Pharmacokinetics, metabolism, excretion and safety of iruplinalkib (WX-0593), a novel ALK inhibitor, in healthy subjects: a phase I human radiolabeled mass balance study.

BACKGROUND: Iruplinalkib is a novel anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ALK-positive crizotinib-resistant NSCLC. RESEARCH DESIGN AND METHODS: A single oral dose of 120 mg/3.7 MBq [14C]iruplinalkib was administered to healthy subjects. Blood, urine and fecal samples were collected and analyzed for iruplinalkib and its metabolites. The safety of iruplinalkib was also assessed. RESULTS: Iruplinalkib was absorbed quickly and eliminated slowly from plasma, with a Tmax of 1.5 h and t1/2 of 28.6 h. About 88.85% of iruplinalkib was excreted at 312 h, including 20.23% in urine and 68.63% in feces. Seventeen metabolites of iruplinalkib were identified, and M3b (demethylation), M7 (cysteine conjugation), M11 (oxidative dehydrogenation and cysteine conjugation of M3b) and M12 (oxidative dehydrogenation and cysteine conjugation) were considered the prominent metabolites in humans. Iruplinalkib-related compounds were found to be covalently bound to proteins, accounting for 7.70% in plasma and 17.96% in feces, which suggested chemically reactive metabolites were formed. There were no serious adverse events observed in the study. CONCLUSIONS: Iruplinalkib was widely metabolized and excreted mainly through feces in humans. Unchanged iruplinalkib, cysteine conjugates and covalent protein binding products were the main drug-related compounds in circulation. Iruplinalkib was well tolerated at the study dose. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (Identifier: Anonymized).

Using voice recognition to measure trust during interactions with automated vehicles.

Trust in an automated vehicle system (AVs) can impact the experience and safety of drivers and passengers. This work investigates the effects of speech to measure drivers' trust in the AVs. Seventy-five participants were randomly assigned to high-trust (the AVs with 100% correctness, 0 crash, and 4 system messages with visual-auditory TORs) and low-trust group (the AVs with a correctness of 60%, a crash rate of 40%, 2 system messages with visual-only TORs). Voice interaction tasks were used to collect speech information during the driving process. The results revealed that our settings successfully induced trust and distrust states. The corresponding extracted speech feature data of the two trust groups were used for back-propagation neural network training and evaluated for its ability to accurately predict the trust classification. The highest classification accuracy of trust was 90.80%. This study proposes a method for accurately measuring trust in automated vehicles using voice recognition.

Corydalis tomentella Franch. Exerts anti-inflammatory and analgesic effects by regulating the calcium signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis tomentella Franch. is a perennial cespitose plant commonly used to treat stomachaches as a folk medicine. The C. tomentella total alkaloids have good protective effects against acute liver injury and potential anti-hepatoma and anti-Alzheimer's disease activities. AIM OF THE STUDY: To establish an effective purification process for total alkaloids from C. tomentella and investigate the mechanism of their anti-inflammatory effects. MATERIALS AND METHODS: Corydalis tomentella were purified using macroporous resin. Then the crude and purified C. tomentella extracts (cCTE and pCTE) were qualitatively analyzed using UPLC-Triple-TOF-MS/MS. The cCTE and pCTE were used to investigate and compare their anti-inflammatory effects on lipopolysaccharide (LPS)-induced RAW264.7 cells. Doses at 100, 200 and 400 mg/kg/d of pCTE were used to study their anti-inflammatory and analgesic activities in mice with xylene-induced ear swelling and acetic acid-induced writhing tests. Content of nitric oxide (NO), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were determined both in RAW264.7 cells and mice. Network pharmacology was used to predict the anti-inflammatory mechanism of C. tomentella, and the key enzymes were validated using qPCR and Western Blot analysis. Concentration of intracellular Ca2+ was detected using flow cytometric analysis. RESULTS: The C. tomentella total alkaloid purity increased from 6.29% to 47.34% under optimal purification conditions. A total of 54 alkaloids were identified from CTE. Both cCTE and pCTE could suppress the LPS-induced production of NO, IL-6, IL-1ß, and TNF-α in RAW264.7 cells. The pCTE exhibited a more potent anti-inflammatory effect; it also inhibited pain induced by xylene and acetic acid in mice. The calcium signaling pathway is associated with the anti-inflammatory and analgesic activities of C. tomentella. The mRNA expression of nitric oxide synthase (NOS) 2, NOS3 and calmodulin1 (CALM1) was regulated by C. tomentella through the reduction of inflammation-induced Ca2+ influx, and it also exhibited a more pronounced effect than the positive control (L-NG-nitro arginine methyl ester). CONCLUSIONS: Purified C. tomentella extract shows anti-inflammatory effect both in vitro and in vivo. It exerts anti-inflammatory and analgesic effects through the calcium signaling pathway by down-regulating NOS2 and CALM1 expression and up-regulating NOS3 expression in LPS-induced RAW264.7 cells, and decreasing intracellular Ca2+ concentration.

