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ObjectivesWe aimed to prospectively investigate the independent and combined relationship between trace elements concentrations [blood (selenium, manganese), serum (copper, zinc), and urine (cobalt, molybdenum, tin, strontium, iodine)] and all-cause mortality.MethodsThis study included 5,412 individuals with demographical, examination, and laboratory data from the National Health and Nutrition Examination Survey. Three statistical models, including Cox proportional hazards models, restricted cubic spline models, and Bayesian kernel machine regression (BKMR) models, were conducted to estimate the longitudinal relationship between trace elements and all-cause mortality.ResultsThere were 356 deaths documented with a median follow-up time of 70 months. In the single-exposure model, the results showed that compared with the lowest quartile, the adjusted hazard ratios (HRs) of mortality for the highest quartile of selenium, manganese, and strontium were 0.47 (95% CI: 0.28–0.79), 1.57 (95% CI: 1.14–2.14), and 0.47 (95% CI: 0.26–0.86), respectively. A nonlinear relationship between zinc, cobalt and mortality was also observed. Furthermore, a significant overall effect of mixtures of trace elements on all-cause mortality was identified, especially when the mixture was at the 60th percentile or lower.ConclusionThe association of multiple trace elements with all-cause mortality was identified in this study. It is recommended that healthcare providers and relevant public health agencies should strengthen the surveillance and management of trace elements. Emphasis should be placed on monitoring the sources of trace elements such as the body, food, and environment. More population studies and animal experiments should be conducted to identify the underlying mechanisms.

Graphene hydrogel (GH) and aerogel (GA) have great application potential as highly effective adsorbents, but the accessibility of their adsorption sites have not yet been identified, restricting our understanding on the adsorption mechanisms and manufacturing. This study comparatively studied the adsorption characteristics of bisphenol A (BPA) and naphthalene (NAP) on GH and GA, focussing on the accessibility of the adsorption sites. The adsorption of BPA on GA was much lower but faster than that on GH. NAP adsorption on GA was very close to that on GH but faster than that on the latter. Considering that NAP is volatilisable, we speculate that some unwetted sites in the air-enclosed pores are available to it, but not to BPA. We applied ultrasonic and vacuum treatments to remove the air in GA pores, which was verified using a CO2 replacement experiment. BPA adsorption was greatly enhanced but slowed, while that of NAP was not enhanced. This phenomenon suggested that some inner pores became accessible in the aqueous phase after air removal from pores. The enhanced accessibility of air-enclosed pores was verified by the increased relaxation rate of surface-bounded water on GA, based on a 1H NMR relaxation analysis. This study highlights that the accessibility of adsorption site plays a crucial role for the adsorption properties of carbon-based aerogel. The volatile chemicals may be quickly adsorbed in the air-enclosed pores, which be useful for immobilizing volatile contaminants.

Background Dementia has become the main cause of disability in older adults aged ≥75 years. Cerebral small vessel disease (CSVD) is involved in cognitive impairment (CI) and dementia and is a cause of vascular CI (VCI), which is manageable and its onset and progression can be delayed. Simple and effective markers will be beneficial to the early detection and intervention of CI. The aim of this study is to investigate the clinical application value of plasma amyloid β1-42 (Aβ42), phosphorylated tau 181 (p-tau181) and conventional structural magnetic resonance imaging (MRI) parameters for cognitive impairment (CI) in patients aged ≥75 years. Methods We retrospectively selected patients who visited the Affiliated Hospital of Xuzhou Medical University and were clinically diagnosed with or without cognitive dysfunction between May 2018 and November 2021. Plasma indicators (Aβ42 and p-tau181) and conventional structural MRI parameters were collected and analyzed. Multivariate logistic regression and receiver operator characteristic (ROC) curve were used to evaluate the diagnostic value. Results One hundred and eighty-four subjects were included, including 54 cases in CI group and 130 cases in noncognitive impairment (NCI) groups, respectively. Univariate logistic regression analysis revealed that the percentages of Aβ42+, P-tau 181+, and Aβ42+/P-tau181+ showed no significant difference between the groups of CI and NCI (all P > 0.05). Multivariate logistic regression analysis showed that moderate/severe periventricular WMH (PVWMH) (OR 2.857, (1.365–5.983), P = 0.005), lateral ventricle body index (LVBI) (OR 0.413, (0.243–0.700), P = 0.001), and cortical atrophy (OR 1.304, (1.079−1.575), P = 0.006) were factors associated with CI. The combined model including PVWMH, LVBI, and cortical atrophy to detect CI and NCI showed an area under the ROC curve (AUROC) is 0.782, with the sensitivity and specificity 68.5% and 78.5%, respectively. Conclusion For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.

Background Systemic Immune-inflammation Index (SII) and body composition parameters are easily assessed, and can predict overall survival (OS) in various cancers, allowing early intervention. This study aimed to assess the correlation between CT-derived body composition parameters and SII and OS in patients with advanced gastric cancer receiving dual programmed death-1 (PD-1) and human epidermal growth factor receptor 2 (HER2) blockade.Materials and methods This retrospective study enrolled patients with advanced gastric cancer treated with dual PD-1 and HER2 blockade from March 2019 to June 2022. We developed a deep learning model based on nnU-Net to automatically segment skeletal muscle, subcutaneous fat and visceral fat at the third lumbar level, and calculated the corresponding Skeletal Muscle Index, skeletal muscle density, subcutaneous fat area (SFA) and visceral fat area. SII was computed using the formula that total peripheral platelet count×neutrophil/lymphocyte ratio. Univariate and multivariate Cox regression analysis were used to determine the associations between SII, body composition parameters and OS.Results The automatic segmentation deep learning model was developed to efficiently segment body composition in 158 patients (0.23 s/image). Multivariate Cox analysis revealed that high SII (HR=2.49 (95% CI 1.54 to 4.01), p

Background Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB+ T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies.Methods To specifically activate the 4-1BB+ T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2×4-1BB bispecific antibody (termed ‘givastomig’ or ‘ABL111’; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner.Results 4-1BB+ T cells were observed to be coexisted with CLDN18.2+ tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-γ-responsive genes in human peripheral blood mononuclear cells when co-cultured with CLDN18.2+ tumor cells. Furthermore, in humanized 4-1BB transgenic mice inoculated with human CLDN18.2-expressing tumor cells, givastomig/ABL111 induced a localized immune activation in tumor as evident by the increased ratio of CD8+/regulatory T cell, leading to the superior antitumor activity and long-lasting memory response against tumor rechallenge. Givastomig/ABL111 was well tolerated, with no systemic immune response and hepatotoxicity in monkeys.Conclusions Givastomig/ABL111 is a novel CLDN18.2×4-1BB bispecific antibody which has the potential to treat patients with gastric cancer with a wide range of CLDN18.2 expression level through the restricted activation of 4-1BB+ T cells in tumor microenvironment to avoid the risk of liver toxicity and systemic immune response.

