Zea mays L.) hybrids may depend on drought intensity, duration, crop growth stage (timing), and the array of drought tolerance mechanisms present in selected hybrids. We hypothesized that corn hybrids containing DT traits would produce more consistent yields compared to non-DT hybrids in the presence of drought stress. The objective of this study was to define types of production environments where DT hybrids have a yield advantage compared to non-DT hybrids. Drought tolerant and non-DT hybrid pairs of similar maturity were planted in six site-years with different soil types, seasonal evapotranspiration (ET), and vapor pressure deficit (VPD), representing a range of macro-environments. Irrigation regimes and seeding rates were used to create several micro-environments within each macro-environment. Hybrid response to the range of macro and micro-environmental stresses were characterized in terms of water use efficiency, grain yield, and environmental index. Yield advantage of DT hybrids was positively correlated with environment ET and VPD. Drought tolerant hybrids yielded 5 to 7% more than non-DT hybrids in high and medium ET environments (>430 mm ET), corresponding to seasonal VPD greater than 1200 Pa. Environmental index analysis confirmed that DT hybrids were superior in stressful environments. Yield advantage for DT hybrids appeared as yield dropped below 10.8 Mg ha-1 and averaged as much as 0.6–1 Mg ha-1 at the low yield range. Hybrids with DT technology can offer a degree of buffering against drought stress by minimizing yield reduction, but also maintaining a comparable yield potential in high yielding environments. Further studies should focus on the physiological mechanisms presented in the commercially available corn drought tolerant hybrids.The potential benefit of drought-tolerant (DT) corn ( Zea mays L.) production for several reasons  and Syngenta ArtesianTM , both promoted as achieving drought tolerance through traditional breeding. The third drought tolerant technology is Monsanto’s GenuityTM DroughtGardTM , promoted as conferring drought tolerance through both traditional plant breeding and the introduction of a transgenic trait. The transgenic trait results in the expression of bacterial cold shock protein B (Seed companies have begun to release corn hybrids classified as drought-tolerant (DT) to provide protection from occasional drought stress in areas where corn has traditionally been grown and to enhance the viability of corn in areas prone to drought stress. Three corn hybrid technologies currently being marketed for DT include Pioneer Optimum AQUAmaxrotein B . Cold shrotein B . A numbeDetermining if there are environments that favor DT hybrids and if DT hybrids are more or less sensitive to plant density would be critical information for the placement and management of these hybrids for the greatest benefit. Questions remain regarding how best to utilize these DT hybrids. The first question regards the yield potential of DT hybrids relative to non-DT hybrids. This is especially important for fields that have variable yield potential within a year or from year to year. Knowing the yield potential of DT hybrids relative to non-DT hybrids in favorable yield conditions would be critical information for growers to have when selecting hybrids. If growers know they are giving up yield potential to gain tolerance to occasional drought, they would have to weigh the benefits and risks when selecting hybrids. If there is no difference in yield potential between the DT and non-DT hybrids, then selection of hybrids would be simplified. This leads to a second question: How do yields of DT hybrids compare to non-DT hybrids in environments with different yield potential? Determining if there are environments that favor DT hybrids is critical information for the proper placement of DT hybrids to realize the greatest benefit from this genetic technology. A third question arises regarding the relative WUE of DT and non-DT hybrids. This information would help better understand why DT hybrids may have an advantage in certain environments.Additional analysis of the existing information about yields of DT and non-DT hybrids can improve our understanding of their behavior at varying yield levels. Table 1) and seeding rates (SRs) were used to create different levels of stress within each macro-environment.Drought tolerant and non-DT hybrid pairs of similar maturity were planted in locations that varied in soil characteristics and seasonal ET to generate a range of macro-environments differing in the likelihood and severity of drought stress. Irrigation (IRRI) regimes  and North Central Experiment Field at Scandia  in 2012 and 2013; Southwest Research Center at Tribune , and South Central Experiment Field, Hutchinson  in 2013. The sites were selected based on the total amount of precipitation and variation in crop ET. Further details related to site differences are presented in -1 in 12,350 increments. Experiments at Topeka, Hutchinson, and Tribune were planted at the four SRs, and stand counts confirmed that final stands were within 95% of the target plant density (data not shown). The experiments at Scandia were planted at a uniformly high density and thinned to three plant densities in 2012  due to space constraints and all four densities in 2013.Two pairs of DT and non-DT hybrids, with similar maturity, were selected as considered being well adapted at each site. At Topeka and Scandia sites the hybrid pairs used in 2012 were Pioneer  P1151 Aquamax  and P1162 , and P1498 Aquamax  and P33D49 . In 2013 at Hutchinson and Topeka sites, the hybrid pairs were Pioneer P1151 Aquamax and P0987  and DeKalb  DKC63-55 DroughtGard  and DKC63-84 , and at Tribune and Scandia, the hybrid pairs were Pioneer P1151 Aquamax and P0987 and DeKalb DKC62-26 DroughtGard  and DKC63-07 . The sub-plots in all experiments were 3 m wide by 10–14 m long in four 0.76 m wide rows at four SRs varying from 61,750 to 98,800 seed haDiabrotica species), and European corn borer, Ostrinia nubilalis (Hubner) utilizing the respective Bt genes. Fungicide applications were not needed because disease severity did not reach economic thresholds for application.The fertility was maintained at optimum for each location, and pre- and post-emerge herbicides were applied at recommended rates to eliminate any confounding factors caused by weeds. All hybrids were protected against corn rootworm  with a split plot treatment structure. IRRI regime was the whole plot, and combinations of hybrid and SR were allocated to the sub-plots. There were three or four replications of all treatment combinations at each site. The macro-environment at Hutchinson in 2013 differed in that IRRI was not a randomized treatment effect, but was simply another environment containing the four replications of all combinations of hybrid and SR. Due to the difference in the design of the study, the data from Hutchinson was not combined with data from another site with similar ET, but analyzed and presented separately. For terminology purposes, the term micro-environment will refer to sub-plot, primarily based on the SR by hybrid combination, at each specific IRRI level within each site.Soil moisture was measured to the effective rooting depth at three macro-environments: Scandia  ; and Trin = 3 or 4). Yield advantage of the DT hybrid in a given micro-environment, calculated as mean DT hybrid yield minus mean non-DT hybrid yield, was regressed on mean non-DT hybrid yield in an iterative process that minimized model sums of squares. Conditions were imposed to assure a continuous, smooth transition from a linear segment to a plateau segment with an unknown point of coincidence.The predicted yield advantage of DT hybrids over the non-DT hybrid across the range of micro-environments generated in this study was modeled by a fitting segmented model using PROC NLIN in SAS 9.4 . Yield pn = 54) to characterize their response to environmental yield potential. The slope of this mathematical function is a measure of yield adaptability  (Table 1). The three-way interaction, IRRI × hybrid type (HT) × SR, significantly influenced yields in the low ET sites  (Table 2), implying a possible differential response of the different HTs depending on micro-environment, although the lack of significance for the interaction of HT and SR may indicate that the differential was not necessarily induced by differential response of drought tolerance to SR. In addition, the main difference on the three-way interaction was observed on the 50% ET IRRI with minor yield variations for HT but similar responses to SR within each HT, whereas for the 100% ET yields did not statistically differ regardless of the SR and IRRI type (averaging 12.9 Mg ha-1). The two-way interaction of SR and IRRI affected yield at the High ET environments  but not at the Medium ET environments  and Low ET environments . SR affected yields in all three ET environment groups (Table 2). HT affected yield independent of IRRI regime in High ET environments, but the response was modified by IRRI regime in Medium and Low ET environments (Table 2). IRRI regime affected yield at all sites except for Hutchinson in 2013, one of the Medium ET environments.Averaged across SRs, grain yield ranged from 7.8  to 14.2 Mg haTables 2 and 3). The yield advantage for the DT over non-DT hybrids in the High and Medium ET environments was approximately 5 to 7% when averaged over all the SRs and IRRI factors (Table 3). In the Low ET environment there was no yield difference between the DT and non-DT hybrids when averaged over all the SRs and IRRI factors (Table 3).Yield advantages were greater for DT over non-DT hybrids in the High and Medium ET environments, but not in the Low ET environments (Table 4). The WUE advantage of DT compared to non-DT hybrids was different depending on the level of ET for the season. The DT hybrids had greater WUE, producing more yield for a given amount of moisture in the High and Medium ET environments (Table 4). For both High and Medium ET environments, averaged across the micro-environment factors, grain yield of DT hybrids averaged 1.3 kg ha-1 mm-1 more than the non-DT hybrids. However, there was no difference in WUE between the DT and non-DT hybrids in the Low ET environment (Table 4). The High ET environments produce less kg of grain per unit of water because a greater portion of the water is lost through evaporation from the soil or leaf surfaces, and through transpiration as the plant tries to cool itself. In contrast with the Low ET environments, the efficiency of corn turning water into grain is increased.Analysis of variance revealed a significant effect of HT but no significant effect of seeding density or interactions of HT with seeding density. In the three environments where water use was measured, WUE increased as seasonal ET decreased  in the data than segmented quadratic-plateau or non-segmented linear or non-linear models. Common sense and the standard precaution of not extrapolating beyond the range of values used to generate this model imply that the yield advantage for the DT hybrid is not likely to continue to increase as yield of the non-DT hybrid continues to decline. However, the model indicates that no consistent yield penalty was evident for the DT hybrid in environments where yields approached 15.7 Mg ha-1. A yield advantage for the DT versus the non-DT hybrid appeared, as yield became less than 10.8 Mg ha-1 and became consistently greater as yield of the non-DT hybrid dropped to 6.3 Mg ha-1 .Yield comparison between DT and non-DT hybrids pairs in all environments are shown in Figure 2). As resource availability, primarily connected to water supply, improved, DT and non-DT corn hybrid yield became more similar. A slope greater than 1 for the non-DT corn hybrid indicates above-average plasticity, and the slope less than 1 for the DT hybrid implies below-average plasticity. This agrees with the regression of DT hybrid yield advantage on non-DT hybrid yield  confirming that yields were similar for the two types of hybrids in environments supporting high yield levels, but DT hybrids performed better in environments supporting lower yields.As the environmental index decreased (associated with the most-limited water environments), DT hybrids had a better yield performance compared to non-DT hybrids , limited-transpiration under high vapor pressure deficit (VPD), and rate