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Guiding an aircraft to 4D waypoints at a certain heading is a multi-dimensional goal aircraft guidance problem. [d=Zu]In order to improve the performance and solve this problem, this paper proposes a multi-layer RL approach.To enhance the performance, in the present study, a multi-layer RL approach to solve the multi-dimensional goal aircraft guidance problem is proposed. The approach [d=Zu]enablesassists the autopilot in an ATC simulator to guide an aircraft to 4D waypoints at certain latitude, longitude, altitude, heading, and arrival time, respectively. To be specific, a multi-layer RL [d=Zu]approach is proposedmethod to simplify the neural network structure and reduce the state dimensions. A shaped reward function that involves the potential function and Dubins path method is applied. [d=Zu]Experimental and simulation results show that the proposed approachExperiments are conducted and the simulation results reveal that the proposed method can significantly improve the convergence efficiency and trajectory performance. [d=Zu]FurthermoreFurther, the results indicate possible application prospects in team aircraft guidance tasks, since the aircraft can directly approach a goal without waiting in a specific pattern, thereby overcoming the problem of current ATC simulators.

Background Although immunotherapy shows tremendous potential in the treatment of bladder cancer (BLCA), the overall prognosis and response rates to immunotherapy in BLCA remain suboptimal. Methods We performed an extensive evaluation of glycosyltransferase expression patterns in BLCA patients by analyzing 210 glycosyltransferase-related genes. Subsequently, we established correlations between these glycosyltransferase patterns, prognosis, and tumor microenvironment (TME) phenotypes. To offer personalized patient assessments, we developed a glycosyltransferase risk score that accurately predicts prognosis, TME phenotypes, and molecular subtypes. Importantly, we developed a RNA-seq cohort, named Xiangya cohort, to validate our results. Results Two distinct patterns of glycosyltransferase expression were identified, corresponding to inflamed and noninflamed TME phenotypes, and demonstrated the potential to predict prognosis. We developed and validated a comprehensive risk score that accurately predicted individual patient prognosis in the TCGA-BLCA cohort. Additionally, we constructed a nomogram that integrated the risk score with several key clinical factors. Importantly, this risk score was successfully validated in external cohorts, including the Xiangya cohort and GSE48075. Furthermore, we discovered a positive correlation between this risk score and tumor-infiltrating lymphocytes in both the TCGA-BLCA and Xiangya cohorts, suggesting that patients with a higher risk score exhibited an inflamed TME phenotype and were more responsive to immunotherapy. Finally, we observed that the high and low risk score groups were consistent with the luminal and basal subtypes of BLCA, respectively, providing further validation of the risk score’s role in the TME in terms of molecular subtypes. Conclusions Glycosyltransferase patterns exhibit distinct TME phenotypes in BLCA. Our comprehensive risk score provides a promising approach for prognostic prediction and assessment of immunotherapy efficacy, offering valuable guidance for precision medicine.

Background Stroke prehospital time is exceptionally long in China. The multifaceted Stroke 1-2-0 Amplifying Version Engagement (SAVE) intervention has substantially reduced onset-to-door time for patients with acute stroke in Shanghai, China. However, there is limited evidence regarding the economic impacts of community educational interventions on reducing hospital delays. Therefore, this study aimed to assess the implementation and downstream healthcare costs associated with the educational program. Methods Data were extracted anonymously from the hospital information systems for all ischemic stroke patients admitted to the hospital from 2016 to 2019. Ischemic stroke patients who presented to the hospital within 2 days of stroke were included in the analysis. Cost data from different years were converted into 2019 Chinese Yuan (CNY) using a 5% discount rate based on China Guidelines for Pharmacoeconomic Evaluations. We used a multivariate generalized linear model (GLM) with a log-link to examine the intervention’s impact on length of stay (LOS) and costs. Results The SAVE intervention was estimated to cost CNY 1,768,067 for Xinzhuang County from October 2016 to December 2019. Most costs (59.51%) were for the mass media broadcast. 2,830 stroke patients met the inclusion criteria, including 490 in the pre-SAVE and 2,340 in the post-SAVE period. Following the multifaceted SAVE intervention, the mean (± standardized deviation [SD]) LOS decreased from 9.48 (± 3.80) days to 8.80 (± 3.55) days, representing a reduction of 7.17%. The mean (± SD) hospitalization costs per patient dropped from CNY 21,951 (± 10,411) to CNY 19,263 (± 12,773) ( P  < 0.001), with a 12.25% reduction in hospitalization costs. In the GLM model, the intervention was associated with reduced LOS (β coefficient [95% CI]: -0.070 [-0.11 to -0.030]; P  < 0.001) and hospitalization costs (β coefficient [95% CI]: -0.11 [-0.17 to -0.053]; P  < 0.001). Conclusions Our findings suggest that the SAVE intervention was associated with potential cost-offsets through its effect on reducing LOS and hospitalization costs. To further enhance stroke awareness at the national level, innovative approaches to educational delivery, such as mobile-based platforms and AI-enhanced strategies, represent promising hypotheses that warrant future evaluation.

