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Abstract Background Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy. Methods We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno‐collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in‐house samples. Additionally, novel therapeutic targets were identified based on these established immuno‐collagenic subtypes. Results Our categorization divided tumors into three subtypes: “soft & hot” (low collagen activity and high immune infiltration), “armored & cold” (high collagen activity and low immune infiltration), and “quiescent” (low collagen activity and immune infiltration). Notably, “soft & hot” tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7‐H3), an available drug target, as strongly expressed in “armored & cold” tumors, relating with poor prognosis. Conclusion This study introduces histopathology‐based universal immuno‐collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

Background Immune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear.Methods In this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of angiotensin receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis.Results AGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy.Conclusion Overall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.

Abstract Background A subset of Graves’ disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration. Methods A prospective cohort study (2018–2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens. Results Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves’ ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium–low cumulative dosage group (average

Abstract Objective In the present study, we aimed to compare the clinical efficacy and safety of omadacycline (OMC) with its comparators for the treatment of complicated skin and soft tissue infections (cSSTIs) in adult patients. Methods Randomized controlled trials (RCTs) evaluating OMC for cSSTIs were searched in databases of PubMed, Embase, Cochrane, Web of Science, and Clinical Trial, up to July 2022. The primary outcomes were clinical efficacy and microbiological response, with secondary outcome was safety. Results Four RCTs consisting of 1,757 patients were included, with linezolid (LZD) as a comparator drug. For clinical efficacy, OMC was not inferior to LZD in the modified intent-to-treat (MITT) (OR: 1.24, 95% Cl: [0.93, 1.66], P = 0.15) and clinically evaluable (CE) populations (OR: 1.92, 95% Cl: [0.94, 3.92], P = 0.07). For microbiological response, OMC was numerically higher than LZD in the microbiologically evaluable (ME) (OR: 1.74, 95% Cl: [0.81, 3.74], P = 0.16) and microbiological MITT (micro-MITT) populations (OR: 1.27, 95% Cl: [0.92, 1.76], P = 0.14). No significant difference was found in subpopulations of monomicrobial or polymicrobial mixed infection populations. The mortality and adverse event rates were similar between OMC and LZD. Conclusions OMC was as good as LZD in terms of clinical efficacy and microbiological response, and has similar safety issues in treating cSSTIs. OMC might be a promising option for treating cSSTIs in adult patients.

Abstract Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.

In a high-speed railway (HSR) corridor, railway companies provide diverse train services with different features such as departure time, running speed, and fare. Furthermore, passengers have varying preferences, which influence their travel choices. Focusing on this problem, this paper proposed a novel train timetable optimization model based on departure time and pricing strategy to analyze their impact on passengers’ travel choices with a consistent operating speed. Additionally, an extended time-space-fare network is constructed to visualize this process. The generalized cost of each arc in the network is used as a criterion for evaluating passenger selection. Then, we adapted a passenger flow distribution method based on the user equilibrium (UE) principle to allocate the passenger flow to each train. We also developed a bi-level planning model with passenger allocation as the lower-level model and timetable decision as the upper-level one to optimize collaboratively. Finally, a genetic algorithm integrated with the Frank-Wolfe method is designed to seek the optimal timetable and pricing strategy and a concrete numerical example in Lanzhou-Xi’an HSR is taken to investigate the effectiveness of the proposed model and algorithm.

ABSTRACT: Objectives: Surgical site infection (SSI) is a serious complication of intestinal surgery. In this meta-analysis, we aimed to explore the efficacy and safety of different preoperative oral antibiotic preparation (OABP) compared with intravenous antibiotic preparation (IVAP) and/or mechanical bowel preparation (MBP). Methods: A meta-analysis consisting of adult patients adopting oral antibiotics versus other regimens during the preoperative preparation of elective intestinal surgery was performed. The outcome included overall SSI, organ space SSI, superficial SSI, deep SSI, and mortality rate. Results: A total of 35 randomized controlled trials (RCTs) consisting of 8445 adult patients were included in our present analysis. OABP regimens were combined with IVAP in 29 RCTs. In general, the incidence of overall SSI in the OABP group was less compared with the IVAP alone or IVAP+MBP group (RR 0.56, 95% CI 0.46–0.69, P < .00001, I2 = 47%). Metronidazoles plus quinolones or aminoglycosides showed the best effect on reducing the overall SSI. OABP in combination with preoperative and postoperative IVAP was both significantly associated with reduced SSI. IVAP before and within 24 h after surgery showed the best advantage. No difference was found between the OABP without IVAP group and the control group in reducing SSI. OABP regimens also demonstrated a lower incidence rate of organ space SSI, superficial SSI, deep SSI, and mortality. Conclusion: OABP in combination with preoperative IVAP and within 24 h post-operation significantly reduced the incidence of SSI in intestinal surgery. Metronidazoles accompanied with quinolones or aminoglycosides might be the appropriate combinations for OABP regimens.

Abstract Background Chronic HBV infection is always accompanied by differences in the balance between regulatory T cells (Tregs) and T-helper 17 (Th17) cells in infection phases. IL-21 plays an important role in the progression of chronic HBV infection. Thus, the aim of our study was to investigate the role of the regulatory function of IL-21 in maintaining the balance between Tregs and Th17 cells in chronic HBV infection. Methods Twenty-five chronic HBV-infected patients in the immune-tolerant (IT) phase and 23 chronic hepatitis B (CHB) patients were recruited in this study. Cytokines production was measured by ELISA. The mRNA expression levels were determined by qPCR. CD4+T cells were stimulated with or without IL-21. Tregs and Th17 cells were measured by flow cytometry. pSTAT3 and STAT3 expression was assessed by Western blotting. Results The concentration of IL-21 in the serum of CHB were significantly higher than that in the serum from IT patients, and IL-21 and IL-21R levels in the PBMCs from CHB were higher than those from IT patients. IL-21 promoted Th17 cells differentiation and function but inhibited Treg cells differentiation and function by activating STAT3 signaling pathways, upregulating RORγt expression, downregulating Foxp3 expression, by increasing IL-17and IL-22 secretion, and decreasing TGF-β secretion in chronic HBV infection. The proportion of Tregs and TGF-β concentrations in CHB was significantly lower than that in IT patients. Furthermore, the percentage of Th17 cells and the IL-17 concentration in CHB was markedly higher than that in IT patients, causing a reduction in the Tregs/Th17 ratio in CHB patients. Conclusions Our results suggest that IL-21 may contribute to inflammation in chronic HBV infection by modulating the balance between Treg and Th17 cells.

