allows comparing the two eyes of the patients and comparison between patients and control subjects.As the size of the pupil recorded by the eye-tracker varies as a function of the eye-camera settings  and as the amplitude of pupil responses is known to be influenced by cognitive factors,9; we foIn the following, we first describe the principle of our method; we then present the results obtained on a population of 22 patients with a history of unilateral ON, and 22 matched control subjects. Using a signal analysis approach to compute pupil data, we show that the power of POs is not as reliable as the frequency of pupil oscillation to detect defects in the afferent pathway of the affected eye of patient with ON, and that this variable is a behavioral biomarker of ON.The method, illustrated in In this situation, an increasing pupil size induces an increase of the stimulus luminance, which in turn entrains a constriction of the pupil, hence producing a luminance decrease, and so on. As pupil size and display luminance are coupled in real-time through biofeedback , the pupil enters a sustained oscillatory activity characterized by its amplitude and its frequency. As oscillatory patterns are best analyzed in the frequency domain using a Fast Fourier Transform (FFT) or other signal analysis methods, we refer in the following to Pupil Oscillation Frequency (POF). In line with previous authors, we propTwenty-two patients  from a neurological clinic with a history of unilateral demyelinating ON within a 5 year-period participated in the study  differences. We expect that in the patient group, the POs of the affected eye will be lower than in their fellow eye, and that the affected eye of the patients will be lower than the paired eye of the control participants.Declaration of Helsinki. Informed consent was obtained from the participants after explanation of the nature and possible consequences of the study which had been approved by the ethic committee of the “CPP Ile-de-France VI, Groupe hospitalier Pitié-Salpêtrière”. This study was registered at http://www.clinicaltrials.gov (identifier: NCT02004054 and NCT02894281)This study follows the tenets of the 2), 3 seconds with maximum luminance (90 cd/m2), 3 seconds with a medium luminance (45 cd/m2); we then used these values to z-normalized the pupil size.The stimuli were displayed on a 22 inch monitor  viewed from a distance of 67cm. The stimulus consisted of a 20° diameter disk displayed on an otherwise black screen. Eye data were sampled at 250 Hz  by an Eye-Link II eye-tracker (SR Research Ldt). A dedicated custom software (JEDA) was used for coupling pupil size and luminance, and for recording the eye-data, at the screen refresh rate . To determine the maximum and minimum pupil size of each participant, every trial started with a pupil calibration procedure: 3 seconds with the lowest luminance , followed by the induction of POs. Participants were instructed to maintain fixation on a central fixation point and to avoid blinking as much as possible. Each recording epoch (30 seconds), was separated from the next by a period of rest (~30 seconds).Ad-hoc programs were developed using Matlab  to analyze the pupil data. Blinks were automatically detected and replaced by a linear interpolation between the start and end of each blink. Each raw data file was visually checked, and missed blinks or artifacts were manually replaced by a linear interpolation. We then computed a z-normalization of each recording of each participant. As pupil oscillated smoothly over time, we computed the fundamental frequency of endogenous pupil oscillations with several methods: Fast Fourier Transform (FFT), autocorrelation and FFT of the auto-correlograms, and time-frequency analysis (Time Frequency maps using a Morlet complex wavelet m = 10). As the power spectrum follows a 1/f function with more power in the low frequency range that could conceal the PO frequency (POF), the power spectrum was flattened by multiplying the power at each frequency by the corresponding squared frequency. Based on previous results–20, we cThe pupil size measured by the eye-tracker (and thus the amplitude of the POs) depends on the eye-camera distance and orientation, which were adapted differently for each participant, introducing a source of variability between subjects. The eye-camera distance and orientation were also different between the right and left eyes of the participants introducing a source of variability between the two eyes of the same subject. Finally, between each trial, the participants could rest and remove the head from the chin-rest that could result in small changes in the eye-camera distance and orientation between two trials introducing a source of variability within the same eye. Altogether these sources of variability could overweight the difference of POF amplitude between affected eye and normal eye measured by the eye-tracker. Indeed, the variation coefficient of the PO power was about 10 times larger than that of the frequency of PO. In addition, recent studies found that the amplitude of the PLR, but not its latency, was modulated by cognitive factors (i.e. attention), suggestiThese findings suggest that the power of POs may not provide a reliable marker of ON, as was confirmed by statistical analyses, not detailed here. Accordingly, we concentrated our analyses on PO frequency in the following.Although the different methods gave similar results , the timIn the ON group, 16 trials were removed from the analyses, either because the screen luminance rose to ceiling for more than half the trial duration, indicating that the gain, G, had not been correctly set for these particular cases, or because of too many saccades and blinks. A total of 116 trials from the group of patients with ON were thus retained for the analysis. All the 132 trials from the control group were retained for the analysis.