Elongating, entwining, and dragging: mechanism for adaptive locomotion of tubificine worm blobs in a confined environment.

Worms often aggregate through physical connections and exhibit remarkable functions such as efficient migration, survival under environmental changes, and defense against predators. In particular, entangled blobs demonstrate versatile behaviors for their survival; they form spherical blobs and migrate collectively by flexibly changing their shape in response to the environment. In contrast to previous studies on the collective behavior of worm blobs that focused on locomotion in a flat environment, we investigated the mechanisms underlying their adaptive motion in confined environments, focusing on tubificine worm collectives. We first performed several behavioral experiments to observe the aggregation process, collective response to aversive stimuli, the motion of a few worms, and blob motion in confined spaces with and without pegs. We found the blob deformed and passed through a narrow passage using environmental heterogeneities. Based on these behavioral findings, we constructed a simple two-dimensional agent-based model wherein the flexible body of a worm was described as a cross-shaped agent that could deform, rotate, and translate. The simulations demonstrated that the behavioral findings were well-reproduced. Our findings aid in understanding how physical interactions contribute to generating adaptive collective behaviors in real-world environments as well as in designing novel swarm robotic systems consisting of soft agents.

Lusutrombopag for thrombocytopenia in Chinese patients with chronic liver disease undergoing invasive procedures.

PURPOSE: Probing efficacy and safety of lusutrombopag in Chinese chronic liver disease (CLD) and severe thrombocytopenia (PLT < 50 × 109/L) patients undergoing elective invasive procedures. METHODS: In this double-blind, parallel-group phase 3 study, 66 patients with CLD and severe thrombocytopenia were randomized 2:1 to lusutrombopag or placebo arm treatment regimens for seven days at 9 centers in China. Responders (PLT ≥ 50 × 109/L that increased to ≥ 20 × 109/L from the baseline and not received rescue therapy for bleeding) on Day 8 (the day after seven-day treatment) were assessed. PLT ≥ 50 × 109/L on or after Day 8 and within 2 days before invasive procedure (alternative criteria for not requiring platelet transfusion) were also analyzed. Adverse events (AEs) were recorded. RESULTS: The proportion of responders on Day 8 was evidently higher (p = 0.0011) in the lusutrombopag group (43.2%, 19/44) versus placebo (4.5%, 1/22). And 72.7% (32/44) patients receiving lusutrombopag met the alternative criteria for not requiring platelet transfusion, while 18.2% (4/22) in the placebo group. The median maximum PLT in lusutrombopag group increased to 80.5 × 109/L, and median time to reach maximum was 14.5 days. Compared with placebo, the lusutrombopag group had a lower incidence of bleeding events (6.8% versus 13.6%), and only one patient had thrombotic-related AE. Overall, the incidence of treatment-emergent AEs was comparable between two groups. CONCLUSIONS: Lusutrombopag was effective in raising PLT, diminishing platelet transfusion requirement, and documented a safety profile like the placebo in CLD and severe thrombocytopenia patients in a Chinese cohort undergoing elective invasive procedures. Chinese clinical trial registration number: CTR20192384.

Active-sensing-based decentralized control of autonomous mobile agents for quick and smooth collision avoidance.

There is an increasing demand for multi-agent systems in which each mobile agent, such as a robot in a warehouse or a flying drone, moves toward its destination while avoiding other agents. Although several control schemes for collision avoidance have been proposed, they cannot achieve quick and safe movement with minimal acceleration and deceleration. To address this, we developed a decentralized control scheme that involves modifying the social force model, a model of pedestrian dynamics, and successfully realized quick, smooth, and safe movement. However, each agent had to observe many nearby agents and predict their future motion; that is, unnecessary sensing and calculations were required for each agent. In this study, we addressed this issue by introducing active sensing. In this control scheme, an index referred to as the "collision risk level" is defined, and the observation range of each agent is actively controlled on this basis. Through simulations, we demonstrated that the proposed control scheme works reasonably while reducing unnecessary sensing and calculations.

Pharmacokinetic Assessment and Treatment Effect of Lusutrombopag in Child-Pugh Class C Patients: Review of Patient Data from Two Clinical Studies and Post-Marketing Surveillance.