IntroductionAntimicrobial resistance (AMR) of Klebsiella pneumoniae (K. pneumoniae) poses a significant global public health threat and is responsible for a high prevalence of infections and mortality. However, knowledge about how ambient temperature influences the AMR of K. pneumoniae is limited in the context of global warming.MethodsAMR data of 31 Chinese provinces was collected from the China Antimicrobial Resistance Surveillance System (CARSS) between 2014 and 2020. Socioeconomic and meteorological data were collected from the China Statistical Yearbook during the same period. A modified difference-in-differences (DID) approach was applied to estimate the association between ambient temperature and third-generation cephalosporin-resistant K. pneumoniae (3GCRKP) and carbapenem-resistant K. pneumoniae (CRKP). Furthermore, moderating effects of socioeconomic factors were also evaluated.ResultsEvery 1°C increase in annual average temperature was associated with a 4.7% (relative risk (RR):1.047, 95% confidence intervals (CI): 1.031–1.082) increase in the detection rate of 3GCRKP, and a 10.7% (RR:1.107, 95% CI: 1.011–1.211) increase in the detection rate of CRKP. The relationships between ambient temperature and 3GCRKP and CRKP were found to be moderated by socioeconomic status (GDP per capita, income per capita, and consumption per capita; the interaction p-values

Background: Sleep disturbances are highly prevalent in movement disorders, potentially due to the malfunctioning of basal ganglia structures. Pallidal deep brain stimulation (DBS) has been widely used for multiple movement disorders and been reported to improve sleep. We aimed to investigate the oscillatory pattern of pallidum during sleep and explore whether pallidal activities can be utilized to differentiate sleep stages, which could pave the way for sleep-aware adaptive DBS. Methods: We directly recorded over 500 h of pallidal local field potentials during sleep from 39 subjects with movement disorders (20 dystonia, 8 Huntington's disease, and 11 Parkinson's disease). Pallidal spectrum and cortical-pallidal coherence were computed and compared across sleep stages. Machine learning approaches were utilized to build sleep decoders for different diseases to classify sleep stages through pallidal oscillatory features. Decoding accuracy was further associated with the spatial localization of the pallidum. Results: Pallidal power spectra and cortical-pallidal coherence were significantly modulated by sleep-stage transitions in three movement disorders. Differences in sleep-related activities between diseases were identified in non-rapid eye movement (NREM) and REM sleep. Machine learning models using pallidal oscillatory features can decode sleep-wake states with over 90% accuracy. Decoding accuracies were higher in recording sites within the internus-pallidum than the external-pallidum, and can be precited using structural (P

This study explores the potential of aerotolerant Bacteroides fragilis (B. fragilis) strains as next-generation probiotics (NGPs), focusing on their adaptability in the gastrointestinal environment, safety profile, and probiotic functions. From 23 healthy infant fecal samples, we successfully isolated 56 beneficial B. fragilis strains. Notably, the SNBF-1 strain demonstrated superior cholesterol removal efficiency in HepG2 cells, outshining all other strains by achieving a remarkable reduction in cholesterol by 55.38 ± 2.26%. Comprehensive genotype and phenotype analyses were conducted, including sugar utilization and antibiotic sensitivity tests, leading to the development of an optimized growth medium for SNBF-1. SNBF-1 also demonstrated robust and consistent antioxidant activity, particularly in cell-free extracts, as evidenced by an average oxygen radical absorbance capacity value of 1.061 and a 2,2-diphenyl-1-picrylhydrazyl scavenging ability of 94.53 ± 7.31%. The regulation of carbohydrate metabolism by SNBF-1 was assessed in the insulin-resistant HepG2 cell line. In enzyme inhibition assays, SNBF-1 showed significant α-amylase and α-glucosidase inhibition, with rates of 87.04 ± 2.03% and 37.82 ± 1.36%, respectively. Furthermore, the cell-free supernatant (CFS) of SNBF-1 enhanced glucose consumption and glycogen synthesis in insulin-resistant HepG2 cells, indicating improved cellular energy metabolism. This was consistent with the observation that the CFS of SNBF-1 increased the proliferation of HepG2 cells by 123.77 ± 0.82% compared to that of the control. Overall, this research significantly enhances our understanding of NGPs and their potential therapeutic applications in modulating the gut microbiome.

Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb), which has a unique resistance to many antimicrobial agents. TB has emerged as a significant worldwide health issue because of the rise of multidrug-resistant strains causing drug-resistant TB (DR-TB). As a result, the development of new drugs or effective strategies is crucial for patients with TB. Mycobacterium marinum (Mm) and Mtb are both species of mycobacteria. In zebrafish, Mm proliferates and forms chronic granulomatous infections, which are similar to Mtb infections in lung tissue. Syringaldehyde (SA) is a member of the phenolic aldehyde family found in various plants. Here, we investigated its antioxidative and antibacterial properties in Mm-infected cells and zebrafish. Our results demonstrated that SA inhibits Mm-infected pulmonary epithelial cells and inhibits the proliferation of Mm in Mm-infected zebrafish, suggesting that SA provides an antibacterial effect during Mm infection. Further study demonstrated that supplementation with SA inhibits the production of malondialdehyde (MDA) and reactive oxygen species (ROS) and increases the levels of reduced glutathione (GSH) in Mm-infection-induced macrophages. SA inhibits the levels of MDA in Mm-infected zebrafish, suggesting that SA exerts antioxidative effects in vivo. Additionally, we found that SA promotes the expression of NRF2/HO-1/NQO-1 and the activation of the AMPK-α1/AKT/GSK-3β signaling pathway. In summary, our data demonstrated that SA exerts antioxidative and antibacterial effects during Mm infection both in vivo and in vitro and that the antioxidative effects of SA may be due to the regulation of NRF2/HO-1/NQO-1 and the AMPK-α1/AKT/GSK-3β signaling pathway.

Satellite networks show the development trend in global coverage, flexible access, and reliable transmission. They are the key to building a wide coverage, massive connection, three-dimensional, all-round, all-weather, space-, air- and ground-integrated information network. Due to its high frequency and large bandwidth, the laser inter-satellite link (ISL) is easily interfered with by sunlight. When sun outage occurs, the laser inter-satellite link will be interrupted for a long time. Most of the existing satellite link failure-routing algorithms are distributed and have poor load balancing capabilities. The centralized algorithm calculates paths independently for different services, and the effect is not ideal. In this paper, a local pre-rerouting algorithm (LPRA) is proposed. The center node collects the link information from the limited area before sun outage and the service information in the link that is about to be interrupted, and reroutes these services before sun outage occurs. After the occurrence of sun outage, services that originally needed to go through the failed link are forwarded according to the path calculated in advance, thereby avoiding link congestion and reducing the packet loss rate. Simulation results show that the proposed algorithm performs better than existing algorithms in terms of packet loss ratio, total delay and load balancing capabilities.

Starchy foods are an essential part of people’s daily diet. Starch is the primary substance used by plants to store carbohydrates, and it is the primary source of energy for humans and animals. In China, a variety of plants, including edible medicinal plants, such as Pueraria root, yam tuber and coix seed, are rich in starch. However, limited by their inherent properties, kudzu starch and other starches are not suitable for the modern food industry. Natural starch is frequently altered by physical, chemical, or biological means to give it superior qualities to natural starch as it frequently cannot satisfy the demands of industrial manufacturing. Therefore, the deep processing market of modified starch and its products has a great potential. This paper reviews the modification methods which can provide excellent functional, rheological, and processing characteristics for these starches that can be used to improve the physical and chemical properties, texture properties, and edible qualities. This will provide a comprehensive reference for the modification and application of starch from medicinal and edible plants.

In order to improve the safety and efficiency of power marketing operation, the power marketing operation safety control technology is studied and applied. Through in-depth analysis of the connotation of power marketing and power marketing operation safety management and control technology, combined with advanced technology methods, the design strategy of security management and control system platform is put forward. It is hoped that this study can provide strong technical support and solutions for the operation security control of the power market.