of transpiration (focus early-season) when soil is drying . For sorFor the current study, the yield advantage documented for DT hybrids in high- and medium-ET environments supports the concept that DT hybrids enhance productivity in water-limited environments relative to non-DT hybrids. In an industry review study (2011–2013), This data shows the greatest benefit from planting DT hybrids can be in environments with greater seasonal ET, with or without IRRI, and sites with smaller ET values if water becomes limiting within the season. The yield advantage of DT hybrids was positively correlated with environment ET, such that DT hybrids yielded more than non-DT hybrids in high and medium ET environments. In these situations, WUE for DT hybrids was significantly greater than for non-DT hybrids. Consequently, DT hybrids can offer some buffer against drought stress by reducing yield loss, but still offer adequate yield potential if drought is not a limiting factor for grain production. This makes DT hybrids a viable option in seasonally variable environments. The ability to offer some yield protection in higher stress environments, yet not sacrifice yield potential in low stress/high yield potential environments would be a benefit in areas where stress can vary considerably from season to season. Further research is needed to analyze the specific mechanisms of the DT hybrids that are involved in their response to drought stress. Improvements in drought tolerance should be further pursued when considering the drastic yield impact of drought at the national scale documented during the 2012 growing season , reflectEA, KR, AS collected data, designed research, and performed research. EA, KR, AS, GB, and IC analyzed, and synthesized data, and wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A P2L2 woman aged 35 years presented to our outpatient department with amenorrhea of 8 months with episodes of on-and-off heavy bleeding per vaginum. She had a history of laparoscopic right salpingectomy for right tubal ectopic pregnancy 8 months previously, which was confirmed on histopathology (HPE). When she presented to us, she was carrying ultrasonography (USG) of her pelvis, computed tomography (CT) of the abdomen and pelvis, and several human chorionic gonadotropin (beta-hCG) reports of last 8 months. Imaging was absolutely normal and beta-hCG values were showing a waxing and waning course , but nevAfter a thorough discussion and failure to find the source of beta-hCG, the decision was taken to perform a whole-body positron emission tomography (PET)-CT scan. On PET-CT, an active 5x4-cm malignant lesion was found in the bowel mesentery. No metastasis was found in any other site. The patient underwent exploratory laparotomy. Intra-operatively, a 5x5-cm, firm, well-circumscribed and encapsulated mass was present over the greater omentum, as shown in 2 has proven to be effective in 90% of cases of ectopic pregnancy and also results in resolution of beta-hCG levels in women with asymptomatic persisting PUL , but may also be present after abortions 25%), normal intrauterine pregnancy (22.5%), and ectopic pregnancy (2.5%) 5%, norma. Chorioc0%, but mWe report this case of choriocarcinoma of the greater omentum not for its rarity, but for the fact that it was missed despite an intensive examination. Our patient was initially managed along the lines of PUL considering that imaging did not support any ectopic site for the source of beta hCG. That an initial baseline CT showed no tumor goes with the understanding that perhaps the lesion was small enough to be missed on CT, yet it produced enough beta hCG, and was uncompromising to chemotherapy. The lesion may have increased in size because no imaging was repeated during MTX cycles. We decided to perform a PET-CT for the whole body in the absence of an adequate response to standard chemotherapy, which was the turning point in our case because we established the source of beta-hCG. The efficacy of PET-CT in defining such lesions is not known, perhaps due to the paucity of such cases, which typically undergo surgery in good time with a provisional diagnosis of ectopic pregnancy.Rare sites of choriocarcinoma can be missed despite intensive examinations. A suspicion of disease should always be kept when serial beta hCG levels show a plateau or rising trends despite chemotherapy. PET-CT may be a useful adjunct to map such lesions. Surgical excision of these tumors remains the best modality in resectable cases. Close follow-up is mandatory to achieve complete remission.


Phase-coherent underwater acoustic (UWA) communication systems typically employ multiple hydrophones in the receiver to achieve spatial diversity gain. However, small underwater platforms can only carry a single transducer which can not provide spatial diversity gain. In this paper, we propose single-carrier with frequency domain equalization (SC-FDE) for phase-coherent synthetic aperture acoustic communications in which a virtual array is generated by the relative motion between the transmitter and the receiver. This paper presents synthetic aperture acoustic communication results using SC-FDE through data collected during a lake experiment in January 2016. The performance of two receiver algorithms is analyzed and compared, including the frequency domain equalizer (FDE) and the hybrid time frequency domain equalizer (HTFDE). The distances between the transmitter and the receiver in the experiment were about 5 km. The bit error rate (BER) and output signal-to-noise ratio (SNR) performances with different receiver elements and transmission numbers were presented. After combining multiple transmissions, error-free reception using a convolution code with a data rate of 8 kbps was demonstrated. Reliable underwater acoustic communications are challenging because of the limited bandwidths, time-varying multipath delay, double-selective channel fading, and strong background noise . For exaSC-FDE is a promising low-complexity approach for mitigating intersymbol interference (ISI). The main advantage of SC-FDE is its ability to cope with long delay spread channels with single-tap equalizers. In addition, the estimated channels can be updated easily via pilot signals on a block-by-blocks. Compared to time-domain equalization, SC-FDE has lower computational complexity . CompareIn phase-coherent UWA communication, multichannel receivers are usually employed to enhance signal-to-noise ratios, mitigate channel fading effects, and reduce the ISI. Spatial diversity assumes the received multichannel signals are independent and the probability that all of them fade at the same time is small. To obtain spatial diversity gain, the optimal element spacing for the receiving array is required on the order of three to four wavelengths for vertical arrays and on the order of 30 to 60 wavelengths for horizontal arrays . RecentlSeveral approaches to achieve phase coherent UWA communication with a single receiver have been developed in recent years ,19,20,21The contributions of this paper include the following: (1) we proposed a SC-FDE approach for synthetic aperture UWA communications; (2) we analyzed the performances of two receiver algorithms, FDE and hybrid time frequency domain equalizer (HTFDE) using data collected from a lake experiment; and (3) we analyzed and compared the influence of receiver element number and transmission number on the performance of the SC-FDE based synthetic aperture communication method.The rest of this paper is organized as follows. The system model is introduced in P to obtain blocks of size N, which is expressed asP and Consider a pseudorandom noise-based (PN) single-carrier block transmission in which the modulated complex-value data streams are divided into blocks of size The known PN sequence in the previous block can be viewed as the cyclic prefix (CP) of the current transmission block. Assuming that the maximum multipath delay spread is shorter than the PN symbol’s duration, the received signal k denotes the k-th block and L is the channel order. On the receiver side, the Doppler is usually compensated by resampling of the incoming signal [k-th hydrophone after resampling processing as follows:k-th block, caused by relative motion between transceivers, A/D, D/A sampling, variant water current, etc.; k-th block; and k-th received block is expressed asAssume that the channel is invariant over each block duration. The CIR at block k between the transmitter and the receiver transducer in the discrete time domain is modeled asg signal ,23. Let k. The received data block isFor simplicity and to avoid a loss of generality, we eliminated the block index A block diagram for the receiver is shown in In summary, the FDE part consists of a rotated-phase compensation, channel estimation, and frequency domain equalization.Channel estimation plays a critical role in underwater acoustic communications ,25,26. Wi-th block, the estimated channel impulse response vector is denoted by i-th blocks:For the We achieved diversity in the combination of different transmissions by maximal ratio combining (MRC) ,27. The We start by describing the 2016 Danjiangkou (DJK16) lake experiment, in which we transmitted QPSK signals from one source to eight receivers. We conducted the DJK16 experiment in Danjiangkou Lake, Henan Province, China, in January 2016. The water depth was 45–50 m. The source was deployed at 20 m below the surface. The receiver array had eight elements that were uniformly spaced at 0.25 m apart and was deployed at depths between 18–20 m. The data were transmitted from the source using QPSK modulation with a carrier frequency of 6 kHz and a bandwidth of 4 kHz. The distances between transmitter and receivers ranged from 4.98 to 5.20 km. The longest distance between different transmitter locations was about 720 m, while the shortest was about 20 m.Each packet consisted of a 200 ms-long linear frequency modulated (LFM) waveform, 100 ms zero padding period, followed by 32 SC-FDE blocks, each of which was 128 ms long. Each packet lasted 4.428 s and included 16,510 symbols. The total transmitted signal included five different packets, and its duration was about 22.14 s. We transmitted identical signals at each location. The LFM waveform at the beginning of the packet was used for synchronization and Doppler shift estimation. The coded data rate is about 2.79 kbps if we consider the synchronization LFM waveform, the additional zero-padding and the extra PN length before the first block. The structured signal was transmitted as shown in The detailed parameters of the communication system used in the lake experiment are shown in Examples of channel impulse responses (CIRs) are shown as a function of geotime in the left panel of The received SNRs of the five transmissions ranged from 4 dB to 11 dB as shown in The estimated transmitter drifting speed (Doppler estimation) for the five transmissions is shown in We used the uncoded bit error rate (BER) and the output SNR as the performance metrics. We investigated the impact of distributed diversity combining on the performances of BERs of Rx #1, as shown in The BERs without combining were quite high . From one to three transmissions, the BER performance improved significantly with increasing diversity. After three transmissions , the performance improvement for the uncoded system was slight. For the MRC and FDE method, after five transmission combinations, the uncoded BER of Rx #1 was For comparison, we also plotted the BER results of conventional multichannel equalization with 1–8 channels for the first and fifth location in A linear array consisting of eight elements was used in the lake experiment. To illustrate the improvements using different receiver elements, we present scatterplots of equalized QPSK signals of the first packet using the IPNLMS channel estimation algorithm in In this paper, we propose an SC-FDE scheme for synthetic aperture communications. The transmitter sent a particular set of data at different locations. Spatial and temporal diversities are obtained using multiple transmission combinations. We exploited two receiver algorithms, MRC-FDE and MRC-HTFDE, and we demonstrated error-free receptions after five transmission combinations using convolution decoding. The addition of a few receiver elements increased the output SNR and decreased the BER significantly and caused a slight increase in the cost of the system.