INTRODUCTION: Patients with thrombocytopenia and chronic liver disease are at increased risk of bleeding during invasive procedures due to low platelet counts. Lusutrombopag, an orally active thrombopoietin receptor agonist, increases platelet count and reduces the need for platelet transfusion in chronic liver disease patients with thrombocytopenia undergoing a planned invasive procedure. The safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease is not known. The present analysis was performed to determine the pharmacokinetics, efficacy, and safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease. METHODS: Data for patients with Child-Pugh class C chronic liver disease were collected from three data sets: a phase 1/2 Child-Pugh class C study (n = 5) (JapicCTI-163289 [Japan Pharmaceutical Information Center]), a phase 3 pivotal study (L-PLUS 2, n = 3) (NCT02389621 [Clinicaltrials.gov]), and ongoing post-marketing surveillance (n = 27) (JapicCTI-163432 [Japan Pharmaceutical Information Center]). Patients received lusutrombopag at 3 mg for up to 7 days. Safety and efficacy assessments were collected from two clinical studies and the post-marketing surveillance; pharmacokinetic data were collected from the phase 1/2 study. RESULTS: Mean Cmax and AUC0-τ were lower in Child-Pugh class C patients than Child-Pugh class A and B; individual patients' Cmax and AUC0-τ values overlapped among Child-Pugh classes. In lusutrombopag patients who did not receive platelet transfusion (n = 4 in phase 1/2, n = 1 in phase 3, n = 24 in post-marketing surveillance), the median (range) maximum platelet count was 88.5 × 109/L (54-105 × 109/L), 80 × 109/L, and 91 × 109/L (41-186 × 109/L; n = 23), respectively. There were no treatment-related adverse events or treatment-related serious adverse events. One patient from the phase 1/2 study had a non-serious portal vein thrombosis, which was not considered treatment-related. CONCLUSIONS: The analysis presented in this study suggests that lusutrombopag increases platelet counts in Child-Pugh class C patients and is safe and well tolerated in this patient population. TRIAL REGISTRATION: L-PLUS 2: NCT02389621 (Clinicaltrials.gov). Phase 1/2: JapicCTI-163289 (Japan Pharmaceutical Information Center [JAPIC]). Post-marketing surveillance: JapicCTI-163432 (JAPIC).

Adaptive Centipede Walking via Synergetic Coupling Between Decentralized Control and Flexible Body Dynamics.

Multi-legged animals such as myriapods can locomote on unstructured rough terrain using their flexible bodies and legs. This highly adaptive locomotion emerges through the dynamic interactions between an animal's nervous system, its flexible body, and the environment. Previous studies have primarily focused on either adaptive leg control or the passive compliance of the body parts and have shown how each enhanced adaptability to complex terrains in multi-legged locomotion. However, the essential mechanism considering both the adaptive locomotor circuits and bodily flexibility remains unclear. In this study, we focused on centipedes and aimed to understand the well-balanced coupling between the two abovementioned mechanisms for rough terrain walking by building a neuromechanical model based on behavioral findings. In the behavioral experiment, we observed a centipede walking when part of the terrain was temporarily removed and thereafter restored. We found that the ground contact sense of each leg was essential for generating rhythmic leg motions and also for establishing adaptive footfall patterns between adjacent legs. Based on this finding, we proposed decentralized control mechanisms using ground contact sense and implemented them into a physical centipede model with flexible bodies and legs. In the simulations, our model self-organized the typical gait on flat terrain and adaptive walking during gap crossing, which were similar to centipedes. Furthermore, we demonstrated that the locomotor performance deteriorated on rough terrain when adaptive leg control was removed or when the body was rigid, which indicates that both the adaptive leg control and the flexible body are essential for adaptive locomotion. Thus, our model is expected to capture the possible essential mechanisms underlying adaptive centipede walking and pave the way for designing multi-legged robots with high adaptability to irregular terrain.

Adaptive Interlimb Coordination Mechanism for Hexapod Locomotion Based on Active Load Sensing.

Insects can flexibly coordinate their limbs to adapt to various locomotor conditions, e.g., complex environments, changes in locomotion speed, and leg amputation. An interesting aspect of insect locomotion is that the gait patterns are not necessarily stereotypical but are often highly variable, e.g., searching behavior to obtain stable footholds in complex environments. Several previous studies have focused on the mechanism for the emergence of variable limb coordination patterns. However, the proposed mechanisms are complicated and the essential mechanism underlying insect locomotion remains elusive. To address this issue, we proposed a simple mathematical model for the mechanism of variable interlimb coordination in insect locomotion. The key idea of the proposed model is "decentralized active load sensing," wherein each limb actively moves and detects the reaction force from the ground to judge whether it plays a pivotal role in maintaining the steady support polygon. Based on active load sensing, each limb stays in the stance phase when the limb is necessary for body support. To evaluate the proposed model, we conducted simulation experiments using a hexapod robot. The results showed that the proposed simple mechanism allows the hexapod robot to exhibit typical gait patterns in response to the locomotion speed. Furthermore, the proposed mechanism improves the adaptability of the hexapod robot for leg amputations and lack of footholds by changing each limb's walking and searching behavior in a decentralized manner based on the physical interaction between the body and the environment.