With the increasing number of submarine cable projects, the terrain and geological conditions of the landing section are becoming increasingly complex, and the traditional implementation of trench burial is becoming increasingly difficult. A landing construction plan for large-section power cables suitable for steep terrain and rugged rock formations is studied and proposed based on sorting out existing submarine cable landing plans. Using directional drilling construction machinery ideal for rock formations, natural cable protection pipes are formed in rock formations after dragging and expanding the holes, meeting submarine cable protection’s safety and economic requirements. In the climbing section of the submarine cable from the seabed to the rock hole, measures such as bottom sandbag raising and top rock throwing security are adopted to avoid vortex-induced vibration and erosion caused by the cable hanging in the climbing section. The construction plan of the directional drilling passage through hard rock and the construction and protection plan of the submarine cable do not affect the current situation of the existing coastal reefs and can effectively protect the submarine cable from external damage, achieving green and environmentally friendly construction.

In a prefabricated composite pipe gallery with socket joints, the repeated loading and unloading effect of shield construction on the overlying soil and the existing pipe gallery may cause considerable deformations to the pipe gallery at the joint while ensuring its own bearing capacity. The shield tunnelling underneath the existing pipe gallery project of the Fuzhou Metro was used as a basis to model the socket pipe gallery on ABAQUS finite element software. The influence of changes in the pipe-tunnel spacing on the deformation and displacement of the pipe gallery and stratum were investigated. It was found that when the shield passes through the pipe gallery with 0.25 times the tunnel diameter, in addition to the settlement area of the disturbance centre, uplift areas are created on both sides of the pipe gallery and the surface. Meanwhile, because of the socket structure of the pipe gallery, the vertical displacement of the pipe gallery is not synchronized with the settlement of the lower soil. Furthermore, with the increase in the pipe-tunnel spacing, the settlement trough of the vertical displacement curve of the pipe gallery and the stratum are gradually broadened, and the peak settlement gradually increases.

Based on user surveys, we identified eight universal information feedback demands of drivers in nighttime driving scenarios, along with users’ preference for the output method of feedback signals from the external environment. Utilizing the KJ-AHP method, a model was established for information demands, spanning from the objective layer to the criterion layer. The calculation of weights for each indicator was also conducted. Using auditory single channel as the feedback method, simulated driving experiments were conducted to verify the above results, the differences in subjective and objective data under different feedback frequencies were analysed. The usability test results of the information feedback intelligent design scheme show that the information feedback system for different demand categories can improve the safety and user experience of night driving.

A type of automated manual transmission gearshift system that uses two linear actuators to perform gearshift events is presented. The shifting mechanism can be made simpler by using linear actuator to drive the shift fork directly. The mathematical model of the actuator is built and analyzed. Coordinated control of the engagement and disengagement processes is created based on a detailed analysis of the gearshift process in order to shorten the shift time. The force characteristics test reveals the nonlinear output characteristics. The precise displacement control need for coordinated control and stable control requirement for the shifting operation are satisfied by a linear extended state observer based controller. To verify the novel gearshift system and the control method, a test bench and control system are constructed. The results of the simulations indicate that the displacement control's accuracy is enhanced. As the speed difference reaches 500 r/min, the testing results demonstrate a noticeably reduced of shift force fluctuation and jerk generated during the gearshift process, from 20 m/s3 to 3.1 m/s3. With the improved gearshift system and control method, the gearshift coordinated control can also save 25 ms of shift time.

Information and communications technology (ICT) has become an indispensable part of our lives. Prior research on climate impact of ICT devices and services mostly makes use of life cycle assessment and energy modeling frameworks focused on embodied greenhouse gas (GHG) emissions. Because these perspectives emphasize the GHGs emissions associated with the construction and distribution of digital devices along production supply chains, not much is known about the GHGs emissions monitored or facilitated by digital device use. In this study, we propose the concept of digital use supply chains (DUSCs) as an orthogonal dimension of digital devices’ life cycle. DUSC refers to the production activities and resource consumption recorded by digital devices. We propose a framework to conceptualize and quantify digital behavior-related GHGs emissions through use of the Screenomics paradigm, where users’ digital screen data are unobtrusively collected moment-by-moment. Through Screenomics’ granular recording of users’ digital behavior, we evaluate behavior-based GHGs emissions traced by the digital devices. DUSC connects individual’s digital behaviors to their global climate change impact, contributing to a more nuanced and complete evaluation of the climate impacts of the digital economy. Our single-case study indicates the estimated scale of the GHGs emissions linked to a user’s one-day digital activities could be three orders of magnitude (1000 times) higher than the emissions associated with the device life cycle alone. DUSC could enable climate change mitigation at a meaningful, actionable level through personalized educational or behavior change programs, and also facilitate novel data-driven feedback loops that may provide digital device users with insights into their personal climate impacts. Recognition and future study of DUSC could accelerate the quantification and standardization of a ‘carbon handprint’ of digital devices and create positive climate impacts from digital products and services.

Estimating the geographic positions in GPS-denied environments is of great significance to the safe flight of unmanned aerial vehicles (UAVs). In this paper, we propose a novel geographic position estimation method for UAVs after road network alignment. We discuss the generally overlooked issue, namely, how to estimate the geographic position of the UAV after successful road network alignment, and propose a precise robust solution. In our method, the optimal initial solution of the geographic position of the UAV is first estimated from the road network alignment result, which is typically presented as a homography transformation between the observed road map and the reference one. The geographic position estimation is then modeled as an optimization problem to align the observed road with the reference one to improve the estimation accuracy further. Experiments on synthetic and real flight aerial image datasets show that the proposed algorithm can estimate more accurate geographic position of the UAV in real time and is robust to the errors from homography transformation estimation compared to the currently commonly-used method.

C13H10N4O7, monoclinic, P21/n (no. 14), a = 10.7017(7) Å, b = 7.1240(5) Å, c = 19.0878(13) Å, β = 99.280(3)°, V = 1436.19(17) Å3, Z = 4, Rgt (F) = 0.0586, wRref (F 2) = 0.1746, T = 296.15 K.

C20H24N2O8, monoclinic, P21/n (no. 14), a = 3.8981(3) Å, b = 16.0675(11) Å, c = 16.2908(10) Å, β = 94.537(3)°, V = 1017.14(12) Å3, Z = 2, R gt(F) = 0.0634, wR ref(F 2) = 0.1746, T = 170 K.

ObjectiveTo investigate an outbreak of norovirus diarrhea in a welfare home for the elderly in Shanghai， and to analyze the epidemiology and virus genotype characteristics of the epidemic， thus providing a scientific basis for the prevention and control of norovirus epidemic.MethodsCase definition was clarified. After case definition， a standardized questionnaire was used to carry out case investigation to make comprehensive analysis in combination with field epidemiological investigation and laboratory tests results.ResultsThe epidemic lasted for 14 days， and 23 cases were reported with an incidence rate of 12.37% （23/186）， including 3 males and 20 females. There were more cases on the 1st， 4th and 6th floor of the main building in the welfare home， accounting for 52.17% （12/23） of total cases. 19 cases were reported in the main building， with an incidence rate of 11.59% （19/164）； 4 cases were reported in the auxiliary building， with an incidence rate of 18.18% （4/22）. There was no significant difference in the morbidity between the main building and the auxiliary building （χ2=0.779，P>0.05）. The main clinical manifestations were vomiting and diarrhea. There was a significant difference in the incidence of vomiting symptoms among the elderly， nursing staff and other staff in the welfare home （χ2=10.216， P0.05）. Fecal samples were collected from 23 cases， 1 case family member， 68 risk personnel and 14 environmental surface swab samples. Norovirus GⅡ was detected in stool samples of 19 cases， 1 family member and 36 risk personnel.ConclusionOutbreak of norovirus infection is reported in a welfare home in Shanghai. The close contact between the elderly and health workers might lead to the outbreak.