HighlightsAn artificial macrophage with hierarchical nanostructure (BaSO4@ZIF-8/TRF NMΦ) is constructed as an alternative to immunoactive macrophages.The Zn2+ chemical messenger as an “artificial cytokine” is released from the artificial macrophage to induce tumor anoikis and enhance immunogenicity.The artificial macrophage can efficiently capture tumor antigens for antigen presentation and T cell activation to fabricate long-term antitumor immunity, successfully mimicking the basic functions of natural immunoactive macrophage.Artificial cells are constructed from synthetic materials to imitate the biological functions of natural cells. By virtue of nanoengineering techniques, artificial cells with designed biomimetic functions provide alternatives to natural cells, showing vast potential for biomedical applications. Especially in cancer treatment, the deficiency of immunoactive macrophages results in tumor progression and immune resistance. To overcome the limitation, a BaSO4@ZIF-8/transferrin (TRF) nanomacrophage (NMΦ) is herein constructed as an alternative to immunoactive macrophages. Alike to natural immunoactive macrophages, NMΦ is stably retained in tumors through the specific affinity of TRF to tumor cells. Zn2+ as an “artificial cytokine” is then released from the ZIF-8 layer of NMΦ under tumor microenvironment. Similar as proinflammatory cytokines, Zn2+ can trigger cell anoikis to expose tumor antigens, which are selectively captured by the BaSO4 cavities. Therefore, the hierarchical nanostructure of NMΦs allows them to mediate immunogenic death of tumor cells and subsequent antigen capture for T cell activation to fabricate long-term antitumor immunity. As a proof-of-concept, the NMΦ mimics the biological functions of macrophage, including tumor residence, cytokine release, antigen capture and immune activation, which is hopeful to provide a paradigm for the design and biomedical applications of artificial cells.

Background In this brief report, we investigated the impact of COVID‐19 on outpatient stroke clinics and inpatient services and their recovery process. Methods We sent a survey to physicians worldwide through the network of the World Stroke Organization to investigate the impact of COVID‐19 on stroke clinics. To farther along in recovering from the outbreak, we reviewed stroke and other neurology outpatient clinic visits (approximately 50% were stroke related) and the number of inpatient services from December 2019 to July 2020 in a large neurology department in Shanghai, China, where there was no official city lockdown. Results We received 112 valid survey responses from 46 countries, representing all continents except for Antarctica. Only seven of the survey responders (7/112, 6.3%) reported that they have kept their outpatient clinics open as usual, but they did exercise increased precautions for COVID‐19 by following recent guidelines regarding use of personal protective equipment and isolation techniques. The remainder of the respondents have either reduced outpatient clinic services or suspended outpatient clinics completely. Telephone consultation or telemedicine with video capability was used for new patients or follow‐ups, with limited in‐person evaluations when necessary. Outpatient clinic visits and inpatient services from a large tertiary hospital in China decreased dramatically during the peak period of the outbreak, but then rebounded back quickly following the partial or full recovery from the outbreak. Compared with the recovery process of inpatient services, outpatient clinic visits decreased faster and recovered much slower. This is consistent with our global survey data which indicates that some outpatient clinics have rescheduled their outpatient visits for 3 to 6 months. Conclusions The COVID‐19 pandemic caused a significant drop of in‐person outpatient visits and inpatient services. Clinic visits recovered slower than inpatient services in stroke and other neurological diseases after the pandemic. The changes in outpatient visits and inpatient services from the neurology department in a tertiary hospital in Shanghai, China, where there was no official city lockdown during the pandemic. A. It indicates the clinic visits from January 2019 to July 2020. Clinic visits dropped by 36.6% in February 2020 as compared to that in February in 2019, with a partial rebound as the effects of the pandemic waned; B. It indicates the inpatient services in stroke and all neurological diseases from January 2019 to July 2020. Inpatient services in stroke and all neurological diseases dropped by 27.4% and 23.8%, respectively, in February 2020 as compared to that in February in 2019 and then rose rapidly to a nearly normal status

[...]we propose our model \"Stroke 1-2-0\" as a novel educational strategy suitable for China.