Relationship between baseline clinical characteristics and efficacy of lusutrombopag in thrombocytopenic patients with chronic liver disease: post hoc analysis of two placebo-controlled phase 3 trials.

OBJECTIVE: Lusutrombopag is a thrombopoietin receptor agonist approved to treat thrombocytopenia in patients with chronic liver disease (CLD). This post hoc analysis of the Japanese L-PLUS 1 and global L-PLUS 2 trials aimed to clarify factors related to platelet count increase after lusutrombopag treatment. METHODS: In L-PLUS 1, Pearson's correlation coefficients were used to evaluate correlations between platelet count and spleen index, thrombopoietin concentration, white blood cell (WBC) counts, and red blood cell counts (intent-to-treat [ITT] population). Associations between platelet count increase after lusutrombopag treatment and each parameter were assessed by regression analysis and mixed-effect model for repeated measures (MMRM). Associations between time-dependent changes in platelet count increase and each parameter were also examined in the L-PLUS 2 lusutrombopag ITT population by MMRM. RESULTS: In L-PLUS 1, the baseline platelet count was correlated with pretreatment spleen index (r = -0.23, 95% confidence interval [CI] -0.41 to -0.03) and WBC count (r = 0.26, 95% CI 0.06 to 0.43). No selected parameters were associated with the maximum platelet count increase from baseline. Patients with WBC counts below the normal range showed smaller platelet count increases after lusutrombopag treatment than patients with WBC counts within the normal range (p = .0028). In L-PLUS 2 (p = .0533), findings were similar and confirmed by larger pooled data of L-PLUS 1/L-PLUS 2 (p = .0021). CONCLUSIONS: This post hoc analysis revealed a possible association between baseline WBC count and platelet count increase after lusutrombopag treatment. WBC count could be a relevant factor for lusutrombopag efficacy.

Simple decentralized control mechanism that enables limb adjustment for adaptive quadruped running.

Quadrupeds exhibit versatile and adaptive running by exploiting the flying phase during the stride cycle. Various interlimb coordination mechanisms focusing on mechanical loads during the stance phase have been proposed to understand the underlying control mechanism, and various gait patterns have been reproduced. However, the essential control mechanism required to achieve both steady running patterns and non-steady behaviours, such as jumping and landing, remains unclear. Therefore, we focus on the vertical motions of the body parts and propose a new decentralized interlimb coordination mechanism. The simulation results demonstrate that the robot can generate efficient and various running patterns in response to the morphology of the body. Furthermore, the proposed model allows the robot to smoothly change its behaviour between steady running and non-steady landing depending on the situation. These results suggest that the steady and non-steady behaviours in quadruped adaptive running may share a common simple control mechanism based on the mechanical loads and vertical velocities of the body parts.

Spontaneous Gait Transitions of Sprawling Quadruped Locomotion by Sensory-Driven Body-Limb Coordination Mechanisms.

Deciphering how quadrupeds coordinate their legs and other body parts, such as the trunk, head, and tail (i.e., body-limb coordination), can provide informative insights to improve legged robot mobility. In this study, we focused on sprawling locomotion of the salamander and aimed to understand the body-limb coordination mechanisms through mathematical modeling and simulations. The salamander is an amphibian that moves on the ground by coordinating the four legs with lateral body bending. It uses standing and traveling waves of lateral bending that depend on the velocity and stepping gait. However, the body-limb coordination mechanisms responsible for this flexible gait transition remain elusive. This paper presents a central-pattern-generator-based model to reproduce spontaneous gait transitions, including changes in bending patterns. The proposed model implements four feedback rules (feedback from limb-to-limb, limb-to-body, body-to-limb, and body-to-body) without assuming any inter-oscillator coupling. The interplay of the feedback rules establishes a self-organized body-limb coordination that enables the reproduction of the speed-dependent gait transitions of salamanders, as well as various gait patterns observed in sprawling quadruped animals. This suggests that sensory feedback plays an essential role in flexible body-limb coordination during sprawling quadruped locomotion.

Emergence of robust self-organized undulatory swimming based on local hydrodynamic force sensing.