Abstract Apolipoprotein E (APOE) plays a pivotal role in lipid including cholesterol metabolism. The APOE ε4 (APOE4) allele is a major genetic risk factor for Alzheimer’s and cardiovascular diseases. Although APOE has recently been associated with increased susceptibility to infections of several viruses, whether and how APOE and its isoforms affect SARS-CoV-2 infection remains unclear. Here, we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients. Utilizing multiple protein interaction assays, we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2; and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2, a key docking site for SARS-CoV-2 Spike protein. In addition, immuno-imaging assays using confocal, super-resolution, and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spike-mediated viral entry into cells. Interestingly, while having a comparable binding affinity to ACE2, APOE4 inhibits viral entry to a lesser extent compared to APOE3, which is likely due to APOE4’s more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2. Furthermore, APOE ε4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed. Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2, which may explain in part increased COVID-19 infection and disease severity in APOE ε4 carriers.

Abstract Background Myocardial infarction (MI) is characterized by coronary artery occlusion, ischemia and hypoxia of myocardial cells, leading to irreversible myocardial damage. Therefore, it is urgent to explore the potential mechanism of myocardial injury during the MI process to develop effective therapies for myocardial cell rescue. Methods We downloaded the GSE71906 dataset from GEO DataSets, and the R software was used to identify the differentially expressed genes (DEGs) in mouse heart tissues of MI and sham controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to understand the significantly activated signaling pathways in MI. Protein–protein interaction (PPI) network was constructed to highlight the hub genes in DEGs. The Western Blot, qRT-PCR and TUNEL staining were used to explore the function of hub gene in hypoxia-induced cardiomyocytes in vitro. Results A total of 235 DEGs were identified in GSE71906 dataset. Functional enrichment analysis revealed that the upregulated genes were primarily associated with the inflammatory response and apoptosis. 20 hub genes were identified in PPI network, and the early growth response 2 (EGR2) was highlighted. In vitro. We confirmed the EGR2 was upregulated induced by hypoxia and revealed the upregulated EGR2 aggravates pro-inflammation and pro-apoptotic genes expression. In addition, EGR2 knockout mitigates hypoxia-induced inflammation and apoptosis in cardiomyocytes. Conclusion The present study identified the EGR2 was a hub gene in myocardial damage during MI process, the excessive EGR2 aggravates hypoxia-induced myocardial damage by accelerating inflammation and apoptosis in vitro. Therefore, targeting EGR2 offers a potential pharmacological strategy for myocardial cell rescue in MI.

Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.

Aiming at the crane scheduling problem for uncertainty tasks in multi-crane scheduling situation, this article proposes a deep reinforcement learning-based crane scheduling modeling method that is not dependent on mathematical planning and has certain generality. First, the crane scheduling process is integrated into deep reinforcement learning framework in which the orbit space of the crane and the transportation task is environmental information and crane is the intelligent agent. Second, the interactive mode between reinforcement learning algorithm and environment is adjusted to adapt to the combined learning of multi-crane scheduling model. Last, the crane scheduling model for uncertainty tasks is constructed by optimizing reward discount factor, learning rate, and reward function intensive mode. Testing of the model is carried out based on practical crane scheduling in one steelmaking workshop. Scheduling proposal is generated and all crane tasks are completed within the planned time, which verifies the feasibility of this model. Results show that compared with manual scheduling plan, the scheduling proposal based on the new model reduces total task completion time by 11.52%, time of collision of crane routes decreases by 57.14%, and negative crane transportation distance shortens by 55.26%. The high efficiency of the scheduling model is therefore verified.

Chiral perovskites have attracted considerable attention as excellent spin-emitting materials for applications in spintronics, quantum optics, and biological. Especially in drug development of biological, weak chirality molecules are frequently selected to reduce the side effects of toxics, and there is a common defect for accurately detecting the weak chirality with common methods at room temperature. In this study, formamidine lead bromide perovskite nanocrystals (FAPbBr3 NCs) were coated with chiral ligands, whose chirality was too weak to be observed in the visible region at room temperature. Thus, by characterizing the transverse shift of photonic spin Hall effect (SHE), the accurate discrimination of weak chirality in the visible region was achieved successfully. By measuring the shift value and light spot splitting of photonic SHE at the same concentration, NEA-coated FAPbBr3 NCs can effectively enhance the chirality of naphthalene ethylamine (NEA) ligands when under the mutually reinforcement of chiral molecular and inorganic parts. In addition, we furtherly clearly distinguished the tiny chiral distinction of NEA-coated FAPbBr3 NCs with different particle sizes, which revealed that the chirality decreases with the increase of particle size. These findings could provide effective solutions for the detection and application of weak chirality in hybrid perovskite nanocrystals in universal environment.

Objective: Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer. Methods: We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment. Results: In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration. Conclusions: The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.

Abstract Background Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it’s role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. Methods In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. Results As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p

Abstract Background To investigate the genetic causes of hearing loss in patients with enlarged vestibular aqueduct (EVA), the SLC26A4-related genotypes and phenotypes were analyzed. SLC26A4 gene is closely associated with EVA and its homozygous mutations or compound heterozygous mutations may cause deafness and strongly affect quality of life. Methods The patients who came to our hospital for hearing test and accompanied by bilateral hearing abnormalities were collected for fifteen deafness-related gene mutations detection. Those who are positive will be verified by Sanger sequencing, combined with family history, hearing test, and computerized tomography (CT) of the temporal bone, aiming to diagnose the enlarged vestibular aqueducts. Whole-exome sequencing were performed when necessary. Results Our patient failed hearing screening on both sides twice, and EVA (> 1.5 mm) was diagnosed by CT. This study has identified a novel missense mutation in the SLC26A4 gene, c.2069T>A, which in compound heterozygosity with c.1174A>T is likely to be the cause of hearing loss. The novel heterozygous c.2069T>A mutation of SLC26A4 gene has been submitted to Clinvar with Variation ID 1,048,780. Conclusion Our findings expand the gene mutation spectrum of SLC26A4 and provide additional knowledge for diagnosis and genetic counseling associated with EVA-induced hearing loss.