ABSTRACTThe treatment of methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia with antibiotics alone poses considerable challenges. To address these challenges, low-frequency ultrasound (LFU) emerges as a promising approach. In this study, a mouse pneumonia model was established through intratracheal injection of MRSA to investigate the therapeutic efficacy of LFU in combination with antibiotics. Minimal inhibitory concentration was assessed, and the distribution of antibiotics in the lung and plasma was determined using liquid chromatography coupled with mass spectrometry. Various parameters, including the survival rate, histopathology, lung bacterial clearance, and the expressions of cytokines and inflammation-related genes, were evaluated before and after treatment. Compared with the infection group, both the antibiotic-alone groups [vancomycin (VCM), linezolid, and contezolid (CZD)] and the groups in combination with LFU demonstrated an improvement in the survival status of mice. The average colony-forming units of lung tissue in the LFU combination groups were lower compared with the antibiotic-alone groups. While no significant changes in C-reactive protein and procalcitonin in plasma and bronchoalveolar lavage fluid were observed, histopathological results revealed reduced inflammatory damage in LFU combination groups. The secretion of interleukin-6 and tumor necrosis factor-alpha was decreased by the combination treatment, particularly in the VCM + LFU group. Furthermore, the expressions of MRSA virulence factors (hla and agrA) and inflammation-related genes (Saa3, Cxcl9, and Orm1) were further reduced by the combinations of LFU and antibiotics. Additionally, LFU treatment facilitated the distribution of VCM and CZD in mouse lung tissue at 30 and 45 min, respectively, after dosage.IMPORTANCETreating pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) with antibiotics alone poses significant challenges. In this in vivo study, we present compelling evidence supporting the efficacy of low-frequency ultrasound (LFU) as a promising approach to overcome these obstacles. Our findings demonstrated that LFU enhanced the effectiveness of vancomycin, linezolid, and contezolid in an MRSA pneumonia model. The combination of LFU with anti-MRSA agents markedly improved the survival rate of mice, accelerated the clearance of pulmonary bacteria, reduced inflammatory injury, inhibited the production of MRSA endotoxin, and enhanced the distribution of antibiotics in lung tissue. The application of LFU in the treatment of pulmonary infections held substantial significance. We believe that readers of your journal will find this topic of considerable interest.

The improvement of workers' employment quality is an important manifestation of high-quality economic development. Based on 13,969 valid samples from the China Family Panel Studies (CFPS) data, the paper examines the impact of urban digital economy development level on individual employment quality from a micro perspective using a multilevel regression model. The study finds that the level of urban digital economy development significantly promotes individual employment quality. For every 1 unit increase in the level of urban digital economy development, the quality of individual employment will increase by 1.033 units. And air quality positively moderates the relationship between urban digital economy development level and individual employment quality, i.e., in cities with good air quality, the urban digital economy development level has a more important role in promoting the quality of individual employment. Further heterogeneity analysis reveals that the level of digital economy development in cities has a more pronounced effect on the employment quality of males, younger workers (40 years old and below), and party members. To be more specific, every increase of one unit in the development level of urban digital economy will increase the employment quality by 1.649, 0.787, and 0.897 units, respectively. The above findings are useful for the formulation of policies to achieve high quality of employment and the implementation of environmental management plans.

Anti-metabotropic glutamate receptor 1 encephalitis is an uncommon autoimmune condition characterized by a subacute onset of cerebellar syndrome. Frequently, it also manifests as sleep disorders and cognitive or behavioral changes. While immunotherapy is the primary treatment approach, the disease remains poorly understood. Herein, we present a case of anti-metabotropic glutamate receptor 1 encephalitis, highlighting its primary cerebellar syndrome manifestation. The first magnetic resonance imaging scan showed no obvious abnormality. Lumbar puncture showed increased cerebrospinal fluid pressure, increased white blood cell count and protein level. The next-generation sequencing of cerebrospinal fluid showed Epstein–Barr virus infection, and the patient was diagnosed with viral cerebellar encephalitis. However, antiviral therapy was ineffective. Finally, anti-metabotropic glutamate receptor 1 was measured at 1:1,000, and the patient was definitely diagnosed with anti-metabotropic glutamate receptor 1 encephalitis. Therefore, clinicians should pay attention to such diseases to avoid misdiagnosis.

Abstract Male breast cancer (MBC) is a rare but aggressive malignancy with cellular and immunological characteristics that remain unclear. Here, we perform transcriptomic analysis for 111,038 single cells from tumor tissues of six MBC and thirteen female breast cancer (FBC) patients. We find that that MBC has significantly lower infiltration of T cells relative to FBC. Metastasis-related programs are more active in cancer cells from MBC. The activated fatty acid metabolism involved with FASN is related to cancer cell metastasis and low immune infiltration of MBC. T cells in MBC show activation of p38 MAPK and lipid oxidation pathways, indicating a dysfunctional state. In contrast, T cells in FBC exhibit higher expression of cytotoxic markers and immune activation pathways mediated by immune-modulatory cytokines. Moreover, we identify the inhibitory interactions between cancer cells and T cells in MBC. Our study provides important information for understanding the tumor immunology and metabolism of MBC.

Abstract Purpose To compare the therapeutic efficacy and safety of microwave ablation (MWA) and lauromacrogol injection for ablation (LIA) for benign predominantly cystic thyroid nodules. Materials and methods In this retrospective study, 85 patients with predominantly cystic thyroid nodules (PCTNs) who underwent microwave ablation (MWA) or lauromacrogol injection for ablation (LIA) between June 2019 and August 2022 at three hospitals were included in our research. Forty-six patients were treated with microwave ablation, and thirty-nine patients were treated with lauromacrogol injection for ablation. The baseline characteristics, nodal volume, volume reduction rate (VRR), and incidence of postoperative complications were compared between these two groups. Results After treatment, there were significant differences in the thyroid nodule volume and the volume reduction rate (VRR) at different follow-up times between the groups (p 0.05). Of note, no serious intraoperative or postoperative complications occurred in the corresponding group. Conclusion MWA and LIA are very effective and safe strategies for the treatment of predominantly cystic thyroid nodules. However, LIA is more advantageous in that it is less expensive and has a shorter length of hospital stay than MWA.

