Amplifying Photon Upconversion in Alloyed Nanoparticles for a Near-Infrared Photodetector.

Photon upconverison has attracted a substantial amount of interest in diverse fields due to its characteristic anti-Stokes emissions. However, obtaining intense emission under low-power laser irradiation has remained a challenge. Here we report a mechanistic design of activator-sensitizer alloyed nanoparticles to achieve bright upconversion under weak infrared irradiation. This design allows a nearest sensitizer-activator separation to facilitate efficient energy transfer that results in remarkably enhanced upconversion (>2 orders of magnitude) under 0.26 W cm-2 irradiation compared to that of the Er sublattice, and the upconversion quantum yield also shows a 20-fold increase. Interestingly, the alloyed nanoparticles exhibit a gradual change in emission color with an increase in Yb3+ content, and moreover, their emission colors can be dynamically controlled by simply modulating the excitation laser power and pulse widths. Such alloyed nanoparticles show great promise for application in a near-infrared photodetector.

Revealing the role of necroptosis microenvironment: FCGBP + tumor-associated macrophages drive primary liver cancer differentiation towards cHCC-CCA or iCCA.

Previous research has demonstrated that the conversion of hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (iCCA) can be stimulated by manipulating the tumor microenvironment linked with necroptosis. However, the specific cells regulating the necroptosis microenvironment have not yet been identified. Additionally, further inquiry into the mechanism of how the tumor microenvironment regulates necroptosis and its impact on primary liver cancer(PLC) progression may be beneficial for precision therapy. We recruited a single-cell RNA sequencing dataset (scRNA-seq) with 34 samples from 4 HCC patients and 3 iCCA patients, and a Spatial Transcriptomic (ST) dataset including one each of HCC, iCCA, and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Quality control, dimensionality reduction and clustering were based on Seurat software (v4.2.2) process and batch effects were removed by harmony (v0.1.1) software. The pseudotime analysis (also known as cell trajectory) in the single cell dataset was performed by monocle2 software (v2.24.0). Calculation of necroptosis fraction was performed by AUCell (v1.16.0) software. Switch gene analysis was performed by geneSwitches(v0.1.0) software. Dimensionality reduction, clustering, and spatial image in ST dataset were performed by Seurat (v4.0.2). Tumor cell identification, tumor subtype characterization, and cell type deconvolution in spot were performed by SpaCET (v1.0.0) software. Immunofluorescence and immunohistochemistry experiments were used to prove our conclusions. Analysis of intercellular communication was performed using CellChat software (v1.4.0). ScRNA-seq analysis of HCC and iCCA revealed that necroptosis predominantly occurred in the myeloid cell subset, particularly in FCGBP + SPP1 + tumor-associated macrophages (TAMs), which had the highest likelihood of undergoing necroptosis. The existence of macrophages undergoing necroptosis cell death was further confirmed by immunofluorescence. Regions of HCC with poor differentiation, cHCC-CCA with more cholangiocarcinoma features, and the tumor region of iCCA shared spatial colocalization with FCGBP + macrophages, as confirmed by spatial transcriptomics, immunohistochemistry and immunofluorescence. Pseudotime analysis showed that premalignant cells could progress into two directions, one towards HCC and the other towards iCCA and cHCC-CCA. Immunofluorescence and immunohistochemistry experiments demonstrated that the number of macrophages undergoing necroptosis in cHCC-CCA was higher than in iCCA and HCC, the number of macrophages undergoing necroptosis in cHCC-CCA with cholangiocarcinoma features was more than in cHCC-CCA with hepatocellular carcinoma features. Further investigation showed that myeloid cells with the highest necroptosis score were derived from the HCC_4 case, which had a severe inflammatory background on pathological histology and was likely to progress towards iCCA and cHCC-CCA. Switchgene analysis indicated that S100A6 may play a significant role in the progression of premalignant cells towards iCCA and cHCC-CCA. Immunohistochemistry confirmed the expression of S100A6 in PLC, the more severe inflammatory background of the tumor area, the more cholangiocellular carcinoma features of the tumor area, S100A6 expression was higher. The emergence of necroptosis microenvironment was found to be significantly associated with FCGBP + SPP1 + TAMs in PLC. In the presence of necroptosis microenvironment, premalignant cells appeared to transform into iCCA or cHCC-CCA. In contrast, without a necroptosis microenvironment, premalignant cells tended to develop into HCC, exhibiting amplified stemness-related genes (SRGs) and heightened malignancy.

Multicenter evaluation of activity of aztreonam in combination with avibactam, relebactam, and vaborbactam against metallo-ß-lactamase-producing carbapenem-resistant gram-negative bacilli.