Abstract Background Protein–protein interaction (PPI) is vital for life processes, disease treatment, and drug discovery. The computational prediction of PPI is relatively inexpensive and efficient when compared to traditional wet-lab experiments. Given a new protein, one may wish to find whether the protein has any PPI relationship with other existing proteins. Current computational PPI prediction methods usually compare the new protein to existing proteins one by one in a pairwise manner. This is time consuming. Results In this work, we propose a more efficient model, called deep hash learning protein-and-protein interaction (DHL-PPI), to predict all-against-all PPI relationships in a database of proteins. First, DHL-PPI encodes a protein sequence into a binary hash code based on deep features extracted from the protein sequences using deep learning techniques. This encoding scheme enables us to turn the PPI discrimination problem into a much simpler searching problem. The binary hash code for a protein sequence can be regarded as a number. Thus, in the pre-screening stage of DHL-PPI, the string matching problem of comparing a protein sequence against a database with M proteins can be transformed into a much more simpler problem: to find a number inside a sorted array of length M. This pre-screening process narrows down the search to a much smaller set of candidate proteins for further confirmation. As a final step, DHL-PPI uses the Hamming distance to verify the final PPI relationship. Conclusions The experimental results confirmed that DHL-PPI is feasible and effective. Using a dataset with strictly negative PPI examples of four species, DHL-PPI is shown to be superior or competitive when compared to the other state-of-the-art methods in terms of precision, recall or F1 score. Furthermore, in the prediction stage, the proposed DHL-PPI reduced the time complexity from $$O(M^2)$$ O ( M 2 ) to $$O(M\log M)$$ O ( M log M ) for performing an all-against-all PPI prediction for a database with M proteins. With the proposed approach, a protein database can be preprocessed and stored for later search using the proposed encoding scheme. This can provide a more efficient way to cope with the rapidly increasing volume of protein datasets.

Abstract Background Automated brain volumetry has been widely used to assess brain volumetric changes that may indicate clinical states and progression. Among the tools that implement automated brain volumetry, AccuBrain has been validated for its accuracy, reliability and clinical applications for the older version (IV1.2). Here, we aim to investigate the performance of an updated version (IV2.0) of AccuBrain for future use from several aspects. Methods Public datasets with 3D T1-weighted scans were included for version comparisons, each with Alzheimer’s disease (AD) patients and normal control (NC) subjects that were matched in age and gender. For the comparisons of the brain volumetric measures quantified from the same scans, we investigated the difference of hippocampal segmentation accuracy (using Dice similarity coefficient [DSC] as the major measurement). As AccuBrain generates a composite index (AD resemblance atrophy index, AD-RAI) that indicates similarity with AD-like brain atrophy pattern, we also compared the two versions for the diagnostic accuracy of AD versus NC with AD-RAI. Also, we examined the intra-scanner reproducibility of the two versions for the scans acquired with short-intervals using intraclass correlation coefficient. Results AccuBrain IV2.0 presented significantly higher accuracy of hippocampal segmentation (DSC: 0.91 vs. 0.89, p

Background: The expression of miR-141-3p in many malignant tumors has been verified. Nevertheless, the relationship between ovarian cancer and miR-141-3p remains undetermined. Therefore, further exploration is required. Results: According to data from 100 samples, the final results of RT-qPCR showed that miR-141-3p was highly expressed in ovarian cancer. Furthermore, miR-141-3p was able to distinguish ovarian cancer cells from ovary tissues. The most significant Kyoto Encyclopedia of Genes and Genomes pathway, was regulation of lipolysis in adipocytes in ovarian cancer. The expression of PIK3R1 was negatively correlated with miR-141- 3p. PIK3R1 has a combing site with miR-141-3p. Conclusions: This study examined the expression levels and mechanism of miR-141-3p in ovarian cancer for the first time. The results suggested that miR-141-3p may promote the occurrence of ovarian cancer by down-regulating PIK3R1.How to cite: Shi L, Sun H-J, Zeng J-J, et al. Evaluation of miR-141-3p over-expression in ovarian cancer. Electron J Biotechnol 2022;58. https://doi.org/10.1016/j.ejbt.2022.04.006

Abstract Background The FAST study identified claudin-18 (CLDN18.2) as a promising novel therapeutic target for gastric cancer (GC). However, the tumor immune microenvironment and clinicopathological features of CLDN18.2-positive GC are unclear, making it difficult to develop and optimize CLDN18.2-targeted treatments. Methods This study included 80 GC patients, 60 of whom received anti-PD-1/PD-L1 treatment. CD4/CD8/CD20/CD66b/CD68/CD163/PD-1/PD-L1/TIM-3/LAG-3/FoxP3/CTLA-4/HLA-DR/STING, and CLDN18.2 were labeled using multiplex immunohistochemistry (m-IHC) to decipher the rate and spatial distribution of T cells, B cells, macrophages, and neutrophils in formalin-fixed, paraffin-embedded tumor tissues isolated from these patients. Tumor immune-microenvironmental features and patient survival stratified by CLDN18.2 expression were analyzed using two independent-sample t-tests and log-rank tests, respectively. Results We considered moderate-to-strong CLDN18.2 expression ≥ 40% of tumor cells as the cut-off for positivity. The proportion of CD8+PD-1−, CD8+LAG-3−, and CD8+TIM-3− T cells was significantly higher in CLDN18.2-positive tumors than in negative tumors (0.039 vs. 0.026, P = 0.009; 0.050 vs.0.035, P = 0.024; 0.045 vs. 0.032, P = 0.038, respectively). In addition, the number of neutrophils (CD66b+) was higher in the CLDN18.2-positive group than in the negative group (0.081 vs. 0.055, P = 0.031, respectively), while the rates of M1 (CD68+CD163−HLA-DR+), M2 macrophages (CD68+CD163+HLA-DR−), and B cells (CD20+) were comparable between the CLDN18.2-positive and negative groups. The average numbers of CD8+PD-1−, CD8+LAG-3−, and CD8+TIM-3−T cells surrounding tumor cells within a 20-μm range were higher in CLDN18.2-positive tumors than in the CLDN18.2-negative tumors (0.16 vs. 0.09, P = 0.011; 0.20 vs. 0.12, P = 0.029; 0.18 vs. 0.12, P = 0.047, respectively). In addition, in the CLDN18.2-positive group, tumor cells surrounded by CD8+PD-1−, CD8+LAG-3− T cells, or M1 macrophages within a 20-μm range accounted for a higher proportion of all tumor cells than those in the CLDN18.2-negative group (10.79% vs. 6.60%, P = 0.015; 12.68% vs. 8.70%, P = 0.049; 9.08% vs. 6.56%, P = 0.033, respectively). These findings suggest that CLDN18.2-positive GC harbors complex immune-microenvironmental features. Additionally, CLDN18.2-positive group had shorter OS and irOS than CLDN18.2-negative group (median OS: 23.33 vs.36.6 months, P

Abstract Background This study attempts to explore the influencing factors and solutions of the colloidal gold method for novel coronavirus (2019-nCoV)-specific IgM/IgG antibody detection, summarize the clinical experience and perfect the examination process, improving the application value of antibody detection in COVID-19 diagnosis. Methods A total of 13,329 peripheral whole blood/plasma/serum samples were obtained for COVID-19 screening from children who visited the Children's Hospital of the Capital Institute of Pediatrics outpatient clinic from April 22, 2020, to November 30, 2020. The colloidal gold method was adopted for 2019-nCoV-specific IgM/IgG antibody detection. The virus nucleic acid test results, clinical records, and serum protein fingerprint results of antibody-positive patients were collected. Results All samples were examined using the colloidal gold method with two 2019-nCoV-specific IgM/IgG antibody detection kits. Four patients were tested single antibody-positive using both kits. The details were as follows: two cases of IgM ( +) and IgG (-) using plasma and serum separately, two cases of IgM (-) and IgG ( +) using serum and whole blood. The protein fingerprinting results and nucleic acid tests of 2019-nCoV antibodies were negative in the 4 cases. Considering the epidemiological history, clinical manifestations, and test results, these 4 children were ruled out for 2019-nCoV infection. Conclusions When the colloidal gold method was used to detect 2019-nCoV-specific IgM/IgG antibodies, it was important to ascertain the test results as precisely as possible. Specimen type and patient history may interfere with the diagnosis.