A mathematical model of catalyst combination design and temperature control in the preparation of C4 olefins through ethanol coupling.

The preparation of C4 olefins through ethanol catalytic coupling is a crucial area of study. According to the experimental data obtained by a chemical laboratory for different catalysts at different temperatures, three mathematical models were developed to provide insights into the relationships among ethanol conversion rate, C4 olefins selectivity, yield, catalyst combination, and temperature. The first model is a nonlinear fitting function that analyses the relationships among ethanol conversion rate, C4 olefins selectivity, and temperature under varying catalyst combinations. Two-factor analysis of variance was employed to determine the influence of catalyst combinations and temperatures on ethanol conversion rate and C4 olefins selectivity. The second model is a multivariate nonlinear regression model that describes the relationships among the yield of C4 olefins, catalyst combination, and temperature. Finally, an optimization model was derived based on the experimental conditions; it provides a solution for the selection of the optimal catalyst combinations and temperatures to achieve the maximum yield of C4 olefins. This work has significant implications for the field of chemistry and the production of C4 olefins.

Inattentional blindness to unexpected hazard in augmented reality head-up display assisted driving: The impact of the relative position between stimulus and augmented graph.

OBJECTIVE: An augmented reality head-up display (AR-HUD) is a promising technology in assisted driving. It provides additional information in the driving environment. However, considering the registration problem related to the limitations of interactive technology, we suspect that an AR-HUD may not be able to recognize unpredictable stimuli in a timely manner, inducing inattentional blindness to these non-augmented stimuli. Actually, non-augmented stimuli may accidentally have a brief superimposition to AR graphics. This condition may also influence the rate of inattentional blindness accordingly. Thus, this study examined the problem of inattentional blindness in AR-HUD systems that may result from the immaturity of AR technology. METHOD: We investigated the impact of AR graphic position (peripheral AOI v.s. central AOI) and the relative position of the AR graphic on unpredictable stimuli (on-HUD hazard v.s. off-HUD hazard) on the occurrence of inattentional blindness. Thirty Participants watched an AR-augmented driving video that included four augmented conditions. Participants were instructed to respond to four critical events (speeding, running of red lights, unexpected pedestrians or motorcycles). The rate of inattentional blindness and response time were recorded. We only analyzed data on unexpected pedestrian and motorcycle incidents. RESULTS: The relative position of the AR graphic on unpredictable stimuli and AR graphic positions significantly affected the rate of inattentional blindness and response time. Drivers had a higher rate of inattentional blindness to the unpredictable stimulus briefly superimposed on the AR graphic (i.e., on-HUD hazard) in the peripheral visual field (i.e., peripheral AOI). Also, drivers exhibited a higher rate of inattentional blindness to the unpredictable stimuli outside the AR graphic (i.e., off-HUD hazard) in the central visual field (i.e., central AOI). CONCLUSION: The study is expected to be beneficial for furthering the design of an AR-HUD-assisted system to reduce inattentional blindness in driving. Our results found that in the peripheral visual field, unpredictable stimuli accidentally superimposed on the AR graphic (i.e., on-HUD hazard) lead to a higher probability of ignoring the accidental events and seemed to require a longer response time for drivers. This study illustrated that inattentional blindness to non-augmented stimuli is also influenced by the AR graphic position when AR technology fails to augment them in a timely manner. An important recommendation emerging from this work is to consider the design of AR graphics according to the AR graphic positions and stimulus types to reduce the occurrence of inattentional blindness.

The Impact of Different Types of Auditory Warnings on Working Memory.