−3,−4, −4). The same differences between the affected eye, the fellow eye and in binocular conditions were found with the direct FFT and the autocorrelation methods used to identify the peak frequency; however, the importance of these differences slightly differ with the method  and lower in binocular condition (Tukey’s HSD test p = 10−4) as shown in The POF variability  curves using individual results obtained with the TF method. We first describe the results obtained with the affected and fellow eyes of ON patients , before For the patients , and usiWe then applied the same method to compute ROC curves using the affected eye of patients and the homologous “affected” eye of Control participants . When usBy coupling pupil size measured with infrared oculography to the luminance of a stimulus displayed on a standard computer screen, we could induce large and sustained pupil oscillations and test whether pupil oscillations were a reliable biomarker of Optic Neuritis. Using signal analyses to characterize the power and frequency of POs with a population of 22 patients diagnosed for unilateral ON within five years, and 22 matched control participants, we found that the frequency and variability of pupil oscillations allowed discriminating the affected and fellow eyes of patients, and patients from controls with a reasonable sensitivity and specificity. In contrast, the amplitude (or power) of POs was not a reliable index of the disease. We now discuss some of our findings in more details in the following.An intriguing finding is the differences of POF found in the monocular and binocular conditions. In all participants, the frequency of POs is higher in binocular than in monocular conditions. Moreover, in binocular conditions, the pupil data of patients is not significantly different from those of the control participants. This is surprising as one simple account of the fastest oscillations in binocular conditions, as compared to monocular conditions, is that the inputs from the two eyes are combined, which should increase the pupil drive and should speed-up the pupil response. Since the affected eye of patients shows slower POs, a simple summation process of the inputs from the two eyes should result in overall slower oscillations for patients than for control participants, which is not the case. This suggests that a simple summation of the inputs from the two eyes is not sufficient to account for the POF data in binocular conditions, and raises questions on how inputs from the 2 eyes are combined to drive the pupil.The choice to analyze the pupil data over time , rather than with direct FFT or other methods that are applied at once on the whole signal, permitted to compute the variability of the PO oscillations over time, which proved to be larger in the affected eye, as compared to the fellow eye, or to the eyes of control participant. As both the frequency and variability measures are independent and derived from a single recording, we computed a mixed index that does not rely on additional assumptions or data collection. This mixed index, based on both PO frequency and PO variability revealed greater sensitivity than PO frequency alone to discriminate patients from control participants.unilateral Optic Neuritis. Thus, the effects of drugs should be similar for both eyes, and should not affect comparisons between the affected and fellow eyes. Although drugs can differently affect pupil reactivity across patients or between patients and controls, and thus limit comparisons of absolute pupil size, adjusting the response gain for each participant, and normalizing the pupil responses permits to overcome this issue. As a general rule, a strategy relying on relative, rather than absolute, comparisons of pupil dynamics, as was done here, should not suffer from this issue. In this view, it is worth noting that our method allows using regional stimuli presented in different location of the visual field, and to compare the relative POF obtained in different conditions in a single individual. On-going work indicates that, indeed, POs can be reliably induced with smaller stimuli than those used here.It is well known that pupil reactivity to light is affected by drugs, such as benzodiazepines or is peIn addition, as pupil activity is influenced by sympathetic inputs see , the chaFurther studies are needed to improve the method, for instance to determine whether POF depends upon cognitive factors, such as attention, stress or fatigue. The method should also be tested with different pathologies  to determine its sensitivity and specificity.Moreover, whether the PO frequency depends on the Gain used to transform pupil data into luminance needs to be fully assessed as well as the effect of the stimulus color. This will be useful to determine whether the modulation of luminance can be decreased to avoid dazzling the participants or inducing photophobia, while still collecting reliable data. Preliminary tests with healthy subjects indicate that changing the Gain does not notably modify the POF, despite changes in the modulation power, indicating that the POF likely reflects the dynamics of pupil reactivity, which is specifically altered by the demyelination characteristic of ON. Moreover, repetition of POF measures in healthy subjects over several days indicated that the POF was stable over time.The present study confirmed that the retino-pupil loop reflects the dynamics of information transfer through the optic nerve, and its defects in neuropathies such as ON.–20 AlthoOverall, the present results indicate that coupling pupil size to stimulus luminance in real time provide robust data and can be employed with standard graphic displays. Although the present results only provide a proof of concept with a small group of patients with ON, this method will further be tested on population of controls and patients with different diseases, to determine whether POF is specific to ON, and to provide a reference data set against which individuals -and methods- can be compared.Routinely assessing the POF of patients could bring a useful tool to characterize the dynamics of the retino-pupil loop whose functioning relies on the retinal neural circuitry and the optic nerve. Previous studies–20,22 alS1 FigPupil Oscillation Frequency with maximum power in the 0.5–2 Hz range for the affected eye (triangles), the fellow eye (squares), and for binocular (circles) recordings, computed with three different methods: direct FFT, Auto-correlation and Time-Frequency maps for ON patients (dash lines) and for controls participants (continuous lines).(TIF)Click here for additional data file.S1 TablePupil oscillation frequency with maximum power in the 0.5-2Hz range computed with the time-frequency maps analysis.(DOCX)Click here for additional data file.S2 TableVariability of the POF was assessed as the standard deviation of the POF computed across time in the time-frequency maps analysis.(DOCX)Click here for additional data file.S1 File(XLSX)Click here for additional data file.