Abstract Background Corneal transplantation is the only way to treat serious corneal diseases caused by corneal endothelial dysfunction. However, the shortage of donor corneal tissues and human corneal endothelial cells (HCECs) remains a worldwide challenge. We cultivated HCECs by the use of a conditioned medium from orbital adipose-derived stem cells (OASC-CM) in vitro. Then the HCECs were used to treat animal corneal endothelial dysfunction models via cell transplantation. The purpose of this study was to conduct a long-term observation and evaluation after cell transplantation. Methods Orbital adipose-derived stem cells (OASCs) were isolated to prepare the conditioned medium (CM). HCECs were cultivated and expanded by the usage of the CM (CM-HCECs). Then, related corneal endothelial cell (CEC) markers were analyzed by immunofluorescence. The cell proliferation ability was also tested. CM-HCECs were then transplanted into monkey corneal endothelial dysfunction models by injection. We carried out a 24-month postoperative preclinical observation and verified the long-term effect by histological examination and transcriptome sequencing. Results CM-HCECs strongly expressed CEC-related markers and maintained polygonal cell morphology even after 10 passages. At 24 months after cell transplantation, there was a CEC density of more than 2400 cells per square millimeter (range, 2408–2685) in the experimental group. A corneal thickness (CT) of less than 550 μm (range, 490–510) was attained. Gene sequencing showed that the gene expression pattern of CM-HCECs was similar to that of transplanted cells and HCECs. Conclusions Transplantation of CM-HCECs into monkey corneal endothelial dysfunction models resulted in a transparent cornea after 24 months. This research provided a promising prospect of cell-based therapy for corneal endothelial diseases.

Abstract Barrett's esophagus (BE) is a well-known precancerous condition of esophageal adenocarcinoma. However, the immune cells and immune related genes involved in BE development and progression are not fully understood. Therefore, our study attempted to investigate the roles of immune cells and immune related genes in BE patients. The raw gene expression data were downloaded from the GEO database. The limma package in R was used to screen differentially expressed genes (DEGs). Then we performed the least absolute shrinkage and selection operator (LASSO) and random forest (RF) analyses to screen key genes. The proportion of infiltrated immune cells was evaluated using the CIBERSORT algorithm between BE and normal esophagus (NE) samples. The spearman index was used to show the correlations of immune genes and immune cells. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of key genes in BE. A total of 103 differentially expressed immune-related genes were identified between BE samples and normal samples. Then, 7 genes (CD1A, LTF, FABP4, PGC, TCF7L2, INSR,SEMA3C) were obtained after Lasso analysis and RF modeling. CIBERSORT analysis revealed that resting CD4 T memory cells and gamma delta T cells were present at significantly lower levels in BE samples. Moreover, plasma cell and regulatory T cells were present at significantly higher levels in BE samples than in NE samples. INSR had the highest AUC values in ROC analysis. We identified 7 immune related genes and 4 different immune cells in our study, that may play vital roles in the occurrence and development of BE. Our findings improve the understanding of the molecular mechanisms of BE.

Abstract This study aimed to explore the risk factors of peripherally inserted central catheter (PICC)-related venous thromboembolism (CRT) in patients with hematological malignancies and the predictive ability of the thrombotic risk assessment models (RAMs). The clinical data of the 117 eligible patients with hematological neoplasms at Mianyang Central Hospital with PICC from May 2018 to May 2020 were analyzed in this retrospective study. Thrombosis risk scores were calculated in patients with image-confirmed PICC-related thromboembolism. CRT occurred in 19 cases. Compared to the CRT-free group, the CRT group was older and showed higher body mass index (BMI), leukocyte count level, and the prevalence of diabetes mellitus. Multivariable logistic regression analysis showed that BMI (P = 0.03) was a significant risk factor for CRT. The area under the receiver operating characteristic curve for the Caprini scale (P = 0.01) was higher than that of the modified Wells scale (P = 0.94), the revised Geneva scale (P = 0.83), Padua scale (P = 0.59), and Michigan scale (P = 0.80). The sensitivity and specificity for the Caprini scale, Padua scale, modified Wells scale, the revised Geneva scale, and Michigan risk score were 63.3%/73.7%, 100%/0.00%, 95.9%/5.3%, 31.6%/73.7%, and 1.0%/99.0%, respectively. Caprini RAM had a better predictive ability for CRT in patients with hematological malignancies. Michigan risk score may not be better than Caprini RAM in this population.

D-chiro-inositol (DCI) is an isomer of inositol, abundant in many foods, such as beans and buckwheat, with insulin-sensitizing, anti-inflammatory, and antioxidant effects. DCI has been used to relieve insulin resistance in diabetes and polycystic ovary syndrome in combination with inositol or D-pinitol. Here, we investigated the effect of DCI on aging and stress resistance in C. elegans. We found that DCI could prolong the lifespan of C. elegans by up to 29.6 %. DCI significantly delayed the onset of neurodegenerative diseases in models of C. elegans. DCI decreased the accumulation of Aβ1–42, alpha-synuclein, and poly-glutamine, the pathological causes of Alzheimer's, Parkinson's, and Huntington's diseases, respectively. DCI significantly increased the stress resistances against pathogens, oxidants and heat shock. Moreover, D-chiro-inositol reduced the content of ROS and malondialdehyde by increasing the total antioxidant capacity and the activity of superoxide dismutase and catalase. Above effects of DCI requires the transcription factors FOXO/DAF-16 and Nrf-2/SKN-1. DCI also increased the expression of downstream genes regulated by FOXO/DAF-16 and Nrf-2/SKN-1. In conclusion, DCI enhanced the antioxidant capacity and healthy lifespan of C. elegans by activating DAF-16, SKN-1, and HSF-1. Our results showed that DCI could be a promising antiaging agent that is worth further research on the mechanism and health supplemental application of DCI.

Introduction Deep brain stimulation (DBS) implantation under general anaesthesia (GA) has been applied to patients with Parkinson’s disease (PD) with severe comorbidities or disabling off-medication symptoms. However, general anaesthetics may affect intraoperative microelectrode recording (MER) to varying degrees. At present, there are few studies on the effects of sedatives or general anaesthetics on multiunit activity characteristics performed by MER in patients with PD during DBS. Therefore, the effect of the choice of anaesthesia on MER remains unclear.Methods/design This is a prospective randomised controlled, non-inferiority study that will be carried out at Beijing Tiantan Hospital, Capital Medical University. Patients undergoing elective bilateral subthalamic nucleus (STN)-DBS will be enrolled after careful screening for eligibility. One hundred and eighty-eight patients will be randomised to receive either conscious sedation (CS) or GA at a 1:1 ratio. The primary outcome is the proportion of high normalised root mean square (NRMS) recorded by the MER signal.Ethics and dissemination The study was approved by the Ethics Committee of Beijing Tiantan Hospital of Capital Medical University (KY2022-147-02). Negative study results will indicate that GA using desflurane has a non-inferior effect on MER during STN-DBS compared with CS. The results of this clinical trial will be presented at national or international conferences and submitted to a peer-reviewed journal.Trial registration number NCT05550714.