Self-sensing capability of composite materials has been the core of intensive research over the years and particularly boosted up by the recent quantum leap in nanotechnology. The capacity of most existing self-sensing approaches is restricted to static strains or low-frequency structural vibration. In this study, a new breed of functionalized epoxy-based composites is developed and fabricated, with a graphene nanoparticle-enriched, dispersed sensing network, whereby to self-perceive broadband elastic disturbance from static strains, through low-frequency vibration to guided waves in an ultrasonic regime. Owing to the dispersed and networked sensing capability, signals can be captured at any desired part of the composites. Experimental validation has demonstrated that the functionalized composites can self-sense strains, outperforming conventional metal foil strain sensors with a significantly enhanced gauge factor and a much broader response bandwidth. Precise and fast self-response of the composites to broadband ultrasonic signals (up to 440 kHz) has revealed that the composite structure itself can serve as ultrasound sensors, comparable to piezoceramic sensors in performance, whereas avoiding the use of bulky cables and wires as used in a piezoceramic sensor network. This study has spotlighted promising potentials of the developed approach to functionalize conventional composites with a self-sensing capability of high-sensitivity yet minimized intrusion to original structures. Nanoparticles which are dispersed in polymer matrices as reinforcement elements have now found their superb niches to functionalize conventional composites with new capabilities, as typified by electro-static discharge , electroConventionally, the self-sensing of composites can be achieved via the instinct electrical conductivity of carbon fibres in carbon fibre-reinforced polymers (CFRPs)  or via tDriven by the recent advances and technical breakthroughs in emerging nanotechnology, conductive nanoparticles in a diversity of modalities have become appealing nanofiller candidates to compete with conventional sensing elements in composites. These conductive nanoparticles can be dispersed in matrices to form conductive networks for strain sensing or damage detection ,11,12,13However, the capacity of such a sensing philosophy is usually restricted to static strains or low-frequency and large magnitude structural vibration signals. This has created a vast barrier that prevents the functionalized composites with self-sensing from being extended to high-precision SHM, in which high-frequency probing signals in an ultrasonic regime are preferred, in order to make use of their superb sensitivity (at higher frequency) to damage of small dimensions. Of particular interest is the ultrasonic guided waves (UGWs) in the order of hundred kilohertz which demonstrate reasonable compromise among detection precision, fast propagation and penetration through composite thickness. When a probing UGW traverses a composite structure, rich information can be documented in captured signals, on which basis the damage in the composites along UGW propagation path, if any, can be scrutinized in a quantitative manner. But, it is noteworthy that UGW signals usually feature ultra-low magnitude at a microstrain degree, making it a daunting task to capture them using conventional nanoparticle-driven composites.In conclusion, existing self-sensing of composites either cannot extract sufficient and effective information on damage or entails a dense grid of electrodes to be installed on the monitored area. Most importantly, they are unwieldy to respond, effectively and accurately, to UGWs propagating in the composites, let alone use of UGW signals for SHM of composites. Motivated by such recognition, in this study, we develop a new breed of nano-engineered polymer composites with dispersed and networked sensing capability. It can be responsive to broadband elastic disturbances from static strains, through low-frequency vibration to UGWs up to hundred kilohertz. To such an end, carbon-based nanoparticles are dispersed in polymer matrix and networked to form a self-sensing system. This dispersed nanoparticle-networked sensing system—denoted by Nano-NSS hereinafter—enables UGW acquisition at any desired part of the structure under monitoring. With ignorable weight penalty, a Nano-NSS can identify damage in a composites structure in a quantitative manner, and consequently evaluate its health status. Based on comparison among various nanoparticle candidates, a graphene nanoparticle-networked self-sensing system (gNano-NSS) is developed. The premise of gNano-NSS-based SHM lies in the quantum tunneling effect present in a built-in conductive network in the composites that is formed by two-dimensional graphene nanoparticles evenly dispersed in polymers. The sensing capability of gNano-NSS is tested by measuring quasi-static strains (high-level strains) in tensile tests, low-frequency dynamic signals (medium-level strains) in vibration tests, and high-frequency UGW signals (low-level strains) in ultrasound tests. Conventional metal foil strain gauges and piezoceramic wafers are used for calibration and comparison.percolation threshold represents such a critical volume fraction of nanoparticles in the matrix beyond which the quantum tunneling effect can be triggered among neighboring non-contacting conductive nanoparticles. The tunneling effect stimulates the formation of a full conductive network macroscopically manifested by the composite. Making use of the tunneling effect, the Nano-NSS achieves its sensing capability via calibrating the changes in nano-structure of the composites under strains that are induced as a result of UGW propagation. The mechanism behind such a sensing capability lies in a hybrid nature of the quantum tunneling effect and breakage of electric paths as a result of applied strains. The Nano-NSS responds to dynamic strains of the host structure between a pair of electrodes, and can perceive UGWs consisting of multiple wave modes propagating omnidirectionally when UGWs traverse Nano-NSS. The piezoresistivity manifested by Nano-NSS originates from induced changes in electrical resistance of the nanoparticles-formed conductive network that is dispersed in the matrix. In the conductive network, numerous electric paths are available through directly-contacted nanoparticles and indirectly-contacted nanoparticles via the quantum tunneling effect, as illustrated schematically in particleR) and tunneling resistance between neighboring nanoparticles (tunnelR), defined as,particle(R ~ 0) compared with that of the polymer, and the tunneling resistance can be determined by [In principle, with an increase in the number of nanoparticles in insulative polymer matrix, the holistic conductivity of a nanoparticle-enriched composites structure enhances progressively; and the mined by (2)RtunnJ denotes the tunneling current density, V the electrical potential difference, e the quantum of electricity, m the mass of electron, h the Planck’s constant, d the inter-particle distance, λ the potential height of insulating layer (0.5–2.5 eV for epoxy), and A the cross-sectional area of the tunnel. When the strain is induced at low-level such as UGW traversing, as a result, the piezoresistivity manifested by Nano-NSS can be mainly attributed to triggered tunneling effect by the change in the inter-particle distance since the UGW-induced strain is too small to break up electric paths. Such a change can be described as a function of strain:ε signifies the coupled strains locally measured by Nano-NSS. If the strain is large enough to break up the linkage among nanoparticles, the resistance changes as a joint consequence of the triggered tunneling effect and breakage of electric paths [α, β, γ and η are three constants that can be determined by experiments.In the above, ic paths , as(4)ΔTargeting high sensitivity to UGWs, the supply of nanoparticles connected via the tunneling effect shall be sufficient, in order to ensure the formed Nano-NSS responsive to UGW-induced weak strains , and otherwise the directly contacted nanoparticles will form a stable and saturated conductive network which responds inertly to UGWs. Good dispersion and well controlled nanoparticle content within the percolation region are the key to achieve this, and in such a way the UGW-induced strains can alter the structure of Nano-NSS at a phenomenal degree.As representative conventional piezoresistive sensors, metal strain gauges, relying on macroscopic mechanical deformation, usually have good performance in measuring static, quasi-static or low-frequency strains. Due to strong directivity of the filaments inside, a metal strain gauge can only capture strain along the filament direction. However, as the frequency of applied strain increases, the material hysteresis becomes a key factor leading to the drop of the gauge factor and an increase of the phase delay . The cutThe innovative piezoresistivity of Nano-NSS in nano-engineered composites makes use of the tunneling effect to perceive UGWs, instead of macroscopic mechanical deformation, endowing the composites with a capability of responding elastic disturbance in broadband without hysteresis, from quasi-static loads, through vibration loads to UGWs, as illustrated in On top of that, opposing to conventional sensors including metal strain gauges and piezoceramic wafers that are to be glued on the sample surfaces, a Nano-NSS comprises of numerous electric paths which are available through directly-contacted nanoparticles and indirectly-contacted nanoparticles via the quantum tunneling effect that are dispersed in the composites, and thus the acquisition of strains  can be performed at any interested areas throughout the entire composites—a key feature that differentiates the Nano-NSS-based SHM from conventional SHM based on the use of external distributed sensors.TM 7000), two-dimensional (2D) disk-like graphene (Tanfeng Tech GRF-H-FLG-01), and zero-dimensional (0D) sphere-like carbon black (Cabot N220). Epoxy resin  and hardener (Aradur HY 956) were used as the matrix  rope-like multi-walled carbon nanotube (FloTubeThe morphology of dispersed nanoparticles in nanoparticle/epoxy hybrid was scrutinized with cryo-fractured cross sections of samples using a scanning electron microscopy (SEM) (JEOL Model JSM-6490). SEM images show that the 2D disk-like graphene-based nanoparticles are uniformly apart from each other a, while σ signifies the electrical conductivity of the composites, p the volume fraction