Abstract Background Bladder cancer (BLCA) represents a highly heterogeneous disease characterized by distinct histological, molecular, and clinical features, whose tumorigenesis and progression require aberrant metabolic reprogramming of tumor cells. However, current studies have not expounded systematically and comprehensively on the metabolic heterogeneity of BLCA. Methods The UCSC XENA portal was searched to obtain the expression profiles and clinical annotations of BLCA patients in the TCGA cohort. A total of 1,640 metabolic-related genes were downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Then, consensus clustering was performed to divide the BLCA patients into two metabolic subtypes according to the expression of metabolic-related genes. Kaplan-Meier analysis was used to measure the prognostic values of the metabolic subtypes. Subsequently, comparing the immune-related characteristics between the two metabolic subtypes to describe the immunological difference. Then, the Scissor algorithm was applied to link the metabolic phenotypes and single-cell transcriptome datasets to determine the biomarkers associated with metabolic subtypes and prognosis. Finally, the clinical cohort included 63 BLCA and 16 para-cancerous samples was used to validate the prognostic value and immunological correlation of the biomarker. Results BLCA patients were classified into two heterogeneous metabolic-related subtypes (MRSs) with distinct features: MRS1, the subtype with no active metabolic characteristics but an immune infiltration microenvironment; and MRS2, the lipogenic subtype with upregulated lipid metabolism. These two subtypes had distinct prognoses, molecular subtypes distributions, and activations of therapy-related pathways. MRS1 BLCAs preferred to be immuno-suppressive and up-regulated immune checkpoints expression, suggesting the well-therapeutic response of MRS1 patients to immunotherapy. Based on the Scissor algorithm, we found that S100A7 both specifically up-regulated in the MRS1 phenotype and MRS1-tumor cells, and positively correlated with immunological characteristics. In addition, in the clinical cohort included 63 BLCA and 16 para-cancerous samples, S100A7 was obviously associated with poor prognosis and enhanced PD-L1 expression. Conclusions The metabolic subtype with S100A7 high expression recognizes the immuno-suppressive tumor microenvironment and predicts well therapeutic response of immunotherapy in BLCA. The study provides new insights into the prognostic and therapeutic value of metabolic heterogeneity in BLCA.

Abstract Background COVID-19 put older individuals at high risk for morbidity and mortality, isolation, reduced coping, and lower satisfaction with life. Many older adults experienced social isolation, fear, and anxiety. We hypothesized that successful coping with these stressors would maintain or improve satisfaction with life, a crucial psychological outcome during the pandemic. Our study investigated relationships between older people’s coping and life satisfaction during the pandemic and their optimism, sense of mastery, closeness with spouse, family, and friends, and vulnerabilities from frailty, comorbid diseases, memory problems, and dependencies in instrumental activities of daily living (IADL). Methods The study was based on a special COVID-19 sample of 1351 community-dwelling older adults who participated in the 2020 Health and Retirement Survey. A comprehensive structural equation modeling was used to test direct and indirect effects, with life satisfaction as the main outcome and coping as a mediator between the other variables and coping. Results Most survey respondents were female and between the ages of 65–74 years. They averaged 1.7 chronic conditions, one in seven was frail, about one-third rated their memory as fair or poor, and about one in seven reported one or more difficulties in IADL. As hypothesized—older people with increased sense of mastery and optimism were better able to cope and had greater life satisfaction. In addition, close relationships with friends and with other family members besides the spouse/partner or children contributed to more successful coping, while the interpersonal closeness of all types contributed directly to greater life satisfaction. Finally, older people with more IADL limitations reported greater difficulty coping and lower life satisfaction, and those older people who were frail or had multiple comorbid diseases reported lower life satisfaction. Conclusions Optimism, sense of mastery and closeness with family/friends promotes coping and life satisfaction, whereas frailty and comorbidities make coping more challenging and lead to lower life satisfaction particularly during a pandemic. Our study improves on prior research because of its nationally representative sample and formal specification and testing of a comprehensive theoretical framework.

Abstract Introduction To assess the safety, tolerability and pharmacokinetics of a single dose of SYHA1402 in healthy Chinese subjects. Methods This was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy subjects. Subjects received a single dose of SYHA1402 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg, or matching placebo. Safety and tolerability were assessed throughout the study. The pharmacokinetic (PK) parameters of SYHA1402 were estimated using non-compartmental analysis. Results In all, 54 subjects were enrolled and completed the study. Specifically, there were no deaths, serious adverse events or withdrawals from study due to adverse events. All treatment-emergent adverse events were mild. The most common drug-related adverse event was sinus bradycardia. The time to maximum concentration ranged from 1.13 to 2.25 h, and the terminal elimination half-life range was 1.51–4.70 h. SYHA1402 exhibited nonlinear PK parameters with less than dose-proportional increases in exposure after single oral doses of 25 to 800 mg. Conclusion SYHA1402 administered as a single dose was well tolerated and safe over the dose range of 25–800 mg. More than 50% of the unchanged SYHA1402 was excreted in urine within the dose range of 25–100 mg. Trial registration NCT03988413 ( https://www.clinicaltrials.gov/ ; registration date: 17 June 2019).

AbstractObjective: To verify that the TiO2 nanofilm dip-coated by sol-gel can reduce titanium alloy implants (TAI)’s heat production after microwave diathermy (MD).Methods: The effect of 40 W and 60 W MD on the titanium alloy substrate coated with TiO2 nanofilm (Experimental Group) and the titanium alloy substrate without film (Control Group) were analyzed in vitro and in vivo. Changes in the skeletal muscle around the implant were evaluated in ex vivo by histology.Results: After 20 min of MD, in vitro the temperature rise of the titanium substrate was less in the Experimental Group than in the Control Group (40 W: 1.4 °C vs. 2.6 °C, p

A comparison was made between the traditional charcoal-grilled lamb shashliks (T) and four new methods, namely electric oven heating (D), electric grill heating (L), microwave heating (W), and air fryer treatment (K). Using E-nose, E-tongue, quantitative descriptive analysis (QDA), and HS-GC-IMS and HS-SPME-GC–MS, lamb shashliks prepared using various roasting methods were characterized. Results showed that QDA, E-nose, and E-tongue could differentiate lamb shashliks with different roasting methods. A total of 43 and 79 volatile organic compounds (VOCs) were identified by HS-GC-IMS and HS-SPME-GC–MS, respectively. Unsaturated aldehydes, ketones, and esters were more prevalent in samples treated with the K and L method. As a comparison to the RF, SVM, 5-layer DNN and XGBoost models, the CNN-SVM model performed best in predicting the VOC content of lamb shashliks (accuracy rate all over 0.95) and identifying various roasting methods (accuracy rate all over 0.92).