Auditory warnings have been shown to interfere with verbal working memory. However, the impact of different types of auditory warnings on working memory tasks must be further researched. This study investigated how different kinds of auditory warnings interfered with verbal and spatial working memory. Experiment 1 tested the potential interference of auditory warnings with verbal working memory. Experiment 2 tested the potential interference of auditory warnings with spatial working memory. Both experiments used a 3 × 3 mixed design: auditory warning type (auditory icons, earcons, or spearcons) was between groups, and task condition (no-warning, identify-warning, or ignore-warning) was within groups. In Experiment 1, earcons and spearcons but not auditory icons worsened the performance on the verbal serial recall task in the identify-warning condition, compared with that in the no-warning or ignore-warning conditions. In Experiment 2, only identifying earcons worsened the performance on the location recall task compared with performance without auditory warnings or when auditory warnings were ignored. Results are discussed from the perspective of working memory resource interference, and their practical application in the selection and design of auditory warning signals is involved.

Effects of sampling strategies and DNA extraction methods on eDNA metabarcoding: A case study of estuarine fish diversity monitoring.

Environmental DNA (eDNA) integrated with metabarcoding is a promising and powerful tool for species composition and biodiversity assessment in aquatic ecosystems and is increasingly applied to evaluate fish diversity. To date, however, no standardized eDNA-based protocol has been established to monitor fish diversity. In this study, we investigated and compared two filtration methods and three DNA extraction methods using three filtration water volumes to determine a suitable approach for eDNA-based fish diversity monitoring in the Pearl River Estuary (PRE), a highly anthropogenically disturbed estuarine ecosystem. Compared to filtration-based precipitation, direct filtration was a more suitable method for eDNA metabarcoding in the PRE. The combined use of DNeasy Blood and Tissue Kit (BT) and traditional phenol/chloroform (PC) extraction produced higher DNA yields, amplicon sequence variants (ASVs), and Shannon diversity indices, and generated more homogeneous and consistent community composition among replicates. Compared to the other combined protocols, the PC and BT methods obtained better species detection, higher fish diversity, and greater consistency for the filtration water volumes of 1 000 and 2 000 mL, respectively. All eDNA metabarcoding protocols were more sensitive than bottom trawling in the PRE fish surveys and combining two techniques yielded greater taxonomic diversity. Furthermore, combining traditional methods with eDNA analysis enhanced accuracy. These results indicate that methodological decisions related to eDNA metabarcoding should be made with caution for fish community monitoring in estuarine ecosystems.

Optimal Time Intervals in Two-Stage Takeover Warning Systems With Insight Into the Drivers' Neuroticism Personality.

Conditional automated driving [level 3, Society of Automotive Engineers (SAE)] requires drivers to take over the vehicle when an automated system's failure occurs or is about to leave its operational design domain. Two-stage warning systems, which warn drivers in two steps, can be a promising method to guide drivers in preparing for the takeover. However, the proper time intervals of two-stage warning systems that allow drivers with different personalities to prepare for the takeover remain unclear. This study explored the optimal time intervals of two-stage warning systems with insights into the drivers' neuroticism personality. A total of 32 drivers were distributed into two groups according to their self-ratings in neuroticism (high vs. low). Each driver experienced takeover under the two-stage warning systems with four time intervals (i.e., 3, 5, 7, and 9 s). The takeover performance (i.e., hands-on-steering-wheel time, takeover time, and maximum resulting acceleration) and subjective opinions (i.e., appropriateness and usefulness) for time intervals and situation awareness (SA) were recorded. The results showed that drivers in the 5-s time interval had the best takeover preparation (fast hands-on steering wheel responses and sufficient SA). Furthermore, both the 5- and 7-s time intervals resulted in more rapid takeover reactions and were rated more appropriate and useful than the 3- and 9-s time intervals. In terms of personality, drivers with high neuroticism tended to take over immediately after receiving takeover messages, at the cost of SA deficiency. In contrast, drivers with low neuroticism responded safely by judging whether they gained enough SA. We concluded that the 5-s time interval was optimal for drivers in two-stage takeover warning systems. When considering personality, drivers with low neuroticism had no strict requirements for time intervals. However, the extended time intervals were favorable for drivers with high neuroticism in developing SA. The present findings have reference implications for designers and engineers to set the time intervals of two-stage warning systems according to the neuroticism personality of drivers.

Incidence and Risk Factors of Postoperative Bleeding in Patients Undergoing Total Thyroidectomy.