of nanoparticle, cp the percolation threshold of the composites, and exponential t a constant associated with the dimensionality of the conductive nanocomposites. Samples made from the nanoparticle/epoxy hybrid with different degrees of nanoparticle contents were prepared to examine their electrical properties, on which basis the percolation thresholds of the formed conductive networks in the hybrid were ascertained. According to the percolation theory, the electrical conductivity of the nano-engineered composites has a power-law relationship with the nanofiller content as (5)σ∝ for measurement of mechanical and piezoresistive properties. During measurement, the sensing area on the surface of each sample is the region confined by a pair of silver electrodes with 1 mm gap. The gap was prudently determined and controlled to possess an electrical resistance that is compatible with that of the digital multimeter. Note that according to Equation (7), the static resistance will not influence the resistance changing ratio or sensitivity. The electrodes were connected to a dynamic digital multimeter (Keithley DMM 7510), as shown schematically in K) is calculated based on a linear fitting of the measured strain from 1% to 2.5% (blue dash line in the change in resistance experiences a steady increase with the strain (except at the beginning where stress curve is not linear due to the preloading of the machine). No major damage occurs at this stage and the gauge factor  of composites have been improved 35% and 8%, respectively see . The resAbove experiment calibrated the high sensitivity of gNano-NSS with quasi-static strains as large as 1%. To fully understand the sensing capability of gNano-NSS, the dynamic response of the nano-engineered composites was assessed under vibration loads with dynamic low-frequency and medium-level strains.π. To capture stable and strong signals under the relatively small strain level of beam subject to vibration loads, a commercial signal amplifier (KYOWA® CDV-900A) with a Wheatstone bridge was used to process signals from both the strain gauge and cable-extracted local gNano-NSS before being outputted to and collected by an oscilloscope (Agilent® DSO 9064A). The sensing performance was examined from 5 Hz to 20 kHz by sinusoidal excitation from a waveform generator (Hioki 7075). The metal strain gauge was used to calibrate the sensing capability of the gNano-NSS with excitation frequency lower than 2 kHz because metal strain gauge failed to respond to dynamic vibration of higher frequency.A cantilever beam made from the above nano-engineered composites, 1.4 mm thick, 220 mm long and 4 mm wide, was fabricated and fixed at one end . An elecG represents the internal gain of the amplifier , outV the output voltage signals, bridgeV the excitation voltage of Wheatstone bridge (2 V used here) and K is the gauge factor of the sensor. With the known gauge factor of the metal strain sensor (K = 2) and the output voltage signals of metal strain gauge and the gNano-NSS, the K of the self-sensing capability was calculated, which is about 7.2 at excitation of 5 Hz and 7.59 at excitation of 2 kHz. The slight difference under different frequency can be attributed to the different levels of strain. The gauge factor under vibration loads (measured strain ±20 με~±400 με (±0.002%~±0.04%)) is fairly lower than that measured under tensile loads (strain 1%~2.5%). This observation has verified that the sensing mechanism features a complicated trend: at low-level strain, tunneling effect is the dominating factor while at high-level strain the resistivity increases more rapidly due to the break-up of electric paths. The response signals of other frequencies are illustrated in As representative results, the obtained vibration signals of strain gauge and gNano-NSS at 5 Hz and 2 kHz are plotted in The nano-engineered composites have already been demonstrated effective and accurate in acquiring quasi-static loading with high-level strain and dynamic loading with medium-level strain. To further study the possibility to combine novel nano-engineered composites with UGW-based SHM, the self-sensing capability of gNano-NSS in perceiving UGWs with high frequency and low-level strain was examined.® US-TXP-3). The system generates tailor-made probing guided waves in narrow-band waveforms at an arbitrary frequency in the range of 0–2.5 MHz. The AWG-generated probing UGW signals were amplified by the linear power amplifier before being applied on the actuator. As illustrated in ® DSO 9064A). To verify the sensing performance, the excitation UGW signals were varied from 50 kHz to 440 kHz and captured signals were compared with PZT sensors attached nearby, for example sensor I-I and I-II around sensing point I in A 300 mm × 300 mm 8-layer composite laminate plate (1.4 mm thick) with the gNano-NSS was fabricated to test the capability of sensing ultrasonic waves. A piezoelectric lead zirconate titanate (PZT) actuator  was mounted on the surface of the laminate to excite probing ultrasonic signals with a self-developed SHM system. The system consists of UGW generation module comprising of an NI PXI-5412 arbitrary waveform generator (AWG) and a linear power amplifier (Ciprian0 hereinafter) of the local gNano-NSS has good agreement with the signals of PZT sensors in term of the arrival time. The obvious extra part of the acquired signal is the crosstalk noise at the initial moment of excitation which comes from the high voltage signal generation system. 0 and A0  modes, although with a slight difference in the magnitude due to the different couple effect in sensing mechanisms discussed earlier. However, because the crosstalk noise is broad enough to cover nearby signals at low frequency, some data points of S0 wave are missing in As some representative results, the captured signals of gNano-NSS at point I with excitation frequency of 180 kHz is demonstrated in the time domain in This experiment has proven that the gNano-NSS has the capability of sensing the ultrasonic waves with little delay, high signal-noise ratio and comparable performance with conventional PZT sensors. Since the gNano-NSS is fully integrated with the composites, the function as “dispersed sensors” can be performed at any desired positions.Well-dispersed Nano-NSS endows conventional composites with a versatile sensing capability of a broad type of loads. The sensing function is realized as “dispersed sensors” and combined with well-established SHM techniques to develop new way of damage sensing and monitoring. In this study, self-sensing functional nano-engineered composites were developed with gNano-NSS. Experiments were elaborately designed to calibrate and verify their sensing performance. In quasi-static test, local resistance change measurement of gNano-NSS has shown sensitive relationship with the strain of the monitored area, which could provide more information of damage status within materials than merely surface strain response from conventional attached sensors. The observed high sensitivity was also found in the vibration test, during which gNano-NSS showed no obvious delay and deviance in low-frequency dynamic response. The acquisition of UGW test promoted the sensing capability to the ultrasonic regime and low-level strains. The gNano-NSS exhibits fast, stable and accurate response to broadband dynamic strains yet less intrusion to the original composites, which pioneers new sensing techniques in developing structural health monitoring systems. As an additional merit, mechanical profiles of the composites have also been improved, benefiting from the networked graphene nanoparticles in polymers. To take a step further, the wires and cables used in the sensing network can further be eliminated using techniques such as screen-printed or 3D-printed circuits, to endow the structures with a fully integrated SHM capability. The application of gNano-NSS in damage localization with UGW-based SHM will be presented in future work.


Local regional recurrence of renal cell cancer post-nephrectomy most often occurs within three years after surgery. Post-nephrectomy, many processes may mimic RCC recurrence. We present the case of a 75 year-old Caucasian male patient with a mass in his renal fossa post-nephrectomy for renal cell cancer, suggesting local recurrence. Use of the technetium-99m sulfur colloid scan showed that the mass was his spleen which had been displaced into the renal fossa. With high index of suspicion, characterization of these processes as splenic in origin would prevent subjecting patients to risks of biopsy or even surgery. It is estimated that 63,920 new cases of kidney and renal pelvis cancer were diagnosed in the United States in 2014, and 13,860 patients succumbed to the disease  PET/CT approximately 3 months following surgery demonstrated an 8.5 x 6.5 cm soft tissue mass in the left renal fossa with mild F-18-FDG uptake  .A review of the patient’s prior imaging and surgical history revealed the presence of a spleen on the pre-operative imaging studies and no splenectomy at the time of left nephrectomy. This raised the possibility that the soft tissue mass in question may represent the spleen that had fallen into the renal fossa. As CT and MRI scans were equivocal in this case, we decided to use radio-nucleotide imaging to further identify the mass before proceeding with any interventional procedure. A technetium-99m sulfur colloid scan was then performed, confirming the location of the spleen in the left renal fossa Local regional recurrence of RCC post-nephrectomy most often occurs within three years after surgery. Metastatic disease to the adrenal gland, perilymphatics and perinephric fat may be the sources of recurrence in the renal fossa. Isolated local recurrence following nephrectomy is uncommon, occurring in less than 2% at 5 years . Post-neOur case report is unique from previously published literature, as displacement of the entire spleen into the renal fossa post-nephrectomy has not been reported in adult patients. It is evident that previous surgery, atypical location and abnormal shape make it difficult to differentiate between spleen and tumor recurrence using CT scan or MRI. Technetium-99m sulfur colloid scan is more sensitive in detecting spleen, making it useful in cases where other imaging modalities show equivocal results.We suggest that with a high index of suspicion, the use of the technetium-99m sulfur colloid scan would allow the characterization of these lesions as splenic in origin and prevent subjecting patients to risks of biopsy or even surgery.