Objectives: Bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have become a worldwide public health threat, and beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) are considered as one reliable carbapenem-sparing antibiotic. However, it is still controversial whether BLBLIs are truly noninferior to carbapenems. Therefore, we conducted this meta-analysis to compare the efficacy of BLBLIs with carbapenems for ESBL-PE BSIs. Methods: A systematic search of PubMed, Cochrane Library, and Embase was conducted until December 2021 to enroll studies comparing BLBLIs with carbapenems for ESBL-PE BSIs. A subgroup analysis was performed based on the choice of therapy (empirical, definitive, and mixed therapy). The protocol was registered in the International Prospective Register of Systematic Reviews (#CRD42022316011). Results: A total of 2786 patients from one randomized clinical trial and 25 cohorts were included. There was no statistically significant difference between BLBLIs and carbapenems groups in therapeutical response (odds ratio [OR] = 1.19, P = 0.45) and mortality (OR = 1.06, P = 0.68). Furthermore, although the statistical difference was also not found in the subgroup analysis, BLBLIs performed better in definitive therapy than empirical therapy than carbapenems, with a numerically higher therapeutical response (OR = 1.42 vs 0.89) and a mildly lower mortality (OR = 0.85 vs 1.14). Conclusion: BLBLIs were noninferior to carbapenems for ESBL-PE BSIs, especially in definitive therapy. BLBLIs may be a valid alternative to spare the use of carbapenems.

Abstract Background Femoral neck fractures are serious consequence of osteoporosis (OP), numbers of people are working on the micro—mechanisms of femoral neck fractures. This study aims to investigate the role and weight of microscopic properties on femoral neck maximum load (Lmax), funding the indicator which effects Lmax most. Methods A total of 115 patients were recruited from January 2018 to December 2020. Femoral neck samples were collected during the total hip replacement surgery. Femoral neck Lmax, micro—structure, micro—mechanical properties, micro—chemical composition were all measured and analyzed. Multiple linear regression analyses were performed to identify significant factors that affected the femoral neck Lmax. Results The Lmax, cortical bone mineral density (cBMD), cortical bone thickness (Ct. Th), elastic modulus, hardness and collagen cross—linking ratio were all significantly decreased, whereas other parameters were significantly increased during the progression of OP (P

The stability of contemporary ice shelves is under threat due to global warming, and the geological records in the Ross Sea offer such an opportunity to test the linkage between them. However, the absence of calcareous microfossils in the sediments of the Ross Sea results in uncertainties in establishing a precise chronology for studies. Hence, three sediment cores were collected and studied in terms of radiocarbon dating, magnetic susceptibility, and sediment grain size to reconstruct the environmental processes in the Ross Sea since the last glacial period. The main results are as follows: (1) two grain-size components were identified for the studied cores, which can be correlated to ice-shelf and sea-ice transport, respectively; (2) due to old-carbon contamination and an inconsistent carbon reservoir, the radiocarbon dates were generally underestimated, and as an alternative, changes in magnetic susceptibility of the studied cores can be tuned to the ice-core records to establish a reliable age–depth model and; (3) integrating sediment grain-size changes and comparisons with other paleoenvironmental proxies in the Antarctic, a process from a sub-ice sheet in the last glacial period to a sub-ice shelf in the glacial maximum, and, finally, to a glaciomarine state since the last deglacial period was identified in the western Ross Sea. Integrating these findings, the warming processes in the Antarctic were highlighted in the retreat processes of the Ross Ice Shelf in the past.

Abstract The antibiotic‐resistant Klebsiella pneumoniae (Kp) has become a significant crisis in treating pneumonia. Low‐frequency ultrasound (LFU) is promising to overcome the obstacles. Mice were infected with bioluminescent Kp Xen39 by intratracheal injection to study the therapeutic effect of LFU in combination with antibiotics. The counts per second (CPS) were assessed with an animal biophoton imaging system. Bacterial clearance, histopathology, and the concentrations of cytokines were determined to evaluate the therapeutic effect. LC–MS/MS was used to detect the distribution of antibiotics in the lung and plasma. LFU in combination with meropenem (MEM) or amikacin (AMK) significantly improved the behavioural state of mice. The CPS of the LFU combination group were more significantly decreased compared with those of the antibiotic alone groups. The average colony‐forming units of lung tissue in the LFU combination groups were also lower than those of the antibiotic groups. Although no significant changes of cytokines (IL‐6 and TNF‐α) in plasma and bronchoalveolar lavage fluid were observed, LFU in combination with antibiotics showed less inflammatory damage from histopathological results compared with the antibiotic‐alone groups. Moreover, 10 min of LFU treatment promoted the distribution of MEM and AMK in mouse lung tissue at 60 and 30 min, respectively, after dosage. LFU could enhance the effectiveness of MEM and AMK in the treatment of Kp‐induced pneumonia, which might be attributed to the fact that LFU could promote the distribution of antibiotics in lung tissue and reduce inflammatory injury.

Abstract Photo composition is one of the most important factors in the aesthetics of photographs. As a popular application, composition recommendation for a photo focusing on a specific subject has been ignored by recent deep-learning-based composition recommendation approaches. In this paper, we propose a subject-aware image composition recommendation method, SAC-Net, which takes an RGB image and a binary subject window mask as input, and returns good compositions as crops containing the subject. Our model first determines candidate scores for all possible coarse cropping windows. The crops with high candidate scores are selected and further refined by regressing their corner points to generate the output recommended cropping windows. The final scores of the refined crops are predicted by a final score regression module. Unlike existing methods that need to preset several cropping windows, our network is able to automatically regress cropping windows with arbitrary aspect ratios and sizes. We propose novel stability losses for maximizing smoothness when changing cropping windows along with view changes. Experimental results show that our method outperforms state-of-the-art methods not only on the subject-aware image composition recommendation task, but also for general purpose composition recommendation. We also have designed a multistage labeling scheme so that a large amount of ranked pairs can be produced economically. We use this scheme to propose the first subject-aware composition dataset SACD, which contains 2777 images, and more than 5 million composition ranked pairs. The SACD dataset is publicly available at https://cg.cs.tsinghua.edu.cn/SACD/ .