Phacoemulsification under local anesthesia is regarded as the major surgery for cataract treatment. Recent research has compared the pain perception between the first eye and the second eye during phacoemulsification. However, these studies have also yielded controversial findings. Consequently, we performed a systematic review and a meta-analysis to investigate the difference in the pain perception between the first and second eyes during phacoemulsification.  We searched the PubMed, EMBASE, and Cochrane CENTRAL databases for the studies published up to October 5, 2018. Prospective observational studies were included. The meta-analysis was conducted by means of random-effects model and fixed-effects model according to the heterogeneity. Evaluation of the methodological quality of studies was based on Newcastle-Ottawa Scale (NOS). P < 0.00001). The average pain scores of the first eye shortly after surgery under the topical anesthesia were also lower than those of the second eye . Conversely, anxiety scores in the first eye surgery were significantly higher than those in the second eye surgery . However, the difference of the pain scores accessed on the first postoperative day between the first and second eye surgeries  as well as cooperation grades of patients between the first and second eye surgeries  was not statistically significant.  Overall, eight studies were included in the meta-analysis. The analysis of pooled data showed that the pain scores of the first eye shortly after surgery under local anesthesia were significantly lower as compared to the second eye (WMD: 0.69; 95% CI: 0.40, 0.98;  Patients experienced more pain in the surgery of the second eye than that of the first eye, which probably related to lower anxiety before the second surgery. It suggests that we should consider preoperative intervention to reduce the perceived pain during second eye cataract surgery. Phacoemulsification with implantation of a foldable intraocular lens is a common methodology applicable in the cataract surgery as a relatively safe procedure for patients. The method can be delivered in a comfortable surgical atmosphere and induce a relatively low stress level to patients under local anesthesia.However, phacoemulsification with local anesthesia, including topical anesthesia, intracameral anesthesia, and sub-Tenon's anesthesia, among others, is not a completely pain-free procedure. Pain level is possible and differs in various stages of phacoemulsification. Additionally, most of the pain experienced during an uneventful surgery was reported when the anterior chamber was extended by irrigation , 2. In tAs far as we know, there is no meta-analysis dealing with this topic. Therefore, we carried out a systematic review and a meta-analysis to examine whether the second eye was more painful during the uneventful phacoemulsification under local anesthesia, and to determine risk factors that influence pain perception. In a case where the result has a statistical difference, surgeons can pay more attention to the patients' perception before or during the second cataract surgery to lower the risk of the complication. Such an intervention can also help to improve clinical performances and reduce health costs.We searched the database of PubMed, EMBASE, and Cochrane to obtain eligible studies published up to October 5, 2018. Taking PubMed research as an example, following groups of keywords or medical terms were used: “Phacoemulsification” OR “Phacoemulsifications” OR “Cataract Surgery” OR “Phaco Surgery”) AND  AND  between the first and the second eyes. Last, the time of accessing the pain was the day of the surgery or the first postoperative day. In the meantime, the exclusion criteria were as follows: We excluded the trials that have not assessed pain scores or that the data were not available.The information provided herein was obtained from the selected studies, in which the following aspects were taken into consideration: every study's first author, publication year, study location, mean age of patients, measurement of outcome for pain and anxiety, scores of pain and anxiety, total numbers of surgery eyes, numbers of first and second eyes, and blind method, among others. In cases of disagreements on the items, a consensus was developed through the discussion among the research groups.κ) of 98%; the differences were alleviated by use of a third investigator. Evaluation of the methodological quality of eligible comparative studies was undertaken based on Newcastle-Ottawa Scale (NOS) [Two independent investigators carried out the reviews of study titles as well as abstracts, focused on retrieving studies that meet the inclusion criteria for the full-text evaluation. Subsequently, we conducted analyses of the trials for comprehensive analysis as well as data extraction with an agreement value (le (NOS) .I2 was regarded as the evaluation of heterogeneity among studies [I2 amounted to more than 50%, we utilized the random-effects model. Otherwise, we applied the use of the fixed-effects model. We estimated the mean deviation (MD) and standard deviation (SD) from the median, range, and the size of a sample which had been estimated by the ascertained calculation methodology [We used Review Manager 5.3  to carry out statistical analysis. For continuous measurements, we used the weighted mean difference (WMD) and standard mean difference (SMD) with 95% confidence interval (CI) as the effect estimate. Moreover,  studies , followehodology . We furtThe progress of the systematic studies search has been displayed in The selected eight studies were published between 2008 and 2018 –6, 11–14P < 0.00001; I2 = 