Multi-coil arrays applied in transcranial magnetic stimulation (TMS) are proposed to accurately stimulate brain tissues and modulate neural activities by an induced electric field (EF). Composed of numerous independently driven coils, a multi-coil array has alternative energizing strategies to evoke EFs targeting at different cerebral regions. To improve the locating resolution and the stimulating focality, we need to fully understand the variation properties of induced EFs and the quantitative control method of the spatial arrangement of activating coils, both of which unfortunately are still unclear. In this paper, a comprehensive analysis of EF properties was performed based on multi-coil arrays. Four types of planar multi-coil arrays were used to study the relationship between the spatial distribution of EFs and the structure of stimuli coils. By changing coil-driven strategies in a basic 16-coil array, we find that an EF induced by compactly distributed coils decays faster than that induced by dispersedly distributed coils, but the former has an advantage over the latter in terms of the activated brain volume. Simulation results also indicate that the attenuation rate of an EF induced by the 36-coil dense array is 3 times and 1.5 times greater than those induced by the 9-coil array and the 16-coil array, respectively. The EF evoked by the 36-coil dispense array has the slowest decay rate. This result demonstrates that larger multi-coil arrays, compared to smaller ones, activate deeper brain tissues at the expense of decreased focality. A further study on activating a specific field of a prescribed shape and size was conducted based on EF variation. Accurate target location was achieved with a 64-coil array 18 mm in diameter. A comparison between the figure-8 coil, the planar array, and the cap-formed array was made and demonstrates an improvement of multi-coil configurations in the penetration depth and the focality. These findings suggest that there is a tradeoff between attenuation rate and focality in the application of multi-coil arrays. Coil-energizing strategies and array dimensions should be based on an adequate evaluation of these two important demands and the topological structure of target tissues. Transcranial magnetic stimulation (TMS) is currently regarded as a noninvasive treatment that holds great promise to be used in basic and clinical neurophysiology ,2,3,4. TModulation of the deep brain structures demand a large EF to be acutely focused on interested tissues deep in the cerebrum. Unfortunately, EFs evoked by common circular coils diffuse and decay rapidly as distance from the cortex increases . The fig2 square. Target regions of various shapes and sizes can be clearly depicted by the segmented head model.We used a homogeneous spherical head model with an isotropic conductivity of 0.33 S/m 170 mm in diameter. This data is consistent with the realistic conductivity of scalp and cortex, which occupy a large proportion of the brain. Various tissue layers  were not differentiated since magnetically induced EF in a sphere is insensitive to radial variations of conductivity ,28,29. TFour types of planar multi-coil arrays, a typical figure-8 coil, and a 36-coil cap-formed array were used to analyze spatial EF properties and make further comparisons. The four types of planar multi-coil arrays with diverse coil number and dimension are shown in Since the structure of stimulating coils plays a crucial part in determining the depth and focality of activation, we first focused on the energizing strategy of coils in a planar array to take full advantage of the control flexibility and develop a procedure of optimizing sets of stimuli coils. Here, the spatial arrangement of stimulating coils reflects the shape and size of a specific combination. Reports have demonstrated that a figure-8 coil composed of two sets of adjoining circular loops can induce a concentrated EF beneath the coil center . Based oEFs induced by different types of TMS coil configurations were determined using the finite element method (FEM). Simulations in this work were implemented in ANSYS 15.0 . Transient calculation was used and selected coils were energized by a monophasic current pulse of a duration of 250 μs. We applied the different current density as a controllable input variable, which is constrained under d itself . This laThe induced EF considerably attenuates in strength as it penetrates into deep tissues of the brain. This is mainly due to the characteristics of the cerebral tissue, acting as a conductor when both the air and the skull can be regarded as insulators. As a result, besides the field  vectors :(4)ETOT=L indicates the distance from the surface of the head model along the direction passing through the brain center. Peak values of EF intensity at different L values are normalized with respect to the maximum of the EF amplitude distribution estimated on the cortex and are quantified as a function of L. Decay rates of the induced EF in Previous studies have shown that the induced EF intensity is largely related to the distance between coil configurations ,22,37 anL. After exceeding the threshold of 4 cm, attenuation rates of the 4-coil combinations gradually slow down and finally, at the depth of 6 cm, reach a stable level of 0.15–0.25. Specifically, different values of CD characterize combinations in the 4-coil group, demonstrating that the coil combination with a high level of CD has a faster attenuation rate compared to the ones with lower CD values. This result can be directly perceived in It is hard to exactly define the dimension of a square multi-coil array because two important parameters, namely the edge length and the winding size, exist simultaneously and interact with each other. To determine the distribution property of EFs induced by multi-coil arrays of different dimensions, a similar simulation process is applied in coil configurations in L and then gradually slows down after a typical value of L. With the same spatial overall dimension but a different individual coil size, the 16-coil array, the 36-coil (dense) array, and the 9-coil array have an approximate variation scale ranging from 1 to about 0.55. Furthermore, the EF induced by the 36-coil (disperse) array decays slowly due to the large spatial dimension of stimulating coils. By analyzing profiles in T (ET = 1 V/cm) [L, the energy input should be represented by the corresponding current density that evokes the EF intensity of ET at a specific brain tissue. To estimate the tissue activation ability of induced EF, we quantified the focality by the percentage of cerebral structures exposed to a suprathreshold EF. If the peak intensity of an EF at a target depth exactly reaches the threshold ET, then L.Penetration focality is traditionally regarded as the proportion where the EF intensity exceeds a certain value at a given depth. A high level of EF focality maximizes EF intensity at targeted regions and minimize it at non-interested tissues. To describe and analyze the focality of induced EFs based on different coil combinations, preconditions should be determined first. (1) The stimulating threshold of the EF intensity should be set at a certain value E 1 V/cm) , and alln volume .(5)V(θ)L. Compared to 4-coil 02 and 4-coil 03, coils in 4-coil 01 are arranged dispersedly and a larger value of L < 5 cm, 4-coil 03 better stimulates targeted tissues without activating non-interested regions. Based on the simulation results, the correlation between the spatial arrangement of coils and focality is thus shown.L > 5.5 cm, 8-coil 04 shows an evident advantage over other combinations among the same group. This result suggests that coil combinations of larger values of CD have a slower increasing rate with the variation of L. To better evaluate different 8-coil combinations synthetically, energy consumptions are presented in However, when the energy consumption is considered in the selection strategy of coil combinations, more detailed factors need to be included. By analyzing The graphs in L. From A to G, the points’ projection ranges of By analyzing the decay property of EF intensity and focality of various coil configurations, we gain a result suggesting that there is a tradeoff between these two factors for the aim to stimulate a certain depth of brain tissue. Diverse coil configurations and geometric characteristics induce a significantly different spatial distribution of EF. However, configurations of various stimulating coils are subjected to an attenuation-focality tradeoff that impedes the achievement of a deep and focal stimulation at the same time. In T = 100 V/m). Any cortical tissue with an EF intensity larger than ET is regarded as the activated region. In order to testify the spatial distribution properties of EF induced by diverse coil combinations and determine feasible control strategies of multi-coil arrays for arbitrary interested tissues, we chose various units in the brain superficial layer as expected target regions and compared these regions with the actually activated parts. Simulation results show that the 36-coil planar array with an edge length of 159 mm and a coil outer radius of 11.9 mm can accurately locate stimulated tissue within an area of 2 units. 36-coil 01 and 36-coil 02 in L increases, the 36-coil planar array has a better performance of focality until L = 3.0 cm. Figure-8 coils are commonly used in TMS treatment . AttenuaTo depict the differences between the planar coil array and the cap-formed array, a further study was made using the same energizing strategies but different coil arrays. All these simulations were completed with the 36-coil cap-formed array. 2  can be accurately stimulated by a 64-coil array with coils 18 mm in diameter, which largely reduces the side effect of TMS. Comparison of the figure-8 coil, the planar array and the cap-formed array demonstrates an improvement in multi-coil configuration in the penetration depth and the focality. This study provides operators with alternative strategies of coil selection and control of the activated regions. Although it is difficult to construct a coil configuration that can achieve a stimulation both deep and focal, the selection and design of proper coil settings can be made on account of a balanced estimation of two factors.In summary, our results suggest that stimulating coils arranged in a disperse form are prone to activating deeper brain regions at the expense of reduced focality. On the contrary, compact distributed coils can evoke an EF with better focality but with fast-decaying intensity. Furthermore, we find that the coil array dimension is significantly related to the attenuation rate of EF intensity, verifying that large multi-coil arrays can activate deeper brain tissues, which satisfies the requirements of TMS. By comprehensively studying the distribution properties of EFs induced by multi-coil arrays, this work provides coil energizing strategies for activating user-defined areas. Results show that a surface area for the cortex of 17 cm