Abstract Background Simiao pill module (SMM), a traditional Chinese medicine formula, has been widely used to treat gout and gouty arthritis. The goal of this study was to investigate the effects of SMM on epithelial-mesenchymal transition (EMT) and activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome in a mouse model of potassium oxonate (PO)-induced chronic hyperuricemic nephropathy (HN). Methods Mice were randomly divided into the following four groups: control, HN model (PO), febuxostat (FEB)-treated (PO + FEB), and SMM-treated (PO + SMM) groups. Following 6 weeks of treatment, blood samples were collected and mice were sacrificed to collect kidney samples to study the biochemical parameters associated with renal function and histopathological changes associated with HN, respectively. The samples were analyzed for the expression of markers of EMT (collagen type 3, α-smooth muscle actin [α-SMA], fibronectin, vimentin and E-cadherin) and activation of NLRP3 inflammasome (NLRP3, apoptosis-associated speck-like protein [ASC], caspase-1, interleukin [IL]-1β, and IL-18). Results Our results showed that hyperuricemia, impaired kidney function, and renal pathological characteristics induced by PO treatment were improved following treatment with SMM and FEB. Additionally, treatment with SMM and FEB decreased the expression of vimentin, collagen 3, fibronectin, and α-SMA, and increased the expression of E-cadherin. Moreover, NLRP3 inflammasome activation, as assessed by the increased expression of NLRP3, ASC, and caspase-1, and secretion of IL-1β and IL-18, was inhibited by treatment with SMM and FEB. Conclusion These results suggest that SMM inhibited EMT and NLRP3 inflammasome activation in chronic HN mice, and the beneficial effect of SMM was compared with a standard drug, FEB.

Abstract Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and its demarcation contributes to various therapeutic outcomes. However, a small subset of tumors shows different molecular features that are in contradiction with pathological classification. Unsupervised clustering was performed to subtype NSCLC using the transcriptome data from the TCGA database. Next, immune microenvironment features of lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), and lung adenoid squamous carcinoma (LASC) were characterized. In addition, diagnostic biomarkers to demarcate LASC among LUSC were screened using weighted gene co-expression network analysis (WGCNA) and validated by the in-house cohort. LASC was identified as a novel subtype with adenoid transcriptomic features in LUSC, which exhibited the most immuno-escaped phenotype among all NSCLC subtypes. In addition, FOLR1 was identified as a biomarker for LASC discrimination using the WGCNA analysis, and its diagnostic value was validated by the in-house cohort. Moreover, FOLR1 was related to immuno-escaped tumors in LUSC but not in LUAD. Overall, we proposed a novel typing strategy in NSCLC and identified FOLR1 as a biomarker for LASC discrimination.

Abstract Background Angiotensin-converting enzyme 2 (ACE2) is known as a tumor suppressor and lowly expressed in most cancers. The expression pattern and role of ACE2 in breast cancer (BC) have not been deeply elucidated. Methods A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). The correlation of ACE2 expression and immunological characteristics in the BC tumor microenvironment (TME) was evaluated. The role of ACE2 in predicting the response to therapeutic options was estimated. Moreover, the pharmacodynamic effect of angiotensin-(1–7) (Ang-1–7), the product of ACE2, on chemotherapy and immunotherapy was evaluated on the BALB/c mouse BC model. In addition, the plasma samples from BC patients receiving neoadjuvant chemotherapy were collected and subjected to the correlation analysis of the expression level of Ang-1–7 and the response to neoadjuvant chemotherapy. Results ACE2 was lowly expressed in BC tissues compared with that in adjacent tissues. Interestingly, ACE2 was shown the highest correlation with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB) in BC. In addition, a high level of ACE2 indicated a low response to endocrine therapy and a high response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. In the mouse model, Ang-1–7 sensitized mouse BC to the chemotherapy and anti-PD-1 immunotherapy, which revealed its significant anti-tumor effect. Moreover, a high plasma level of Ang-1–7 was associated with a better response to neoadjuvant chemotherapy. Conclusions ACE2 identifies immuno-hot tumors in BC, and its enzymatic product Ang-1–7 sensitizes BC to the chemotherapy and immunotherapy by remodeling the TME.

Abstract Critical illness refers to the clinical signs of severe, variable and life-threatening critical conditions, often accompanied by insufficiency or failure of one or more organs. Bone health of critically ill patients is severely affected during and after ICU admission. Therefore, clinical work should focus on ICU-related bone loss, and early development and implementation of related prevention and treatment strategies: optimized and personalized nutritional support (high-quality protein, trace elements and intestinal prebiotics) and appropriate physiotherapy and muscle training should be implemented as early as possible after ICU admission and discharge. At the same time, the drug regulates excessive metabolism and resists osteoporosis.

Abstract Background Although the lack of estrogen receptor β (ERβ) is a risk factor for the development of inflammatory bowel disease (IBD) and psychiatric disorders, the underlying cellular and molecular mechanisms are not fully understood. Herein, we revealed the role of gut microbiota in the development of IBD and related anxiety-like behavior in ERβ-deficient mice. Results In response to dextran sodium sulfate (DSS) insult, the ERβ knockout mice displayed significant shift in α and β diversity in the fecal microbiota composition and demonstrated worsening of colitis and anxiety-like behaviors. In addition, DSS-induced colitis also induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in ERβ-deficient mice, which was associated with colitis and anxiety-like behaviors. In addition, RNA sequencing data suggested that ErbB4 might be the target of ERβ that is involved in regulating the HPA axis hyperactivity caused by DSS insult. Gut microbiota remodeling by co-housing showed that both the colitis and anxiety-like behaviors were aggravated in co-housed wild-type mice compared to single-housed wild-type mice. These findings suggest that gut microbiota play a critical role in mediating colitis disease activity and anxiety-like behaviors via aberrant neural processing within the gut-brain axis. Conclusions ERβ has the potential to inhibit colitis development and anxiety-like behaviors via remodeling of the gut microbiota, which suggests that ERβ is a promising therapeutic target for the treatment of IBD and related anxiety-like behaviors. Video Abstract