BackgroundThere is a higher risk of preterm delivery (PTD) in singleton live births conceived after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) compared with spontaneously conceived pregnancies. The objective of our study was to build a predictive nomogram model to suggest the possibility of PTD in singleton pregnancies after IVF/ICSI treatment.Method11513 IVF/ICSI cycles with singleton live births were enrolled retrospectively. These cycles were randomly allocated into a training group (80%) and a validation group (20%). We used the multivariate logistics regression analysis to determine prognostic factors for PTD in the training group. A nomogram based on the above factors was further established for predicting PTD. Receiver operating characteristic curves (ROC), areas under the ROC curves (AUC), concordance index (C-index), and calibration plots were analyzed for assessing the performance of this nomogram in the training and validation group.ResultsThere were fourteen risk factors significantly related to PTD in IVF/ICSI singleton live births, including maternal body mass index (BMI) > 24 kg/m2, smoking, uterine factors, cervical factors, ovulatory factors, double embryo transferred (DET), blastocyst transfer, FET, vanishing twin syndrome (VTS), obstetric complications (placenta previa, placenta abruption, hypertensive of pregnancies, and premature rupture of membrane), and a male fetus. These factors were further incorporated to construct a nomogram prediction model. The AUC, C-index, and calibration curves indicated that this nomogram exhibited fair performance and good calibration.ConclusionsWe found that the occurrence of PTD increased when women with obesity, smoking, uterine factors, cervical factors, ovulatory factors, DET, VTS, and obstetric complications, and a male fetus. Furthermore, a nomogram was constructed based on the above factors and it might have great value for clinic use.

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit.Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N = 8, received saline only) or LPS (N = 60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 h by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only; LPS +5, 25, or 100 mg/kg intravenous STC3141 every 8 h (LPS + L, LPS + M, LPS + H, respectively); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 h for 56 h (LPS + D). The animals were observed for 72 h.Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS + H and +D groups had significantly lower circulating histone levels and lung wet-to-dry ratio, and the LPS + D group also had lower BALF histone concentrations; the blood neutrophils and platelets counts in LPS + D group did not change, meanwhile, the LPS + L, +M and +H groups had significantly lower neutrophil counts and higher platelet counts in the blood; the total number of BALF WBC, platelet counts, MPO and H3 were significantly lower in the LPS + L, +M, +H and +D groups than in the LPS only group; and the degree of inflammation was significantly less in the LPS + L, +M, +H and +D groups, moreover, inflammation in the LPS + L, +M and +H animals showed a dose-dependent response; finally, the LPS + L, +M, +H and +D groups had improved oxygenation compared to the LPS group, and there were no statistical differences in PCO2 or pH among groups. All animals survived.Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved acute lung injury and oxygenation.

BackgroundFocal motor seizures that originate in the motor region are a considerable challenge because of the high risk of permanent motor deficits after resection. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a potential treatment for motor epilepsy that may enhance the antiepileptic actions of the substantia nigra pars reticulata (SNr). Orexin and its receptors have a relationship with both STN-DBS and epilepsy. We aimed to investigate whether and how STN inputs to the SNr regulate seizures and the role of the orexin pathway in this process.MethodsA penicillin-induced motor epileptic model in adult male C57BL/6 J mice was established to evaluate the efficacy of STN-DBS in modulating seizure activities. Optogenetic and chemogenetic approaches were employed to regulate STN-SNr circuits. Selective orexin receptor type 1 and 2 antagonists were used to inhibit the orexin pathway.ResultsFirst, we found that high-frequency ipsilateral or bilateral STN-DBS was effective in reducing seizure activity in the penicillin-induced motor epilepsy model. Second, inhibition of STN excitatory neurons and STN-SNr projections alleviates seizure activities, whereas their activation amplifies seizure activities. In addition, activation of the STN-SNr circuits also reversed the protective effect of STN-DBS on motor epilepsy. Finally, we observed that STN-DBS reduced the elevated expression of orexin and its receptors in the SNr during seizures and that using a combination of selective orexin receptor antagonists also reduced seizure activity.ConclusionSTN-DBS helps reduce motor seizure activity by inhibiting the STN-SNr circuit. Additionally, orexin receptor antagonists show potential in suppressing motor seizure activity and may be a promising therapeutic option in the future.

ObjectivesTo explore the suicide risk-specific disruption of cortical hierarchy in major depressive disorder (MDD) patients with diverse suicide risks.MethodsNinety-two MDD patients with diverse suicide risks and 38 matched controls underwent resting-state functional MRI. Connectome gradient analysis and stepwise functional connectivity (SFC) analysis were used to characterize the suicide risk-specific alterations of cortical hierarchy in MDD patients.ResultsRelative to controls, patients with suicide attempts (SA) had a prominent compression from the sensorimotor system; patients with suicide ideations (SI) had a prominent compression from the higher-level systems; non-suicide patients had a compression from both the sensorimotor system and higher-level systems, although it was less prominent relative to SA and SI patients. SFC analysis further validated this depolarization phenomenon.ConclusionThis study revealed MDD patients had suicide risk-specific disruptions of cortical hierarchy, which advance our understanding of the neuromechanisms of suicidality in MDD patients.

ObjectiveThe reverse digital artery island flap (RDAF) is widely used in repairing fingertip skin defects based on its good appearance and practicability. However, the donor area of the flap needs skin grafting, which can lead to complications. This retrospective study explored the clinical application of digital dorsal advance flap (DDAF) in repairing the donor site of the reverse digital artery island flap.MethodFrom June 2019 to February 2022, 17 patients with a soft tissue defect of the finger had been restored with the reverse digital artery island flap, and at the same time, the donor area was repaired with digital dorsal advance flap (DDAF). The sensitivity, the active range of motion (ROM) and patient satisfaction were assessed after the operation.ResultsAll flaps survived completely without skin grafting with only one linear scar. The sensory and motor functions of all patients recovered well. Assessment based on the Michigan Hand Outcomes Questionnaire (MHQ) showed satisfactory functional recovery for all patients.ConclusionsReconstruction using RDAF combined with DDAF represents an effective alternative for repairing fingertip skin defects.

ObjectiveVasovagal syncope (VVS) is the commonest form of syncope, and malignant VVS draws substantial attention due to its life-threatening cardiac asystolic risk. This study aimed to explore the predictive role of a wide panel of clinical indicators for malignant VVS in children, and further to develop a nomogram model.MethodsThis is a retrospective case-control study. VVS is diagnosed based on head-up tilt test (HUTT). STATA software (version 14.0) was used for statistical analysis, and effect sizes are expressed as odds ratio (OR) and 95% confidence interval (CI).ResultsTotal 370 children with VVS were analyzed, and of them 16 children had malignant VVS. Sixteen malignant VVS and 64 non-malignant VVS were matched on age and sex by a 1:4 propensity scores matching method. Mean corpuscular hemoglobin (MCH) and standard deviation of average RR intervals milliseconds (SDANN) were significantly and independently associated with malignant VVS after adjusting for confounders, with OR reaching 1.437 (95% CI: 1.044 to 1.979; P = 0.026) and 1.035 (95% CI: 1.003 to 1.068; P = 0.029), respectively. Calibration and discrimination analyses revealed that the addition of MCH and SDANN can enhance model performance. Then, a nomogram to predict malignant VVS was developed using general characteristics and two above significant factors, and higher values in medical history, number of syncope, MCH and SDANN were associated with a greater risk of malignant VVS.ConclusionMCH and SDANN were two promising factors for the development of malignant VVS, and modeling of significant factors in a nomogram can provide strong reference to aid clinical decision-making.