Undulatory swimming represents an ideal behavior to investigate locomotion control and the role of the underlying central and peripheral components in the spinal cord. Many vertebrate swimmers have central pattern generators and local pressure-sensitive receptors that provide information about the surrounding fluid. However, it remains difficult to study experimentally how these sensors influence motor commands in these animals. Here, using a specifically designed robot that captures the essential components of the animal neuromechanical system and using simulations, we tested the hypothesis that sensed hydrodynamic pressure forces can entrain body actuation through local feedback loops. We found evidence that this peripheral mechanism leads to self-organized undulatory swimming by providing intersegmental coordination and body oscillations. Swimming can be redundantly induced by central mechanisms, and we show that, therefore, a combination of both central and peripheral mechanisms offers a higher robustness against neural disruptions than any of them alone, which potentially explains how some vertebrates retain locomotor capabilities after spinal cord lesions. These results broaden our understanding of animal locomotion and expand our knowledge for the design of robust and modular robots that physically interact with the environment.

An incidentally identified 15 cm cavernous hemangioma of the small intestine: Case report and literature review.

INTRODUCTION: Hemangiomas of the small intestine are rare, usually present with symptoms such as anemia, gastrointestinal bleeding or abdominal pain and are resected. We report resection of an incidentally identified cavernous hemangioma of the small intestine that did not present symptoms referable to the hemangioma. Although it was a large lesion, it was resected using laparoscopy and a mini-laparotomy. PRESENTATION OF CASE: A 29-year-old otherwise healthy man was referred for evaluation of ileal wall thickening found on a contrast-enhanced computed tomography scan obtained for the workup of chronic diarrhea. Double balloon enteroscopy (DBE) showed a cavernous hemangioma of the small intestine. The lesion was 15 cm and resected using laparoscopy and a mini-laparotomy to prevent future bleeding. The histopathological diagnosis was a cavernous hemangioma of the ileum. DISCUSSION: Though there have been no reports of the asymptomatic patients of the disease, the recent spread of double balloon enteroscopy and capsule endoscopy will allow us to diagnose more asymptomatic hemangiomas like this patient. Also, this large lesion was able to be resected through a small incision due to its compressible nature. CONCLUSION: Future studies in asymptomatic patients of the disease may help to determine the optimal management for these patients. Even large hemangiomas are compressible, facilitating minimally invasive resection.

Assessing the periprocedural magnitude of platelet count change in response to lusutrombopag.

BACKGROUND & AIMS: Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This post-hoc analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials. METHODS: Adults with chronic liver disease-induced thrombocytopaenia and platelet count <50 (× 109/L) received lusutrombopag 3 mg or placebo ≤7 days before invasive procedure scheduled 9-14 days after randomisation. Platelet transfusion was required per protocol if the platelet count remained <50 no more than 2 days before the planned invasive procedure. Post-hoc analysis included: proportion of patients with platelet count ≥50, ≥1.5-fold increase, and a doubling of platelet count; maximum and maximum change in platelet count; and platelet count time course. RESULTS: Platelet count ≥50, a platelet count increase ≥1.5-fold, and at least a doubling in platelet count were achieved in 88.3%, 86.9%, and 52.6% of patients in the lusutrombopag group (n = 137) vs. 58.6%, 32.3%, and 6.0% of patients in the placebo group (n = 133), respectively. In the lusutrombopag group, median maximum platelet count across baseline platelet counts of <30, ≥30 to <40, and ≥40 was 46, 76, and 87, respectively. Median maximum change in platelet count by baseline platelet count was +24, +42, and +40, respectively. Patients who received lusutrombopag without platelet transfusion achieved a median platelet count ≥50 for 3 weeks. CONCLUSIONS: Patients treated with lusutrombopag experienced a clinically relevant response in platelet count for a substantial duration of time. LAY SUMMARY: Patients with low platelet counts caused by chronic liver disease may not receive planned invasive procedures or surgeries because of an increased risk of bleeding. Lusutrombopag has previously demonstrated efficacy in raising platelet counts and is approved to treat chronic liver disease patients with low platelet counts in advance of a planned surgery. Physicians need to understand more clearly what to expect in terms of platelet count change when using lusutrombopag; this integrated analysis provides data to help guide its clinical application.

An agent-based model of the interrelation between the COVID-19 outbreak and economic activities.