Abstract Background The ketogenic diet (KD) has anti-tumor and anti-diabetic effects in addition to its anti-epileptic role. It could also improve cardiac function and attenuate neurological insult. However, the effect of KD on blood perfusion or tissue recovery after ischemia remains largely unknown. Thus, we observed blood flow and ischemic tissue recovery following hind limb ischemia (HLI) in mice. Methods C57 mice were fed with either a KD or normal diet (ND) for 2 weeks, before inducing hind limb ischemia, blood perfusion of ischemic limb tissue was observed at 0, 7, and 21 days post operation. Results KD not only decreased blood perfusion of ischemic limb tissue but also delayed muscle recovery after ischemia, induced muscle atrophy of non-ischemic tissue compared to mice fed with ND. Furthermore, KD delayed wound healing at the surgical site and aggravated inflammation of the ischemic tissue. At the cellular level, KD altered the metabolic status of limb tissue by decreasing glucose and ketone body utilization while increasing fatty acid oxidation. Following ischemia, glycolysis, ketolysis, and fatty acid utilization in limb tissue were all further reduced by KD, while ketogenesis was mildly increased post KD in this mice model. Conclusion The KD may cause impaired tissue recovery after ischemia and possible muscle atrophy under a prolonged diet. Our results hint that patients with limb ischemia should avoid ketogenic diet.

Summary: Immune checkpoint inhibitors have transformed the management of advanced cancers, but biomarkers for the prediction of therapeutic responses have not been fully uncovered. Here, we provide a step-by-step approach for the identification of novel biomarkers from public transcriptomic datasets. We comprehensively summarize the available transcriptomic datasets containing immunotherapy information and describe the necessary procedures to evaluate the effectiveness of a novel immunotherapy biomarker, which may accelerate the identification of novel immunotherapy biomarkers.For complete details on the use and execution of this protocol, please refer to Mei et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al, but the specific action on human brain development remains unclear. Al hydroxide (Al(OH)3), the most common vaccine adjuvant, is the major source of Al and poses risks to the environment and early childhood neurodevelopment. In this study, we explored the neurotoxic effect of 5 μg/ml or 25 μg/ml Al(OH)3 for six days on neurogenesis by utilizing human cerebral organoids from human embryonic stem cells (hESCs). We found that early Al(OH)3 exposure in organoids caused a reduction in the size, deficits in basal neural progenitor cell (NPC) proliferation, and premature neuron differentiation in a time and dose-dependent manner. Transcriptomes analysis revealed a markedly altered Hippo-YAP1 signaling pathway in Al(OH)3 exposed cerebral organoid, uncovering a novel mechanism for Al(OH)3-induced detrimental to neurogenesis during human cortical development. We further identified that Al(OH)3 exposure at day 90 mainly decreased the production of outer radial glia-like cells(oRGs) but promoted NPC toward astrocyte differentiation. Taken together, we established a tractable experimental model to facilitate a better understanding of the impact and mechanism of Al(OH)3 exposure on human brain development.

One of the major limitations in the clinical use of existing oxazolidinone antibiotics is their characteristic adverse reactions, in particular thrombocytopenia. In anti-infective treatment, if patients are suspected of having drug-induced thrombocytopenia, the first step is to immediately discontinue the offending drug. Even in patients with severe infections, the antibacterial drug may need to be changed or the antibacterial treatment may need to be discontinued because thrombocytopenia may have a more serious clinical prognosis. In addition, if the patient needs to continue antibacterial treatment after discharge, the lack of conditions for monitoring platelet levels may also pose hidden dangers to the patient. Contezolid is an orally administered oxazolidinone antibacterial agent approved by the National Medical Products Administration of China in 2021. We found that contezolid may have an improved safety profile with a significantly reduced potential for myelosuppression based on the results of our observational clinical study. In this article, we review the advantages of contezolid as a new oxazolidinone antibiotic and describe three typical clinical cases of patients who experienced drug-induced thrombocytopenia after using linezolid. The platelet levels of these different patients were all significantly improved to varying degrees after initiation of contezolid treatment.

This study further investigates the effect of potential on the corrosion resistance, the self-healing performance and the durability of CrN/Cr-coated SS316L bipolar plates with artificial defects (CR-316) in simulated cathodic HT-PEFC environments by means of electrochemical methods. The self-healing ability initiated by oxygen is relatively weak and needs the assistance of the cathode working potential for sealing. In some cases, the defects have spread over large parts of the bipolar plate. The influence of the potential on the corrosion resistance of the bare 316L and CR-316 specimens in the simulated cathodic HT-PEFC environments were investigated by electrochemical impedance spectroscopy. Moreover, the durability of the CR-316 specimens was examined under the various potential cycles in the simulated cathodic environment of HT-PEFC and O2 atmosphere. After 5000 CV cycles in the potential range of 0.4–1.0 V vs. RHE, the CR-316 specimens could maintain the integrity and good corrosion resistance against the hot phosphoric acid. The results demonstrate the superior performance of CR-316 and make it a prime candidate as a non-precious coating for metallic bipolar plates on the cathode side of HT-PEFCs.

Abstract Background Femoral neck fractures are the worst consequence of osteoporosis (OP), and its early prevention and treatment have become a public health problem. This study aims to investigate the relationship of bone-related biomarkers, femoral neck bone mineral density (BMD) and maximum load (Lmax), selecting the indicator which can reflect femoral neck bone loss and reduced bone strength. Methods A total of 108 patients were recruited from January 2017 to December 2019. Venous blood samples were collected from patients before total hip replacement, and femoral neck samples were collected during the surgery. Femoral neck BMD, femoral neck Lmax, bone-related markers (serum levels of bone turnover markers, protein expression of type I collagen (COL-I) and osteopontin (OPN) in femoral neck) were all measured and analyzed. Results The expression of COL-I in femoral neck were significantly decreased, whereas other markers were all significantly increased with the decreasing of femoral neck BMD and Lmax (P