IntroductionProcessing speed is defined as the ability to quickly process information, which is generally considered as one of the affected cognitive functions of multiple sclerosis and schizophrenia. Paper–pencil type tests are traditionally used in the assessment of processing speed. However, these tests generally need to be conducted under the guidance of clinicians in a specific environment, which limits their application in cognitive assessment or training in daily life. Therefore, this paper proposed an intelligent evaluation method of processing speed to assist clinicians in diagnosis.MethodsWe created an immersive virtual street embedded with Stroop task (VR-Street). The behavior and performance information was obtained by performing the dual-task of street-crossing and Stroop, and a 50-participant dataset was established with the label of standard scale. Utilizing Pearson correlation coefficient to find the relationship between the dual-task features and the cognitive test results, and an intelligent evaluation model was developed using machine learning.ResultsStatistical analysis showed that all Stroop task features were correlated with cognitive test results, and some behavior features also showed correlation. The estimated results showed that the proposed method can estimate the processing speed score with an adequate accuracy (mean absolute error of 0.800, relative accuracy of 0.916 and correlation coefficient of 0.804). The combination of Stroop features and behavior features showed better performance than single task features.DiscussionThe results of this work indicates that the dual-task design in this study better mobilizes participants’ attention and cognitive resources, and more fully reflects participants’ cognitive processing speed. The proposed method provides a new opportunity for accurate quantitative evaluation of cognitive function through virtual reality.

BackgroundGastric cancer with synchronous distant metastases indicates a dismal prognosis. The success in survival improvement mainly relies on our ability to predict the potential benefit of a therapy. Our objective is to develop an artificial intelligence annotated clinical-pathologic risk model to predict its outcomes.MethodsIn participants (n=47553) with gastric cancer of the surveillance, epidemiology, and end results program, we selected patients with distant metastases at first diagnosis, complete clinical-pathologic data and follow-up information. Patients were randomly divided into the training and test cohort at 7:3 ratio. 93 patients with advanced gastric cancer from six other cancer centers were collected as the external validation cohort. Multivariable analysis was used to identify the prognosis-related clinical-pathologic features. Then a survival prediction model was established and validated. Importantly, we provided explanations to the prediction with artificial intelligence SHAP (Shapley additive explanations) method. We also provide novel insights into treatment options.ResultsData from a total 2549 patients were included in model development and internal test (median age, 61 years [range, 53-69 years]; 1725 [67.7%] male). Data from an additional 93 patients were collected as the external validation cohort (median age, 59 years [range, 48-66 years]; 51 [54.8%] male). The clinical-pathologic model achieved a consistently high accuracy for predicting prognosis in the training (C-index: 0.705 [range, 0.690-0.720]), test (C-index: 0.737 [range, 0.717-0.757]), and external validation (C-index: 0.694 [range, 0.562-0.826]) cohorts. Shapley values indicated that undergoing surgery, chemotherapy, young, absence of lung metastases and well differentiated were the top 5 contributors to the high likelihood of survival. A combination of surgery and chemotherapy had the greatest benefit. However, aggressive treatment did not equate to a survival benefit. SHAP dependence plots demonstrated insightful nonlinear interactive associations among predictors in survival benefit prediction. For example, patients who were elderly, or poor differentiated, or presence of lung or bone metastases had a worse prognosis if they undergo surgery or chemotherapy, while patients with metastases to liver alone seemed to gain benefit from surgery and chemotherapy.ConclusionIn this large multicenter cohort study, we developed an artificial intelligence annotated clinical-pathologic risk model to predict outcomes of advanced gastric cancer. It could be used to discuss treatment options.

ObjectivesTo develop and validate a CT-based radiomics nomogram that can provide individualized pretreatment prediction of the response to platinum treatment in small cell lung cancer (SCLC).MaterialsA total of 134 SCLC patients who were treated with platinum as a first-line therapy were eligible for this study, including 51 patients with platinum resistance (PR) and 83 patients with platinum sensitivity (PS). The variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) were applied for feature selection and model construction. The selected texture features were calculated to obtain the radiomics score (Rad-score), and the predictive nomogram model was composed of the Rad-score and the clinical features selected by multivariate analysis. Receiver operating characteristic (ROC) curves, calibration curves, and decision curves were used to assess the performance of the nomogram.ResultsThe Rad-score was calculated using 10 radiomic features, and the resulting radiomics signature demonstrated good discrimination in both the training set (area under the curve [AUC], 0.727; 95% confidence interval [CI], 0.627–0.809) and the validation set (AUC, 0.723; 95% CI, 0.562–0.799). To improve diagnostic effectiveness, the Rad-score created a novel prediction nomogram by combining CA125 and CA72-4. The radiomics nomogram showed good calibration and discrimination in the training set (AUC, 0.900; 95% CI, 0.844-0.947) and the validation set (AUC, 0.838; 95% CI, 0.534-0.735). The radiomics nomogram proved to be clinically beneficial based on decision curve analysis.ConclusionWe developed and validated a radiomics nomogram model for predicting the response to platinum in SCLC patients. The outcomes of this model can provide useful suggestions for the development of tailored and customized second-line chemotherapy regimens.

BackgroundNeonatal infections, especially neonatal sepsis, are one of the major causes of incidence and mortality in pediatrics. However, the global burden of neonatal sepsis and other neonatal infections (NSNIs) remains unclear.MethodsFrom the 2019 global disease burden study, we collected annual incident cases, deaths, age-standardized incidence rates (ASIRs), and age-standardized deaths rates (ASDRs) of NSNIs in the past 30 years. Analysis indicators included the percentage of relative changes in incident cases and deaths, and the estimated annual percentage changes (EAPCs) of ASIRs and ASDRs. Correlations were assessed between the EAPCs of ASIRs and ASDRs and social evaluation indicators, including sociodemographic index (SDI) and universal health coverage index (UHCI).ResultsGlobally, the number of incident cases of NSNIs grew by 12.79% per year, and the number of deaths dropped by 12.93% per year. During this period, global ASIR of NSNIs increased by 46% annually on average, while ASDR decreased by 53% annually on average. The ASIR and ASDR of female NSNIs were consistently lower than that of male NSNIs. The EAPC of female ASIR was 0.61, nearly twice that of male ASIR, and female ASIR was growing rapidly. The same declining trends of ASDR were noted in males and females. The ASIR of NSNIs in high-SDI regions grew by an average of 14% annually from 1990 to 2019. Except for high-SDI regions, the ASIRs of other 4 SDI regions maintained a rising trend at a high level, and were improved in the past 10 years. The ASDRs of all 5 SDI regions generally showed a downward trend. The region with the highest ASIR of NSNIs was Andean Latin America, and Western Sub-Saharan Africa had the highest mortality. We found a negative correlation between EAPCs of ASDRs and UHCI in 2019.ConclusionThe global health situation was still not optimal. The incidence of NSNIs remained high, and continues to rise. The mortality of NSNIs has decreased, especially in the countries/territories with high UHCI. Therefore, it is crucial to improve the overall awareness and management of NSNIs, and take interventions for NSNIs worldwide.