80%). The pain value was lower in patients who underwent the first eye surgery. As demonstrated excluding one study at a time, the heterogeneity is still kept at high level and overall effect showed no obvious change. Therefore, we concluded that no single study markedly affected the overall pooled prevalence estimate. Sensitivity analysis showed the consistent result  by dropping the study with quality score less than 7, which suggested the robust outcome.The meta-analysis of seven studies of comparing the pain scores assessed shortly following the phacoemulsification under the local anesthesia showed that there were statistical differences in pain values between the first and the second eyes  compared with the high heterogeneity of the comparison under the local anesthesia, which may explain the source of heterogeneity. Because the rest of three studies used different anesthesia, they could not be included into one subgroup. Sensitivity analysis also showed the consistent result  by dropping the study with quality score less than 7.We also carried out an analysis of the pain scores only under the topical anesthesia as one of the subgroups. Four of seven studies were included, which also showed a difference . Three studies compared the anxiety values between the first and the second eye surgeries . The anxiety value was lower in patients who underwent the second eye surgery. Analyses of the cooperation values of the patients graded by surgeons were also carried out and showed no difference between the first and second eyes .In two studies, pooled data of pain scores on the first postoperative day did not show a significant difference  by the Egger test.Furthermore, an assessment of the publication bias was conducted for the outcome of pain score on the day of surgery under the local anesthesia and then presented as a funnel plot . No evidOur meta-analysis showed that there was a significant difference in pain perception assessed shortly after phacoemulsification between the first and the second eye surgery, which meant that the patients felt more pain during the second eye surgery. The meta-analysis of the two studies confirmed that there was a substantial decline in anxiety values in the second eye surgery. This was likely to relate more with pain in the second eye, even if the results of three studies showed no variations in cooperation of the patients. What's more, on the first postoperative day, the meta-analysis of two studies showed that pain perception had no statistical difference between the first and second eyes.Phacoemulsification is commonly accepted as one of the best surgeries for the treatment of cataract with the benefits of small incision, minimal induced astigmatism, as well as early visual rehabilitation . The topAs reported by the first study conducted by Sharma et al., no substantial difference was observed between the first and the second eyes . SubsequThe result of present meta-analysis shows that patients have more pain in the second surgery, which is explained by the assumption that patients who have successfully undergone the first eye surgery are likely to have less anxiety and expect lower pain perception for the second eye surgery. However, few studies support the fact that less anxiety is likely to induce the analgesia rather than hyperalgesia . As suchIn the recent past, one trial on patients undergoing laser-assisted in situ keratomi (LASIK) revealed that they experience more pain during the second eye surgery . ConsideThere were numbers of hypotheses considered to explain more pain in the second eye surgery. At first, the patients that had successfully undergone the first eye surgery were more probable to feel less anxiety while paying more attention to the pain perception during the second eye surgery , 14. SecIn consideration of the factors that had an association with pain during the surgery, Tan et al. showed that female patients tended to feel more pain during cataract surgery . As wellIn our meta-analysis, we encountered some limitations. Firstly, some studies did not use blind assessment in the methodology or bilateral eyes from an individual person were not available. Moreover, the interval time between two surgeries for some studies was not clearly stated. However, those problems did not strongly influence the overall effect of meta-analysis in pain because the results were quite consistent by sensitivity analysis of dropping the study with low quality. Secondly, the pain scores on the first postoperative day as well as the anxiety scores were only obtained from two studies that were likely to suggest the low reliability of the outcome. Therefore, further investigations are needed. Thirdly, the search strategy impacted on the number of included studies, since the search language was constrained only to English, possibly contributing to languages bias. However, we made use of specific analysis methodology to screen the studies and extract data with the consensus of discussion groups, in addition to assessing the maximum likely information in the studies. These approaches were effective in minimizing the likelihood of bias, thereby contributing to achieving reliable outcomes.Summarily, our findings have clearly shown that patients perceived more pain in the second eye surgery than in the first, which is likely to be associated with various anxiety values between the first and second eye surgeries. Still, there is need for further studies to figure out the reasons for second eye surgery during phacoemulsification being more painful, so that we can take the preoperative administration to reduce the perceived pain during second eye cataract surgery.