ObjectiveThe objective of this research is to investigate the clinical application value of cerebrospinal fluid (CSF) cytology and circulating tumor DNA (ctDNA) in lung adenocarcinoma (LUAD) meningeal metastasis-meningeal carcinomatosis (MC), and to further explore the possible molecular mechanisms and drug treatment targets of LUAD meningeal metastasis by next-generation sequencing (NGS).MethodsWe retrospectively analyzed LUAD with MC in 52 patients. CSF cytology was carried out using the slide centrifugation precipitation method and May-Grüwald-Giemsa (MGG) staining. Tumor tissue, plasma and CSF ctDNA of some MC patients were detected by NGS.ResultsOf the 52 MC patients, 46 (88.46%) were positive for CSF cytology and 34 (65.38%) were positive for imaging, with statistically significant differences in diagnostic positivity (P < 0.05). In 32 of these patients, CSF cytology, cerebrospinal fluid ctDNA, plasma ctDNA and MRI examination were performed simultaneously, and the positive rates were 84.38, 100, 56.25, and 62.50% respectively, the difference was statistically significant (P < 0.001). Analysis of the NGS profiles of tumor tissues, plasma and CSF of 12 MC patients: the mutated gene with the highest detection rate was epidermal growth factor receptor (EGFR) and the detection rate were 100, 58.33, and 100% respectively in tumor tissues, plasma and CSF, and there were 6 cases of concordance between plasma and tissue EGFR mutation sites, with a concordance rate of 50.00%, and 12 cases of concordance between CSF and tissue EGFR mutation sites, with a concordance rate of 100%. In addition, mutations not found in tissue or plasma were detected in CSF: FH mutation, SETD2 mutation, WT1 mutation, CDKN2A mutation, CDKN2B mutation, and multiple copy number variants (CNV), with the most detected being CDKN2A mutation and MET amplification.ConclusionCSF cytology is more sensitive than traditional imaging in the diagnosis of meningeal carcinomatosis and has significant advantages in the early screening and diagnosis of MC patients. CSF ctDNA can be used as a complementary diagnostic method to negative results of CSF cytology and MRI, and CSF ctDNA can be used as an important method for liquid biopsy of patients with MC, which has important clinical significance in revealing the possible molecular mechanisms and drug treatment targets of meningeal metastasis of LUAD.

Pork floss is a traditional Chinese food with a long history. Nowadays, pork floss is known to consumers as a leisure food. It is made from pork through a unique process in which the muscle fibers become flaky or granular and tangled. In this study, a deep learning-based approach is proposed to detect the quality characteristics of pork floss structure. Describe that the experiments were conducted using widely recognized brands of pork floss available in the grocery market, omitting the use of abbreviations. A total of 8000 images of eight commercially available pork flosses were collected and processed using sharpening, image gray coloring, real-time shading correction, and binarization. After the machine learning model learned the features of the pork floss, the images were labeled using a manual mask. The coupling of residual enhancement mask and region-based convolutional neural network (CRE-MRCNN) based deep learning framework was used to segment the images. The results showed that CRE-MRCNN could be used to identify the knot features and pore features of different brands of pork floss to evaluate their quality. The combined results of the models based on the sensory tests and machine vision showed that the pork floss from TC was the best, followed by YJJ, DD and HQ. This also shows the potential of machine vision to help people recognize the quality characteristics of pork floss structure.

In large areas of the ocean, iron concentrations are insufficient to promote phytoplankton growth. Numerous studies have been conducted to characterize the effect of iron on algae and how algae cope with fluctuating iron concentrations. Fertilization experiments in low-iron areas resulted primarily in diatom-dominated algal blooms, leading to laboratory studies on diatoms comparing low- and high-iron conditions. Here, we focus on the short-term temporal response following iron addition to an iron-starved open ocean diatom, Thalassiosira oceanica. We employed the NanoString platform and analyzed a high-resolution time series on 54 transcripts encoding proteins involved in photosynthesis, N-linked glycosylation, iron transport, as well as transcription factors. Nine transcripts were iron-responsive, with an immediate response to the addition of iron. The fastest response observed was the decrease in transcript levels of proteins involved in iron uptake, followed by an increase in transcript levels of iron-containing enzymes and a simultaneous decrease in the transcript levels of their iron-free replacement enzymes. The transcription inhibitor actinomycin D was used to understand the underlying mechanisms of the decrease of the iron-responsive transcripts and to determine their half-lives. Here, Mn-superoxide dismutase (Mn-SOD), plastocyanin (PETE), ferredoxin (PETF) and cellular repressor of EA1-stimulated genes (CREGx2) revealed longer than average half-lives. Four iron-responsive transcripts showed statistically significant differences in their decay rates between the iron-recovery samples and the actD treatment. These differences suggest regulatory mechanisms influencing gene transcription and mRNA stability. Overall, our study contributes towards a detailed understanding of diatom cell biology in the context of iron fertilization response and provides important observations to assess oceanic diatom responses following sudden changes in iron concentrations.

Abstract With the growing aging population and high prevalence of chronic illnesses, there is an increasing demand for palliative care. In the US state of Indiana, an estimated 6.3 million people are living with one or more chronic illnesses, a large proportion of them reside in rural areas where there is limited access to palliative care leading to major healthcare inequities and disparities. This study aims to identify common barriers and facilitators to access palliative care services in rural areas of Indiana from the perspectives of healthcare providers including clinicians, educators, and community stakeholders. Using a community-based participatory approach, a purposive sample of palliative care providers (n = 15) in rural areas of Indiana was obtained. Penchansky and Thomas (1981) theoretical framework of access was used to guide the study. A semi-structured individual in-depth interview guide was used to collect the data. All the interviews were conducted online, audio-recorded, and transcribed. Barriers to palliative care include: misconceptions about palliative care as an underrecognized specialty; lack of trained palliative care providers; late involvement of inpatient palliative care and community hospice services; inadequate palliative care education and training; financial barriers, attitudes and beliefs around PC; and geographical barriers. Facilitators to palliative care include financial gains supporting palliative care growth, enhanced nurses’ role in identifying patients with palliative care needs and creating awareness and informing the community about palliative care. Robust education and awareness, enhancing advanced practice nurses’ roles, increasing funding and resources are essential to improve the access of palliative care services in the rural communities of Indiana.