Purpose: Our goal was to analyze postoperative bleeding in patients undergoing total thyroidectomy and to explore the possible risk factors. Materials and Methods: Patients undergoing total thyroidectomy were retrospectively enrolled, and the main study outcomes were postoperative bleeding and 30-day mortality. Univariate and multivariate analyses were used to determine the independent risk factors for postoperative bleeding. Results: A total of 31,706 patients were enrolled for analysis during January 2010 and December 2018 from the Affiliated First Hospital of Zhengzhou University. Benign and malignant disease was reported in 4,521 and 27,185 patients, respectively. Postoperative bleeding occurred in 48 patients with benign disease and in 263 patients with malignant disease. There was one bleeding site in 243 patients. The branch of the superior thyroid artery was the most common arterial bleeding site, occurring in 124 patients, and the anterior jugular vein was the most common venous bleeding site, occurring in 85 patients. Multivariable analysis confirmed that hypertension, diabetes, BMI, and disease pathology were independent factors affecting postoperative bleeding in patients with benign disease and that hypertension, diabetes, BMI, operation time, tumor stage, and tracheotomy were independent factors affecting postoperative bleeding in patients with malignant disease. In patients with postoperative bleeding, there were 5 deaths; in patients without postoperative bleeding, there were 42 deaths, and the difference was significant (p < 0.001). Conclusions: Compared with malignant disease patients, benign disease patients have a similar postoperative bleeding rate. A previous history of chemotherapy or radiotherapy has no significant effect on postoperative bleeding.

Promote or inhibit: An inverted U-shaped effect of workload on driver takeover performance.

OBJECTIVE: In conditional automated driving (SAE Level 3), drivers are required to take over their vehicles when the automated systems fail. Non-driving related tasks (NDRTs) can positively or negatively affect takeover safety, but the underlying reasons for this inconsistency remain unclear. This study aims to investigate how various workload levels generated by NDRTs may influence the takeover performance of drivers and the lead time they require. METHOD: Fifty drivers were randomly distributed into five groups, which corresponded to five workload levels (1-4 levels generated by Tetris game; control level generated by monitoring). Each driver completed vehicle takeover tasks upon receiving takeover requests with various lead times (3, 5, 7, 9, and 11 s) while engaging in NDRTs. The drivers' takeover performance and subjective opinions were recorded. RESULTS: Drivers in the moderate workload condition (i.e., level 3) had significantly shorter takeover times and better takeover quality than those in the lower (i.e., level 1 and level 2) or higher (i.e., level 4) workload conditions. They also subjectively required less lead time in the moderate condition. Moreover, the drivers rated 7 s as the most appropriate lead time despite the improvement in their overall takeover performances with increased lead time. CONCLUSIONS: This study found an inverted U-shaped relationship between the drivers' workload generated by NDRTs and takeover performance. The moderate workload level (rather than the lower or higher workload level) led to a faster and better takeover performance, and it seemed to require minimal lead time for drivers. These findings help understand the relationship of drivers' workload during the automation and takeover performance in conditional automated driving. An important recommendation emerging from this work is to investigate what should be the most efficient method to detect the drivers' workload state real-time and give feedback to them when it comes to overload or underload during the automated driving.

Impact of Learning Methods on Spatial Knowledge Acquisition.

Research on the acquisition of spatial knowledge not only enriches our understanding of the theory of spatial knowledge representation but also creates practical value for the application of spatial knowledge. The aim of this study is to understand the impact of different learning methods on the acquisition of spatial knowledge, including the role of 2D maps, the difference between physical interaction and virtual interaction, and whether passive learning can replace active learning in virtual environments. One experiment was conducted, in which landmark knowledge and configurational knowledge were measured. Results indicate that 2D maps play a supporting role in acquiring both landmark knowledge and configurational knowledge. In addition, physical learning was associated with better spatial knowledge representation compared with virtual learning. An analysis of observational data in the third comparison found no significant difference between passive learning and active learning using virtual street view maps. However, with high-quality learning materials, passive learning can contribute to the acquisition of spatial knowledge more efficiently than active learning.

Influences of Experience and Visual Cues of Virtual Arm on Distance Perception.

Egocentric distance perception refers to the perception of distance from a target to a perceiver, which is an important component of visual space perception. It is important to activities in virtual environments and influenced by several factors, such as action capacities and visual cues. However, few studies have investigated such aspects. Hence, Experiments 1 and 2 investigated the effect of using experience and visual cues, respectively, of virtual arms on egocentric distance perception in near and far spaces at equal, prolonged, and shortened lengths of a virtual arm. Results revealed that using experience and visual cues of the virtual arm had a significant effect on egocentric distance perception when the length of virtual arm was equal to the real arm and prolonged but not when shortened. The egocentric distance perception on the conditions of having using experience and virtual arm was most precise. The findings provide implications for the design and implementation of virtual body self-representation in virtual environments.