Drosophila. Characteristic events of myoblast fusion include the recognition and adhesion of myoblasts, and the formation of branched F-actin by the Arp2/3 complex at the site of cell–cell contact. At the ultrastructural level, these events are reflected by the appearance of finger-like protrusions and electron-dense plaques that appear prior to fusion. Severe defects in myoblast fusion are caused by the loss of Kette , a member of the regulatory complex formed by Scar or WAVE proteins . kette mutants form finger-like protrusions, but the electron-dense plaques are extended. Here, we show that the electron-dense plaques in wild-type and kette mutant myoblasts resemble other electron-dense structures that are known to function as cellular junctions. Furthermore, analysis of double mutants and attempts to rescue the kette mutant phenotype with N-cadherin, wasp and genes of members of the regulatory Scar complex revealed that Kette has two functions during myoblast fusion. First, Kette controls the dissolution of electron-dense plaques. Second, Kette controls the ratio of the Arp2/3 activators Scar and WASp in FCMs.The fusion of founder cells and fusion-competent myoblasts (FCMs) is crucial for muscle formation in  Summary: The Drosophila protein Kette is essential for myoblast fusion. It controls the dissolution of electron-dense plaques and the ratio of Scar and WASp proteins in fusion-competent myoblasts during fusion pore formation. Drosophila. The fusion of myoblasts requires many morphological changes in cells before the lipid bilayers of the plasma membranes mix and combine their cytoplasmic contents. In the first steps, myoblasts migrate towards each other, and recognize and adhere to each other. The plasma membranes of the adhering myoblasts are then destabilized, which leads to membrane fusion and to the formation of a growing muscle. The remodeling of cellular shapes depends on the reorganization of filamentous (F-)actin underneath the plasma membrane  homolog Kette is part of this regulatory complex. WASp is inhibited by an intra-molecular association of the WASp protein domains (Drosophila). Myoblast fusion in vrp1 mutants is impaired  and a GFP fusion assay. Homozygous kette mutants carrying the J4-48kette null allele showed severe myoblast fusion defects  and 1 µm (kette mutants (Table S1). The abnormal size of the plaque length indicates that kette function is associated with the plaques and that a fusion pore fails to form in kette mutants.To investigate the role of Kette during electron-dense plaque formation, we reinvestigated the  defects  compared defects . We foun defects C and elekette mutant myoblasts to form a fusion pore in a GFP diffusion assay. We observed that GFP was present in FCMs after specifically being expressed in founder cells, indicating that GFP had diffused into FCMs after fusion pore formation  and in an Arp3 mutant . However, we observed fusion pore formation more often in Arp3 mutants . For this reason, we used high-pressure freezing and freeze substitution to analyze whether kette mutant myoblasts are still able to form finger-like protrusions  to two known cellular junctions, i.e. adherens junctions  and septate junctions . Normally, N-cadherin expression is absent at stage 15  or Sra1ΔCMyr that lacks the Kette interaction region . Moreover, these genes are all required for oogenesis, and the induction of scar, abi and sra1 maternal and zygotic germline clones leads to abnormal egg development cadherin seems to compensate for the loss of N-cadherin . The M19N-cadherin null mutant was provided by Tadashi Uemura . UAS-rac1-myc was obtained from the Bloomington Stock Center. For the expression of UAS-transgenes, we used sns4,5-GAL4 . For conventional chemical fixation embryos were fixed as previously described in We investigated wild-type embryos and


To evaluate the analgesic efficacy and safety of ASP8477 in patients with peripheral neuropathic pain (PNP).Enriched enrollment randomized withdrawal.Centers in Poland (four), Czech Republic (six), and the United Kingdom (two).Patients aged 18 years or older with PNP resulting from painful diabetic peripheral neuropathy or postherpetic neuralgia.A four-week screening period followed by a single-blind period (six-day dose titration and three-week maintenance period with ASP8477 [20/30 mg BID]). Treatment responders (defined as a ≥30% decrease in the mean average daily pain intensity during the last three days of the single-blind period) were stratified by disease and randomized to receive placebo or continue ASP8477 during a three-week, double-blind, randomized withdrawal period. The primary end point was change in mean 24-hour average numeric pain rating scale (NPRS) from baseline to end of double-blind period.P = 0.644) or in time-to-treatment failure (P = 0.485) between ASP8477 and placebo. During the single-blind period, 57.8% of patients were treatment responders. ASP8477 was well tolerated. During the single-blind period, 22% of patients experienced at least one treatment-related adverse event (TEAE); during the double-blind period, 8% in the ASP8477 arm and 18% in the placebo arm experienced at least one TEAE.Among 132 patients who enrolled, 116 entered the single-blind period and 63  completed the double-blind period. There was no difference in mean 24-hour average NPRS score (ASP8477 was well tolerated in patients with PNP; however, ASP8477 did not demonstrate a significant treatment difference compared with placebo. Peripheral neuropathic pain (PNP), a complex chronic syndrome resulting from lesions to the peripheral nervous system, is caused by multiple etiologic factors  ,2. CommoThe enzyme fatty acid amide hydrolase (FAAH) is responsible for the degradation of several endogenous fatty acid amides, including the endocannabinoids anandamide (AEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA) . Endocan50) value of 3.99 (unpublished data). In phase I studies, ASP8477 was shown to increase plasma endocannabinoid concentrations in healthy subjects (unpublished data). Multiple doses of ASP8477 of 60 mg or less daily were also well tolerated and exhibited analgesic properties in an integrated pain model in healthy volunteers (unpublished data).ASP8477, a novel, potent, selective inhibitor of FAAH, selectively inhibits human FAAH-1 activity in vitro with a 50% inhibitory concentration  trial designed to assess the analgesic efficacy, safety, and tolerability of ASP8477 in patients with PNP resulting from painful diabetic peripheral neuropathy (PDPN) or PHN.The phase IIa EERW MOBILE study was designed to assess the analgesic efficacy and safety of ASP8477 in patients with PNP resulting from PDPN or PHN (NCT02065349). The study was a multinational, multicenter study conducted at 12 centers in three countries: Poland (four centers), the Czech Republic (six centers), and the United Kingdom (two centers). Prior to the study, independent ethics committee (IEC) approvals were obtained for ethical, scientific, and medical appropriateness of the study and IEC-approved written informed consent was obtained from each patient or from a legally authorized representative prior to the start of any study-related procedures. This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, EU Clinical Trials Directive, and applicable laws and regulations.The study consisted of a screening period of up to four weeks , a single-blind treatment period , a double-blind randomized withdrawal period (three weeks), and a follow-up period (two weeks) . Each paDuring the single-blind treatment period, patients were initiated on ASP8477 10 mg twice daily (BID) for three days and then escalated to 20 mg BID for a further three days. Patients who tolerated three days of ASP8477 at the 20 mg BID dose entered the three-week single-blind maintenance period at 30 mg BID; patients who did not tolerate either the 10 mg or 20 mg BID dose during the single-blind treatment period were discontinued from the study. During the single-blind maintenance period, patients who did not tolerate ASP8477 after three to seven days of 30 mg BID were permitted to reduce their dose to 20 mg BID and continued treatment on this dose for the remainder of the study. After seven days on the 30 mg BID dose or a reduction to the 20 mg BID dose, no dose modifications were allowed.Upon completion of the single-blind period, patients who had been compliant with e-diary and were responders to treatment were entered into the three-week, double-blind, randomized withdrawal period. Response to treatment was defined as a 30% or greater decrease in the mean average daily pain intensity during the last three days of the single-blind maintenance period  compared with the pain intensity at the last three days of the placebo run-in period (baseline of the single-blind period). Eligible patients were stratified based on disease (PDPN or PHN) and randomized in a 1:1 ratio to receive placebo or to continue on the ASP8477 regimen. Patients who did not respond to treatment (nonresponders) and who did not comply with diary entries were discontinued from the study.To maintain patient blinding during the placebo run-in period and during the single-blind period, patients were unaware of whether they received active ASP8477 or matching placebo tablets. Drug assignment during the placebo run-in, single-blind, and double-blind periods were performed via IRT, and all tablets (ASP8477 and placebo) looked identical. For the three-week, double-blind period, patients were randomized using IRT in a 1:1 ratio to receive placebo or to continue on the ASP8477 regimen.Adult patients (aged ≥ 18 years) with PNP resulting from PDPN or PHN were eligible for enrollment. Eligible patients with PDPN included those with a history of PDPN for one or more years; an established diagnosis of diabetes (type I or II) with PDPN; HbA1c of 11% or lower at screening; stable glycemic control for at least three months prior to screening; and stable diabetic distal symmetrical polyneuropathy symptoms (including pain) for at least three months prior to screening . Eligible patients with PHN were required to have pain present for six or more months after healing of herpes zoster rash. All patients were required to have an average daily pain score of 4 or higher during the screening period, and a mean average daily pain score between 4 and less than 9 out of 10 over the last three days of the seven-day placebo run-in period. All patients were required to maintain their current medications at the same dose throughout the study. Patients taking chronic pain medications were required to be on a stable regimen for one or more months prior to screening. The stable regimen could not include occasional or as-needed (PRN) analgesia or PRN nonmedication therapy. Concomitant medications permitted during the trial included stable medications for neuropathic pain (excluding cannabinoids and opioids), ketoprofen , and stable medications for chronic diseases . No rescue medication was allowed during the double-blind period.Patients were excluded if they had significant pain from an etiology other than PDPN or PHN that could interfere with assessment of PDPN- or PHN-related pain, a history of (within one