Perioperative infections, particularly surgical site infections pose significant morbidity and mortality. Phagocytosis is a critical step for microbial eradication. We examined the effect of commonly used anesthetics on macrophage phagocytosis and its mechanism. The effect of anesthetics (isoflurane, sevoflurane, propofol) on macrophage phagocytosis was tested using RAW264.7 mouse cells, mouse peritoneal macrophages, and THP-1 human cells. Either opsonized sheep erythrocytes or fluorescent labeled Escherichia coli were used as phagocytic objects. The activation of Rap1, a critical protein in phagocytosis was assessed using the active Rap1 pull-down and detection kit. To examine anesthetic binding site(s) on Rap1, photolabeling experiments were performed using azi-isoflurane and azi-sevoflurane. The alanine scanning mutagenesis of Rap1 was performed to assess the role of anesthetic binding site in Rap1 activation and phagocytosis. Macrophage phagocytosis was significantly attenuated by the exposure of isoflurane (50% reduction by 1% isoflurane) and sevoflurane (50% reduction by 1.5% sevoflurane), but not by propofol. Photolabeling experiments showed that sevoflurane directly bound to Rap1. Mutagenesis analysis demonstrated that the sevoflurane binding site affected Rap1 activation and macrophage phagocytosis. We showed that isoflurane and sevoflurane attenuated macrophage phagocytosis, but propofol did not. Our study showed for the first time that sevoflurane served as a novel small GTPase Rap1 inhibitor. The finding will further enrich our understanding of yet-to-be determined mechanism of volatile anesthetics and their off-target effects. The sevoflurane binding site was located outside the known Rap1 functional sites, indicating the discovery of a new functional site on Rap1 and this site would serve as a pocket for the development of novel Rap1 inhibitors.

Boron nitride nanoparticles have been reported for boron drug delivery. However, its toxicity has not been systematically elucidated. It is necessary to clarify their potential toxicity profile after administration for clinical application. Here, we prepared erythrocyte membrane-coated boron nitride nanoparticles (BN@RBCM). We expect to use them for boron neutron capture therapy (BNCT) in tumors. In this study, we evaluated the acute toxicity and subacute toxicity of BN@RBCM of about 100 nm and determined the half-lethal dose (LD50) of the particles for mice. The results showed that the LD50 of BN@RBCM was 258.94 mg/kg. No remarkable pathological changes by microscopic observation were observed in the treated animals throughout the study period. These results indicate that BN@RBCM has low toxicity and good biocompatibility, which have great potential for biomedical applications.

Volatile anesthetics have been in clinical use for a long period of time and are considered to be promiscuous by presumably interacting with several ion channels in the central nervous system to produce anesthesia. Because ion channels and their existing evolutionary analogues, ion transporters, are very important in various organisms, it is possible that volatile anesthetics may affect some bacteria. In this study, we hypothesized that volatile anesthetics could affect bacterial behaviors. We evaluated the impact of anesthetics on bacterial growth, motility (swimming and gliding) and biofilm formation of four common bacterial pathogens in vitro. We found that commonly used volatile anesthetics isoflurane and sevoflurane affected bacterial motility and biofilm formation without any effect on growth of the common bacterial pathogens studied here. Using available Escherichia coli gene deletion mutants of ion transporters and in silico molecular docking, we suggested that these altered behaviors might be at least partly via the interaction of volatile anesthetics with ion transporters.

This project implemented the Stroke 1-2-0 stroke awareness programme across China and investigated its impact over a 2-year period. We initiated the Stroke 1-2-0 educational campaign and Stroke 1-2-0 special task forces (STF) across the nation. Massive media coverage, community-based educational sessions with videos and other related materials and induction of Stroke 1-2-0 STF were the major means of promotion. We delivered a survey at the end of 2016 and 2018 to evaluate the impact of our effort. A total of 3066 participants responded to the first survey in 2016, and 15 207 participants responded in 2018 across China. The acceptance rate for Stroke 1-2-0 versus FAST (an English-language stroke awareness tool) was 50.2% versus 19.1% in 2016, and changed significantly to 82.2% versus 8.0% in 2018 (p<0.001). Stroke 1-2-0 was well accepted by all ages and by people with different academic qualifications. Only 6.5% of survey respondents were aware that there was a therapeutic window for thrombolytic therapy in 2016, but this awareness increased significantly to 32.8% in 2018. Only 12.6% of people in 2016 indicated that they would send patients with stroke to the nearest hospital capable of performing thrombolytic therapy, but there was a nearly threefold increase (52.5%) in this number by 2018. More than 1000 major hospitals joined the Stroke 1-2-0 STF, and more than 20 000 ‘stroke warriors’ have joined our stroke awareness improvement effort so far. Stroke 1-2-0 stroke awareness programme is well-implemented and accepted, and is generating profound improvement in stroke awareness in China.