Treatment options for carbapenem-resistant gram-negative bacilli (CR-GNB), especially metallo-ß-lactamase (MBL)-producing CR-GNB, are limited. Aztreonam (ATM) in combination with avibactam (AVI) has shown potential for treating MBL-producing carbapenem-resistant Enterobacterales (CREs) and Stenotrophomonas maltophilia. However, data on ATM in combination with other ß-lactamase inhibitors (BLIs) are limited. We performed a multicenter study to evaluate the in vitro activities of ATM in combination with AVI, vaborbactam (VAB), relebactam (REL), tazobactam (TAZ) as well as with their commercially available formulations against CREs and S. maltophilia using broth microdilution. AVI restored ATM activity for MBL-producing CREs (ATM: 9.8% vs ATM-AVI: 78.0%) and S. maltophilia (ATM: 0% vs ATM-AVI: 93.3%). REL also moderately restored activity of ATM in MBL-producing CREs (ATM: 9.8% vs ATM-REL: 42.7%) and S. maltophilia (ATM: 0% vs ATM-REL: 68.9%). VAB and TAZ demonstrated very limited effect on the activity of ATM against CR-GNB evaluated. The combination of ATM with ceftazidime-AVI (CAZ-AVI) demonstrated maximum activity against CREs. Although ATM-CAZ-AVI is the most potent regimen available for CREs and S. maltophilia, ATM-IMI-REL might be a reasonable alternative.

A multi-species outbreak of VIM-producing carbapenem-resistant bacteria in a burn unit and subsequent investigation of rapid development of cefiderocol resistance.

Carbapenem resistance due to metallo-ß-lactamases (MBLs) such as the Verona integron-encoded metallo-ß-lactamase (VIM) is particularly problematic due to the limited treatment options. We describe a case series of bacterial infections in a tertiary care hospital due to multi-species acquisition of a VIM gene along with our experience using novel ß-lactam antibiotics and antibiotic combinations to treat these infections. Four patients were treated with the combination of ceftazidime-avibactam and aztreonam, with no resistance to the combination detected. However, cefiderocol-resistant Klebsiella pneumoniae isolates were detected in two out of the five patients who received cefiderocol within 3 weeks of having started the antibiotic. Strain pairs of sequential susceptible and resistant isolates from both patients were analyzed using whole-genome sequencing. This analysis revealed that the pairs of isolates independently acquired point mutations in both the cirA and fiu genes, which encode siderophore receptors. These point mutations were remade in a laboratory strain of K. pneumoniae and resulted in a significant increase in the MIC of cefiderocol, even in the absence of a beta-lactamase enzyme or a penicillin-binding protein 3 (PBP3) mutation. While newer ß-lactam antibiotics remain an exciting addition to the antibiotic armamentarium, their use must be accompanied by diligent monitoring for the rapid development of resistance.

Rhein exerts anti-multidrug resistance in acute myeloid leukemia via targeting FTO to inhibit AKT/mTOR.

Chemotherapy failure and resistance are the leading causes of mortality in patients with acute myeloid leukemia (AML). However, the role of m6A demethylase FTO and its inhibitor rhein in AML and AML drug resistance is unclear. Therefore, this study aimed to investigate the antileukemic effect of rhein on AML and explore its potential mechanisms underlying drug resistance. Bone marrow fluid was collected to assess FTO expression in AML. The Cell Counting Kit 8 reagent was used to assess cell viability. Migration assays were conducted to assess the cell migration capacity. Flow cytometry was used to determine the apoptotic effects of rhein and western blot analysis was used to detect protein expression. Online SynergyFinder software was used to calculate the drug synergy scores. The in-vivo antileukemic effect of rhein was assessed in an AML xenograft mouse model. We analyzed different types of AML bone marrow specimens to confirm that FTO is overexpressed in AML, particularly in cases of multidrug resistance. Subsequently, we conducted in-vivo and in-vitro investigations to explore the pharmacological activity and mechanism of rhein in AML and AML with multidrug resistance. The findings demonstrated that rhein effectively suppressed the proliferation and migration of AML cells in a time- and dose-dependent manner and induced apoptosis. Rhein targets FTO, inhibits the AKT/mTOR pathway, and exhibits synergistic antitumor effects when combined with azacitidine. This study elucidates the significant role of FTO and its inhibitor rhein in AML and AML with multidrug resistance, providing new insights for overcoming multidrug resistance in AML.

Infrared photodetectors based on wide bandgap two-dimensional transition metal dichalcogenides via efficient two-photon absorption.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) have attracted considerable attention due to their outstanding optoelectronic properties and ease of integration, making them ideal candidates for high-performance photodetectors. However, the excessive width of the bandgap in some 2D TMDs presents a challenge for achieving infrared photodetection. One approach to broaden the photoresponse wavelength range of TMDs is through the utilization of two-photon absorption (TPA) process. Unfortunately, the inefficiency of TPA hinders its application in infrared photodetection. In this study, we propose the design of two photodetectors utilizing high TPA coefficient materials, specifically ReSe2and MoS2, to exploit their TPA capability and extend the photoresponse to the near-infrared region at 1550 nm. The ReSe2photodetector demonstrates an unprecedented responsivity of 43µA W-1, surpassing that of current single-material TPA photodetectors. Similarly, the MoS2photodetector achieves a responsivity of 18µA W-1, comparable to state-of-the-art TPA photodetectors. This research establishes the potential of high TPA coefficient 2D TMDs for infrared photodetection.