year) or current orthostatic  hypotension and associated symptoms, and a history of adverse reactions or clinically significant intolerance to nonsteroidal anti-inflammatory drugs or ASP8477 medication. Patients were also excluded if they had a Hospital Anxiety and Depression Scale (HADS) score higher than 12 on either subscale, an established history of major depressive disorder not controlled with medication, or used opioids for pain for more than four days in the week preceding screening or cannabinoids during the three months prior to screening. Prohibited concomitant medications, therapies, or surgical procedures included strong inhibitors or inducers of cytochrome P-450 enzymes, specifically 2C8, 2C9, or 3A, medications that are almost exclusively metabolized by CYP2C19 and/or CYP2D6 and have a narrow therapeutic window, benzodiazepines, transcutaneous electrical nerve stimulation machines, heat and cold packs, and acupuncture.The primary end point was change in mean 24-hour average pain intensity (NPRS) from the double-blind baseline (last three days of the single-blind period) to the last three days of the double-blind randomized withdrawal period. The key secondary end point was time-to-treatment failure during the double-blind period. Treatment failure was defined as the occurrence of three consecutive days during which mean 24-hour NPRS was 4 or higher, and with at least a 30% increase in pain intensity (on each day) relative to baseline of the double-blind period, with the time-to-treatment failure being the first of these three consecutive days . Other sAll patient-reported assessments, including all efficacy and sleep interference, were recorded using a handheld e-diary. Quality of life improvements were assessed using the EQ-5D level 5 instrument, which was completed by all patients during visits at the beginning of the single-blind and beginning and end of the double-blind periods. PGIC was assessed by a self-administered seven-grade scale that evaluated patient’s clinical condition relative to the end of the single-blind period. HADS and NPSI were assessed using a self-report scale and a self-report questionnaire, respectively, which were completed by patients during visits at the beginning of the single-blind and end of the double-blind periods. HADS was also assessed at the beginning of the screening period.Safety and tolerability were assessed throughout the study via adverse event (AE) monitoring , electrocardiogram measurements, physical examinations, vital sign measurements, and clinical laboratory evaluations. The severity of AEs was classified as mild , moderate , or severe (inability to perform daily activities). Plasma concentrations of ASP8477 at predose and at one, two, four, or six hours postdose were measured in responders and nonresponders at the end of the single-blind maintenance period. Blood samples were also collected for the measurement of the FAAH substrates  at single-blind baseline, predose, and four hours postdose at the end of the single-blind maintenance period, predose at double-blind baseline, predose, and four hours postdose seven days into the double-blind period, and two weeks after the last dose of study medication.A sample size of 30 patients per treatment group in the responder population was estimated to provide an 80% power to detect an effect size of 0.67 (mean treatment difference/pooled standard deviation) at the one-sided significance level of 5%. Data were analyzed based on predefined study populations. Full analysis set 1 (FAS1) included all patients who started the single-blind period and received at least one dose of study drug. Full analysis set 2 (FAS2) included all patients who were responders (≥30% decrease in mean average daily pain intensity over the single-blind treatment phase), received at least one dose of double-blind study drug after randomization, had a pain intensity score at double-blind baseline, and had at least one pain intensity score postbaseline during the double-blind treatment period. Safety analysis set 1 (SAF1) included all patients who took at least one dose of study medication during the placebo run-in period. Safety analysis set 2 (SAF2) included all patients who took at least one dose of double-blind study medication after randomization. PK analysis set included all patients in the FAS1 population for whom at least one quantifiable plasma concentration of ASP8477 was obtained and for whom the time of dosing on the day of sampling was known. PD analysis set 1 included all patients from the FAS1 population for whom sufficient PD measurements were collected. PD analysis set 2 included all patients from the SAF2 population for whom sufficient PD measurements were collected.All continuous end points and time-to-treatment failure were tested using a one-sided 5% significance level, with corresponding one-sided 95% confidence intervals. The primary end point was analyzed using an analysis of covariance (ANCOVA) model with model terms for treatment group, pooled site, and baseline NPRS score as a covariate. The double-blind mean 24-hour average NPRS scores were analyzed using a repeated measures mixed model with model terms for treatment group, time, time by treatment group, pooled site, baseline NPRS score, and time by baseline NPRS score. The time-to-treatment failure was summarized using Kaplan–Meier estimates and analyzed using the Cox proportional hazards model with model terms for treatment, pooled sites, and baseline NPRS score. Of note, the stratification parameter of disease (PHN or PDPN) was not included in the analysis models due to the very small number of patients included in the double-blind period with PHN. Summaries for the single-blind period were based on FAS1 and included the total number of patients who took ASP8477. Summaries for the double-blind randomized withdrawal period were based on SAF2 for safety analyses and on FAS2 for efficacy analyses.A total of 132 patients were enrolled and entered the placebo run-in period (SAF1). During the placebo run-in period, 16 patients discontinued treatment; of these, 15 (11%) did not maintain mean average daily pain scores between 4 and less than 9 out of 10 over the last three days of the placebo run-in period and one (1%) withdrew consent. A total of 116 patients entered the single-blind period and received ASP8477 (FAS1). During the single-blind period, 67 patients (58%) were treatment responders and were randomized to the double-blind period. However, four nonresponders were randomized to the double-blind period in error; hence a total of 71 patients were entered . One patient who was assigned to the ASP8477 arm received placebo in error; based on intention-to-treat analysis principles, the patient was assigned to the ASP8477 arm  for efficacy analyses on FAS2 and to the placebo arm  for safety analyses on SAF2. The double-blind randomized withdrawal period was completed by 63 patients  .Demographic and baseline disease characteristics were similar across all study groups . Of the P = 0.644)  . A secon= 0.644) .Table 2P = 0.485) (Five patients (15%) in the ASP8477 arm and four patients (12%) in the placebo arm experienced treatment failure in the double-blind randomized withdrawal period . The haz= 0.485) . At the = 0.485) . No signAt the end of the single-blind maintenance period, mean trough ASP8477 levels were 114 ng/mL  and 190 ng/mL  . Peak plThe single-blind baseline mean plasma concentrations for the FAAH substrates AEA, OEA, and PEA were 0.45 ng/mL, 2.32 ng/mL, and 2.08 ng/mL, respectively. By the end of the single-blind maintenance period, the levels of AEA, OEA, and PEA more than doubled their baseline levels, with the greatest increases seen in AEA . At the Overall, ASP8477 was well tolerated, with a good safety profile in both the single- and double-blind periods. No deaths were reported during the study. Serious AEs (SAEs) were reported in two patients. During the single-blind period, one patient experienced two serious treatment-emergent AEs (TEAEs), acute renal failure (deemed by the investigator as “moderate severity”) and constipation (deemed as “severe”). Neither was considered related to treatment. During the double-blind period, one patient in the placebo arm experienced two serious TEAEs ; both events were judged as severe, but neither was considered related to treatment. Other than the aforementioned SAEs, no other TEAEs were judged to be severe in the ASP8477 arm.During the single-blind period, 26 patients (22%) experienced at least one TEAE. The most commonly reported TEAE was peripheral edema, experienced by three patients (2.6%) , none ofOverall, three patients discontinued treatment due to TEAEs. Two patients in the single-blind period experienced two TEAEs of moderate severity (burning sensation and pruritus) that led to treatment discontinuation. The TEAEs in one of these patients were considered to be probably related to the study drug. During the double-blind period, one patient in the ASP8477 arm experienced allergic dermatitis that was considered to be probably related to the study drug.There were no clinically significant effects on laboratory parameters and no clinically significant liver chemistry abnormalities. During the double-blind period, five mild laboratory-related TEAEs  were observed in two patients, both in the placebo arm. There was no apparent effect on vital signs or orthostatic blood pressure measures related to study drug administration or dose levels.This phase IIa EERW MOBILE study evaluated the analgesic efficacy, safety, and tolerability of ASP8477 in patients with PNP resulting from PDPN or PHN. Plasma concentrations of ASP8477 and substrates of FAAH inhibition  were also evaluated. During the single-blind period, nearly 60% of patients who received ASP8477 met the responder criteria. During the double-blind period, the ASP8477 and placebo groups maintained the levels of improvement observed at the end of the single-blind period. No significant treatment differences in 24-hour average NPRS score or time-to-treatment failure were detected at the end of the double-blind randomized withdrawal period, which was also confirmed by other secondary efficacy analyses. Although one patient, who was randomized to the ASP8477 group, received placebo, the results of the primary analyses were not affected by this; a sensitivity analysis that included this patient in the placebo group  had similar results to the primary efficacy analysis and did not change the conclusions of the withdrawal period. PK/PD analyses suggest that target exposures were reached, resulting in expected increases in targeted peripheral biomarkers .Overall, ASP8477 was well tolerated and had a good safety profile in both the single- and double-blind periods. Of note, during the double-blind period, fewer AEs were reported in the ASP8477 arm compared with the placebo arm. This may be due to patients reporting TEAEs that started (or worsened) during the double-blind randomized withdrawal period as occurring in the double-blind period or may be related to the potential withdrawal effects of discontinuing ASP8477 treatment.Although the