Considering the urgent need for disposal of red mud and the comprehensive treatment of coal mined-out areas, this paper presented red mud-based cementitious paste filling material (RMFM) to achieve the purpose of green filling treatment. However, the solidification performance of alkaline RMFM for contaminants can be affected when in contact with acid goaf water in practice, which may in turn cause secondary pollution to the surroundings. The leaching tests of RMFM under different pH and redox potential (Eh) conditions were designed to investigate the effects of environmental elements on the solidification performance of RMFM, and primarily investigated the treatment effectiveness of RMFM on goaf water. The test results manifest that the acidic and oxidizing environments could damage the hydration products generated by alkali and sulfate activation, thus affecting the solidification performance, while the alkaline and reducing environments could effectively prevent the release of the contaminants by enhancing the degree of alkali activation and inhibiting oxidation acid forming process. In the possible exposure environment, RMFM could effectively stabilize its own pollutants without secondary pollution. In addition, the powder RMFM samples had significant removal effects on heavy metals, the values of Cu, Pb, and As removal efficiency all reached more than 96.15%. HIGHLIGHTS RMFM can be used to achieve the purpose of green goaf filling treatment.; RMFM could effectively stabilize/solidify heavy metals through alkali and sulfate activation.; RMFM could release more contaminants in the acidic and oxidizing environment.; The alkaline and reducing environments could effectively prevent the release of the contaminants.; The powder RMFM samples had significant removal effects on heavy metals.;

Background: Accurate motion tracking in head-mounted displays (HMDs) has been widely used in immersive VR interaction technologies. However, tracking the head motion of users at all times is not always desirable. During a session of HMD usage, users may make scene-irrelevant head rotations, such as adjusting the head position to avoid neck pain or responding to distractions from the physical world. To the best of our knowledge, this is the first study that addresses the problem of scene-irrelevant head movements. Methods: We trained a classifier to detect scene-irrelevant motions using temporal eyehead-coordinated information sequences. To investigate the usefulness of the detection results, we propose a technique to suspend motion tracking in HMDs where scene-irrelevant motions are detected. Results: /Conclusions Experimental results demonstrate that the scene-relevancy of movements can be detected using eye-head coordination information, and that ignoring scene-irrelevant head motions in HMDs improves user continuity without increasing sickness or breaking immersion.

Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.

ABSTRACT Pseudomonas aeruginosa (PA) biofilm infection is clinically prevalent and difficult to eradicate. In the present work, we aimed to evaluate the in vitro and in vivo efficacy of colistin (COL)-based combinations against PA biofilm. MICs and fractional inhibitory concentration indexes (FICIs) of four antibiotics (COL, amikacin, levofloxacin, and meropenem) to bioluminescent strain PAO1, carbapenem-resistant PAO1 (CRPAO1), and clinically isolated strains were assessed. Minimal biofilm eradication concentrations (MBECs) of monotherapy and combinations were examined by counting the live bacteria in biofilm, accompanied by visual confirmation using confocal laser-scanning microscopy. An animal biofilm infection model was established by implanting biofilm subcutaneously, and the therapeutic effect was evaluated according to the change in luminescence through a live animal bio-photonic imaging system. In vitro, even combined with 4 or 8 mg/L COL, meropenem needed to reach 128 or 256 mg/L to eradicate the biofilm. Moreover, 2 mg/L COL combined with 32 mg/L amikacin or 4-8 mg/L levofloxacin could kill the PAO1 and CRPAO1 in biofilm within 24 h. In vivo, COL combined with amikacin or levofloxacin could shorten the eradication time of biofilm than monotherapy. For PAO1 biofilm, combination therapy could eradicate the biofilm in all mice on the 5th day, whereas monotherapy only eradicated biofilms in almost half of the mice. For CRPAO1 biofilm, the biofilm eradication rate on the 6th day in the COL+ amikacin, amikacin, or COL alone regimen was 90%, 10%, or 40%, respectively. COL combined with levofloxacin did not show a better effect than each individual antibiotic. COL-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. IMPORTANCE Infections associated with PA biofilm formation are extremely challenging. When monotherapy fails to achieve optimal efficacy, combination therapy becomes the last option. After evaluating multiple drug combinations through a series of experiments in vitro and in vivo, we confirmed that colistin-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. The efficacy of these combinations derives from the different bactericidal mechanisms and the bacterial susceptibility to each antibiotic. This study provided a new regimen to solve the incurable problem of biofilm by using COL combined with other antibiotics.

Abstract Background Males and females differ in their immunological responses to foreign pathogens. However, most of the current COVID-19 clinical practices and trials do not take the sex factor into consideration. Methods We performed a sex-based comparative analysis for the clinical outcomes, peripheral immune cells, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) specific antibody levels of 1558 males and 1499 females COVID-19 patients from a single center. The lymphocyte subgroups were measured by Flow cytometry. The total antibody, Spike protein (S)-, receptor binding domain (RBD)-, and nucleoprotein (N)- specific IgM and IgG levels were measured by chemiluminescence. Results We found that male patients had approximately two-fold rates of ICU admission (4.7% vs. 2.7% in males and females, respectively, P = 0.005) and mortality (3% vs. 1.4%, in males and females, respectively, P = 0.004) than female patients. Survival analysis revealed that the male sex is an independent risk factor for death from COVID-19 (adjusted hazard ratio [HR] = 2.22, 95% confidence interval [CI]: 1.3–3.6, P = 0.003). The level of inflammatory cytokines in peripheral blood was higher in males during hospitalization. The renal (102/1588 [6.5%] vs. 63/1499 [4.2%], in males and females, respectively, P = 0.002) and hepatic abnormality (650/1588 [40.9%] vs. 475/1499 [31.7%], P = 0.003) were more common in male patients than in female patients. By analyzing dynamic changes of lymphocyte subsets after symptom onset, we found that the percentage of CD19+ B cells and CD4+ T cells was generally higher in female patients during the disease course of COVID-19. Notably, the protective RBD-specific IgG against SARS-CoV-2 sharply increased and reached a peak in the fourth week after symptom onset in female patients, while gradually increased and reached a peak in the seventh week after symptom onset in male patients. Conclusions Males had an unfavorable prognosis, higher inflammation, a lower percentage of lymphocytes, and indolent antibody responses during SARS-CoV-2 infection and recovery. Early medical intervention and close monitoring are important, especially for male COVID-19 patients.