As of July 2020, COVID-19 caused by SARS-COV-2 is spreading worldwide, causing severe economic damage. While minimizing human contact is effective in managing outbreaks, it causes severe economic losses. Strategies to solve this dilemma by considering the interrelation between the spread of the virus and economic activities are urgently needed to mitigate the health and economic damage. Here, we propose an abstract agent-based model of the COVID-19 outbreak that accounts for economic activities. The computational simulation of the model recapitulates the trade-off between the health and economic damage associated with voluntary restraint measures. Based on the simulation results, we discuss how the macroscopic dynamics of infection and economics emerge from individuals' behaviours. We believe our model can serve as a platform for discussing solutions to the above-mentioned dilemma.

Is platelet monitoring during 7-day lusutrombopag treatment necessary in chronic liver disease patients with thrombocytopenia undergoing planned invasive procedures? A phase IIIb open-label study.

AIM: Lusutrombopag is approved for thrombocytopenia in chronic liver disease patients planned to undergo invasive procedures. In previous clinical studies, lusutrombopag treatment was stopped in patients with an increase in platelet count (PC) of ≥20 × 109 /L from baseline and whose PC was ≥50 × 109 /L (discontinuation criteria). We assessed the influence of platelet monitoring during lusutrombopag treatment in lusutrombopag-naïve patients. METHODS: In this open-label study, Child-Pugh class A and B (A/B) patients were enrolled and treated with lusutrombopag (3 mg/day) for 7 days. In the treatment-naïve A/B-1 group, the discontinuation criteria were applied on day 6. In the treatment-naïve A/B-2 group, the criteria were not applied. In a non-naïve A/B group, the criteria were applied on days 3 and 5-7. The main efficacy end-point was the proportion of patients without platelet transfusion (PT) before the primary invasive procedure. RESULTS: In the A/B-1, A/B-2, and non-naïve A/B groups, the proportions of patients without PT were 80.9% (38/47), 83.0% (39/47), and 75.0% (6/8), respectively. The mean durations of PC ≥ 50 × 109 /L without PT were 20.7, 20.3, and 22.8 days, respectively. Excessive PC increases (≥200 × 109 /L) were not detected in any group. Treatment-related adverse events occurred in 4.3%, 6.4%, and 0% of A/B-1, A/B-2, and non-naïve A/B patients, respectively. Severe portal vein thrombosis occurred in one A/B-2 patient (PC 75 × 109 /L at onset). CONCLUSIONS: No meaningful efficacy and safety differences were observed among the groups with or without discontinuation criteria and the non-naïve group. These findings support lusutrombopag treatment without platelet monitoring and retreatment with lusutrombopag.

Evaluation of drug-drug interaction of lusutrombopag, a thrombopoietin receptor agonist, via metabolic enzymes and transporters.

PURPOSE: Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling. METHODS: The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.5-mg dose). The effect of cyclosporine on lusutrombopag pharmacokinetics was assessed in 16 healthy subjects receiving a single lusutrombopag 3-mg dose with or without a single cyclosporine 400- to 600-mg dose. PBPK modeling was employed to extrapolate the effect of lusutrombopag at the clinical dose (3 mg once daily) on midazolam pharmacokinetics. RESULTS: In the clinical study, mean ratios (90% confidence intervals [CIs]) of with/without lusutrombopag for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of midazolam were 1.01 (0.908-1.13) and 1.04 (0.967-1.11), respectively, indicating no effect of lusutrombopag on midazolam pharmacokinetics. PBPK modeling suggested no effect of lusutrombopag at the clinical dose on midazolam pharmacokinetics. Mean ratios (90% CIs) of with/without cyclosporine for lusutrombopag Cmax and AUC were 1.18 (1.11-1.24) and 1.19 (1.13-1.25), respectively, indicating a slight increase in lusutrombopag exposure. CONCLUSIONS: In consideration with in vitro data, the in vivo and in silico results suggested no clinically significant DDI potential of lusutrombopag with other medical products via metabolic enzymes and transporters.

Decentralized Control for Swarm Robots That Can Effectively Execute Spatially Distributed Tasks.

A swarm robotic system is a system in which multiple robots cooperate to fulfill a macroscopic function. Many swarm robots have been developed for various purposes. This study aims to design swarm robots capable of executing spatially distributed tasks effectively, which can be potentially used for tasks such as search-and-rescue operation and gathering scattered garbage in rooms. We propose a simple decentralized control scheme for swarm robots by extending our previously proposed non-reciprocal-interaction-based model. Each robot has an internal state, called its workload. Each robot first moves randomly to find a task, and when it does, its workload increases, and then it attracts its neighboring robots to ask for their help. We demonstrate, via simulations, that the proposed control scheme enables the robots to effectively execute multiple tasks in parallel under various environments. Fault tolerance of the proposed system is also demonstrated.