present study failed to meet its primary end point, nearly 60% of patients reported a reduction of 30% or more in their pain during the single-blind period, suggesting the potential analgesic activity of ASP8477 in a subset of patients with PNP. However, the lack of worsening pain when patients were switched from ASP8477 (in the single-blind period) to placebo  makes it difficult to interpret the results from the single-blind period but suggests that the single-blind effect may not have been primarily due to the effect of an active treatment. Despite promising preclinical and phase I biomarker results, the clinical evidence supporting FAAH inhibitors for the treatment of pain has not been established in either the current study or other studies that are in phase II development. FAAH inhibition as a treatment for patients with osteoarthritis pain showed no analgesic effect, compared with naproxen, in a phase II proof-of-concept study , despiteThe limitations in the MOBILE study may have contributed to the lack of treatment effects with ASP8477. In this study, the sample size was small and there was large variability associated with the primary end point. Furthermore, although four countries were selected to participate in this study and three of these enrolled patients, only patients from participating centers in the Czech Republic and Poland ended up being randomized. Therefore, data in this study may not be representative of a wider PNP population. Moreover, study participants were not blinded to the inclusion criteria or to the time of randomization; likewise, investigators were not blinded to entry criteria for either the single-blind or double-blind periods, which may have influenced patients’ perception and reporting of pain. In addition, response to ASP8477 treatment during the single-blind period was not confirmed as stable because patients were required to meet responder criteria only once  rather than over a longer period of time during the maintenance period. Verifying stability of ASP8477 treatment over a period of weeks would be more consistent with a maintenance design. The trial design may also be a limitation, as discussed below.This study highlights the importance of trial design when studying drugs for the treatment of pain, as with many other conditions. The EERW design was used in the MOBILE study because it has been reported to be useful in evaluating drugs that may only benefit a subset of a disease population . In addiHowever, there are other limitations with the EERW study design; the present study was designed based on a previous report . The oveIn conclusion, in spite of evidence of a peripheral biomarker demonstrating peripheral FAAH inhibition, ASP8477 did not demonstrate a significant treatment difference compared with placebo in an EERW study in patients with PNP. As the primary end point in the current study and other phase II trials with FAAH inhibitors was not met, future development of compounds targeting FAAH inhibition for chronic pain may need to be re-examined. The use of the EERW study design in clinical trials of pain should take into consideration the duration of the withdrawal period to minimize potential carryover effects, as well as incorporate methods to blind patients to the timing of transition between treatment periods. These changes may reduce bias and placebo response and optimize the potential for detection of a drug signal.Supplementary DataClick here for additional data file.


Patients with NAFLD  had remarkably higher 1-year all-cause and cardiac re-hospitalization rates compared with their counterparts without NAFLD. Both event rates were particularly increased in those with advanced NAFLD fibrosis. NAFLD was associated with a 5-fold increased risk of 1-year all-cause re-hospitalization  after adjustment for established risk factors and potential confounders. Similar results were found for 1-year cardiac re-hospitalization . In conclusion, NAFLD and its severity were strongly and independently associated with an increased risk of 1-year all-cause and cardiac re-hospitalization in elderly patients admitted with acute HF.Nonalcoholic fatty liver disease (NAFLD) is an emerging risk factor for heart failure (HF). Although some progress has been made in improving survival among patients admitted for HF, the rates of hospital readmissions and the related costs continue to rise dramatically. We sought to examine whether NAFLD and its severity  was independently associated with a higher risk of 1-year all-cause and cardiac re-hospitalization in patients admitted for acute HF. We studied 212 elderly patients who were consecutively admitted with acute HF to the Hospital of Negrar (Verona) over a 1-year period. Diagnosis of NAFLD was based on ultrasonography, whereas the severity of advanced NAFLD fibrosis was based on the fibrosis (FIB)-4 score and other non-invasive fibrosis scores. Patients with acute myocardial infarction, severe valvular heart diseases, end-stage renal disease, cancer, known liver diseases or decompensated cirrhosis were excluded. Cox regression was used to estimate hazard ratios (HR) for the associations between NAFLD and the outcome(s) of interest. The cumulative rate of 1-year all-cause re-hospitalizations was 46.7% ( The prevalence of heart failure (HF) is high ≥10%) among persons aged 70 years or older and its incidence is rapidly increasing, due to better life expectancy 0% among . To dateNonalcoholic fatty liver disease (NAFLD) is a multisystem disease that affects many organ systems, including both the heart and the vasculature ,5. GrowiThese findings support the view that NAFLD is implicated in HF development and might be also a predictor of higher hospital readmissions for acute HF. We have previously explored the association between NAFLD and the risk of all-cause hospital readmissions in a small sample of elderly patients admitted for acute HF . HoweverConsequently, it remains currently uncertain whether NAFLD and its severity may independently predict 1-year hospital re-admissions after HF. Thus, the aim of this study was to examine whether ultrasound-diagnosed NAFLD and its severity–using the fibrosis (FIB)-4 score or other non-invasive markers of advanced NAFLD fibrosis–were associated with an increased risk of 1-year all-cause and cardiac re-hospitalization in patients admitted initially to the hospital with HF.n = 314). All patients were initially eligible for the study if they had a confirmed clinical diagnosis of acute HF (pre-existing or de novo HF). In agreement with the 2012 European Society of Cardiology guidelines , is not only associated with an increased risk of CHD, but is also strongly associated with functional and structural cardiomyopathy that may lead to the development of HF over time ,10,25,26Our study has some limitations that should be mentioned. Firstly, this study is limited by its single-center, observational design, which limits our ability to establish the causality of the observed associations. Secondly, although our statistical models were extensive, unmeasured confounding factors might partially explain the observed associations. Thirdly, the diagnosis of NAFLD was based on ultrasonography and exclusion of secondary causes of chronic liver disease but was not confirmed by liver biopsy, which is considered as the reference standard for diagnosing and staging NAFLD . HoweverDespite these limitations, our study has important strengths, including its relatively large sample size, the ultrasonographic diagnosis of NAFLD, the completeness of the dataset, the ability to adjust for multiple clinical risk factors and potential confounding factors, and the exclusion of patients with end-stage renal disease, cancer or cirrhosis.In conclusion, our results show that NAFLD and its severity—using the FIB-4 score or other non-invasive markers of advanced NAFLD fibrosis—were strongly and independently associated with an increased risk of 1-year all-cause and cardiac re-hospitalization in elderly patients admitted for acute HF. Further prospective studies are needed to corroborate these findings in other independent samples.S1 Table(DOCX)Click here for additional data file.


Despite intensive research it is unknown if treatment with antipsychotic drugs contributes to the reduced life-expectancy observed in patients with schizophrenia and other severe mental disorders. As randomized controlled trials (RCT) are considered the best evidence to examine causal relationship, we aimed to analyze mortality related to antipsychotics based on all placebo-controlled RCTs conducted so far.We evaluated mortality in pair-wise meta-analysis of RCTs comparing second-generation-antipsychotics versus placebo across all diagnostic fields.Information about deaths was extracted from summary data of clinical trials as identified by two searches (last 01/28/2017) in several electronic databases. Furthermore, manufacturing companies and regulatory authorities were contacted, and their websites were searched for trial reports and supplemental information about fatal events. We examined mortality due to any reason (primary outcome), due to natural causes, suicide, and other unnatural causes. We synthesized the results with odds ratios (OR) in a common-effect meta-analysis. We addressed the effects of age, diagnostic field, gender, study duration, antipsychotic drug used, drug dose and polypharmacy with subgroup- and meta-regression-analyses. We used the GRADE framework to evaluate the confidence in the evidence.We included 596 randomized trials that reported 207 deaths in 53804 patients on placebo (0.38%) and 99 deaths in 31184 patients on drug (0.32%). There was no evidence of significant difference between antipsychotics and placebo regarding mortality due to any reason , natural causes , suicide  and other unnatural causes . The number-needed-to-harm for all-cause mortality was 6 more deaths in 10 000 drug-treated patients compared to placebo, with a 95% CI ranging from 2 helped to 14 harmed. Most deaths occurred in patients with dementia and these patients also had the highest drug-related mortality in subgroup analysis . The OR for patients with schizophrenia (based on 32807 patients) was 0.69 .We found no evidence of increased mortality related to treatment with second generation antipsychotic drugs, neither in the overall sample nor in the subgroup of patients with schizophrenia. Results of subgroup analyses indicated however that mortality of patients with dementia might be increased when they are exposed to antipsychotics. Strength of the analysis are the use of data from RCTs and the comprehensive search, which aimed to identify all placebo-controlled RCTs of second generation antipsychotics conducted so far. Limitations of our analysis are the remaining imprecision of the results with a 95% confidence interval including the risk of more than 1 patient harmed in 1000 patients treated with antipsychotics. Moreover, we could only address short-term effects leading to death, but not long-term effects - such as induction of metabolic syndrome – which also contribute to the increased mortality over the whole life-span.