Influences of Augmented Reality Assistance on Performance and Cognitive Loads in Different Stages of Assembly Task.

According to the assembly task model proposed by Stork and Schubö (2010), the assembly task is divided into commissioning and joining subtasks. Each subtask includes two sequential stages, namely, perception and response selection, and action. This division enables a convenient discussion of the influences of Augmented reality (AR) assistance on operators during different stages of an assembly task. Research results can provide a basis for the further analysis of the influence mechanism of AR assistance on an assembly task. This study is composed of three experiments. Experiment 1 explores the influences of AR assistance on the performance of the overall assembly task and the commissioning and joining subtasks. Combining a variation of task complexities, Experiments 2 and 3 discuss the influences of AR assistance on the different stages of the commissioning and joining subtasks. We found that AR assistance can shorten the time of the overall assembly task and subtasks (commissioning and joining) and reduce mistakes during these tasks. Moreover, AR assistance can decrease cognitive load in the commissioning subtask, but it increases cognitive load in the joining task with low complexity. In the perception and response selection stage of the commissioning and joining subtasks, AR assistance can shorten the time for users to recognize the target part and understand the assembly relation. This advantage is extremely significant for the high-complexity task. In the action stage of two subtasks, AR assistance can shorten the time for users to capture parts, but it prolongs the time for users to build parts.

Effect of spatial enhancement technology on input through the keyboard in virtual reality environment.

Scientific developments have enabled the application of virtual reality (VR) technology in various fields. However, this technology is disadvantaged by low recognition, existence of bias, lack of precision, and fatigue of text input in VR environments. To address these problems, this study proposed a spatial enhancement technique. This study investigated the effectiveness of spatial enhancement keys of a virtual keyboard from various angles and explored the impact of enhanced response time and enhanced protrusion distance on the spatial enhancement technology. Finally, the following conclusions are obtained: (1) The average text input performance of the keyboard using the spatial enhancement technique is significantly better than that of the ordinary virtual keyboard without using the spatial enhancement technique. (2) The recommended time interval for enhanced response time and the protrusion distance are 0-100 ms and 1.85 diopter, respectively. The keyboard angle insignificantly affects the input through the keyboard performance.

Evaluation of MEDAG gene expression in papillary thyroid microcarcinoma: associations with histological features, regional lymph node metastasis and prognosis.

Papillary thyroid microcarcinoma accounts for a large proportion of papillary thyroid carcinoma, especially among new cases. Many  PTMC patients have regional lymph node metastasis, with some experiencing recurrence and even death. However, the risk factors and mechanism by which PTMC relates to these factors are unknown. In this study, differentially expressed genes were identified with microarray from The Cancer Genome Atlas, followed by analysis using the Kyoto Encyclopedia of Genes and Genomes. Immunohistochemistry, immunofluorescence, western blot and Oil Red O staining were carried out to evaluate expression levels and functional alterations. Mesenteric Estrogen Dependent Adipogenesis expression was observed in almost all cases of papillary thyroid microcarcinomas, and the location of expression was associated with histological subtype. High expression was correlated with metastasis and poor disease-free survival. Furthermore, the enrichment analysis indicated that Mesenteric Estrogen Dependent Adipogenesis expression may be associated with metabolic reprogramming to influence metastasis and prognosis. These findings contribute to a better understanding of how Mesenteric Estrogen Dependent Adipogenesis affects metastasis and the prognosis of papillary thyroid microcarcinoma patients and suggest that Mesenteric Estrogen Dependent Adipogenesis expression may be a novel prognostic marker in these patients.

Inhibitory control differentiates rare target search performance in children.

Age-related differences in rare-target search are primarily explained by the speed-accuracy trade-off, primed responses, or decision making. The goal was to examine how motor inhibition influences visual search. Children pressed a key when a rare target was detected. On no-target trials, children withheld reactions. Response time (RT), hits, misses, correct rejection, and false alarms were measured. Tapping tests assessed motor control. Older children tapped faster, were more sensitive to rare targets (higher d'), and reacted more slowly than younger ones. Girls outperformed boys in search sensitivity but not in RT. Motor speed was closely associated with hit rate and RT. Results suggest that development of inhibitory control plays a key role in visual detection. The potential implications for cognitive-motor development and individual differences are discussed.