Decoding Decentralized Control Mechanism Underlying Adaptive and Versatile Locomotion of Snakes.

Snakes have no limbs and can move in various environments using a simple elongated limbless body structure obtained through a long-term evolutionary process. Specifically, snakes have various locomotion patterns, which they change in response to conditions encountered. For example, on an unstructured terrain, snakes actively utilize the terrain's irregularities and move effectively by actively pushing their bodies against the "scaffolds" that they encounter. In a narrow aisle, snakes exhibit concertina locomotion, in which the tail part of the body is pulled forward with the head part anchored, and this is followed by the extension of the head part with the tail part anchored. Furthermore, snakes often exhibit three-dimensional (3-D) locomotion patterns wherein the points of ground contact change in a spatiotemporal manner, such as sidewinding and sinus-lifting locomotion. This ability is achieved possibly by a decentralized control mechanism, which is still mostly unknown. In this study, we address this aspect by employing a synthetic approach to understand locomotion mechanisms by developing mathematical models and robots. We propose a Tegotae-based decentralized control mechanism and use a 2-D snake-like robot to demonstrate that it can exhibit scaffold-based and concertina locomotion. Moreover, we extend the proposed mechanism to 3D and use a 3-D snake-like robot to demonstrate that it can exhibit sidewinding and sinus-lifting locomotion. We believe that our findings will form a basis for developing snake-like robots applicable to search-and-rescue operations as well as understanding the essential decentralized control mechanism underlying animal locomotion.

Lusutrombopag Is Safe and Efficacious for Treatment of Thrombocytopenia in Patients With and Without Hepatocellular Carcinoma.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) secondary to chronic liver disease often require invasive procedures but frequently have thrombocytopenia. Lusutrombopag is an agonist of the thrombopoietin receptor that activates platelet production. METHODS: We performed an integrated analysis of data from 2 phase 3 trials (L-PLUS 1, Japan, October 2013 to May 2014, and L-PLUS 2, global, June 2015 to April 2017) that compared the efficacy and safety of lusutrombopag with placebo in patients with chronic liver disease, with and without HCC. Our analysis included patients with Eastern Cooperative Oncology Group grades of 0 or 1, Child-Pugh classes A or B, and a platelet count less than 50 × 109/L who were scheduled to undergo invasive procedures in 9 to 14 days. Patients received lusutrombopag (3 mg) or placebo daily for 7 days or fewer before an invasive procedure. Imaging studies assessed treatment-emergent adverse events, including asymptomatic portal vein thrombosis. The primary end point was no requirement for platelet transfusion before the invasive procedure and rescue therapies for bleeding 7 days or fewer after the invasive procedure. RESULTS: The per-protocol population included 270 patients (95 with HCC). A significantly higher proportion of patients with HCC who received lusutrombopag achieved the primary end point (68.0%) vs patients who received placebo (8.9%) (P < .0001); in patients without HCC, these proportions were 77.0% vs 21.6% (P < .0001). Lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events in patients with and without HCC compared with placebo. Risk of thrombosis was similar to that of placebo. CONCLUSIONS: Patients with and without HCC receiving lusutrombopag had a reduction in the number of platelet transfusions before invasive procedures compared with patients receiving placebo, with no increase in thrombosis or bleeding. L-PLUS 1: JapicCTI-132323; L-PLUS 2: ClinicalTrials.gov number no: NCT02389621.

Sprawling Quadruped Robot Driven by Decentralized Control With Cross-Coupled Sensory Feedback Between Legs and Trunk.

Quadruped animals achieve agile and highly adaptive locomotion owing to the coordination between their legs and other body parts, such as the trunk, head, and tail, that is, body-limb coordination. This study aims to understand the sensorimotor control underlying body-limb coordination. To this end, we adopted sprawling locomotion in vertebrate animals as a model behavior. This is a quadruped walking gait with lateral body bending used by many amphibians and lizards. Our previous simulation study demonstrated that cross-coupled sensory feedback between the legs and trunk helps to rapidly establish body-limb coordination and improve locomotion performance. This paper presented an experimental validation of the cross-coupled sensory feedback control using a newly developed quadruped robot. The results show similar tendencies to the simulation study. Sensory feedback provides rapid convergence to stable gait, robustness against leg failure, and morphological changes. Our study suggests that sensory feedback potentially plays an essential role in body-limb coordination and provides a robust, sensory-driven control principle for quadruped robots.