Lenalidomide Treatment of Isolated Central Nervous System Relapse in Acute Lymphoblastic Leukemia after Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T (CAR-T) cell are effective treatments for acute lymphoblastic leukemia (ALL). Various forms of intra- and extramedullary relapses have been reported after HSCT and CAR-T-cell therapy for ALL; however, no reports have investigated isolated central nervous system (CNS) relapse after HSCT and CAR-T-cell therapy. Hence, no clinical treatment has been established for such rare patients. CASE PRESENTATION: An 18-year-old male patient with B-cell ALL suffered from isolated CNS relapse after HSCT and CAR-T-cell therapy. Conventional systemic intravenous and intrathecal chemotherapies were ineffective and intolerable. A unique immunosuppressive microenvironment of decreasing NK cell percentage and increasing IL-8 concentration and CAR-T-cell exhaustion had been illustrated in the cerebrospinal fluid. Finally, the patient received immunomodulatory therapy with lenalidomide and obtained complete remission. CONCLUSION: Lenalidomide might be a therapeutic strategy for isolated CNS relapse after HSCT and CAR-T-cell therapy.

Diagnostic value of plasma-derived exosomal miR-223 for epithelial ovarian cancer.

OBJECTIVES: To evaluate the diagnostic value of plasma exosomal miR-223 and its combination with CA125 for the diagnosis of early-stage epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Exosomes derived from the plasma of 78 EOC patients, 40 patients with epithelial benign ovarian tumors, and 52 healthy participants were isolated using the ultracentrifugation method and identified by transmission electron microscopy (TEM) and western blot. RESULTS: The expression of exosomal miR-223 was significantly upregulated in the plasma of EOC patients compared to that in healthy subjects and patients with benign diseases. The combination of exosomal miR-223 and CA125 from plasma had an equivalent area under the ROC curve (AUC) to CA125 alone for discriminating between EOC and non-EOC cases, including healthy subjects and benign ovarian tumors. However, the AUC value of the combination was 0.944 (95% CI: 0.899-0.990) for differentially diagnosing early-stage EOC from healthy subjects, slightly higher than that of CA125 alone (0.928, 95% CI: 0.875-0.981), with a sensitivity and specificity of 0.9784 and 0.885, respectively. CONCLUSION: Our data suggest that plasma exosomal miR-223 can be used as a complement to CA125 to increase the diagnostic power for differentiating early-stage EOC from healthy subjects.

Comparing the diagnostic performance of lung ultrasonography and chest radiography for detecting pneumothorax in patients with trauma: a meta-analysis.

INTRODUCTION: To compare the diagnostic performance of ultrasonography (US) and chest radiography for detecting pneumothorax in patients with trauma using a meta-analytic approach. METHODS: PubMed, EMBASE, and the Cochrane Library were systematically searched to identify eligible studies until March 2023. The diagnostic performance of US and chest radiography was assessed using sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic score, diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC). RESULTS: Overall, 21 studies involving 4,087 patients with trauma were included. The overall sensitivity, specificity, PLR, NLR, diagnostic score, DOR, and AUC of US for detecting pneumothorax were 0.83, 0.99, 73.72, 0.17, 6.06, 427.80, and 0.99, respectively. The corresponding values of chest radiography for detecting pneumothorax were 0.37, 1.00, 175.59, 0.63, 5.63, 279.97, and 0.86. US was associated with a higher sensitivity (ratio: 2.24; 95% confidence interval [CI]: 1.70-2.95; P < 0.001) or AUC (ratio: 1.15; 95% CI: 1.11-1.19; P < 0.001) and lower NLR (ratio: 0.27; 95% CI: 0.17-0.43; P < 0.001) compared with chest radiography. CONCLUSION: Lung US was associated with better diagnostic performance than chest radiography for detecting pneumothorax in patients with trauma.

Selectively Manipulating Interactions between Lanthanide Sublattices in Nanostructure toward Orthogonal Upconversion.

Smart control of ionic interactions is a key factor to manipulate the luminescence dynamics of lanthanides and tune their emission colors. However, it remains challenging to gain a deep insight into the physics involving the interactions between heavily doped lanthanide ions and in particular between the lanthanide sublattices for luminescent materials. Here we report a conceptual model to selectively manipulate the spatial interactions between erbium and ytterbium sublattices by designing a multilayer core-shell nanostructure. The interfacial cross-relaxation is found to be a leading process to quench the green emission of Er3+, and red-to-green color-switchable upconversion is realized by fine manipulation of the interfacial energy transfer on the nanoscale. Moreover, the temporal control of up-transition dynamics can also lead to an observation of green emission due to its fast rise time. Our results demonstrate a new strategy to achieve orthogonal upconversion, showing great promise in frontier photonic applications.

[Deep Learning-Based Key Frame Recognition Algorithm for Adrenal Vascular in X-Ray Imaging].

Adrenal vein sampling is required for the staging diagnosis of primary aldosteronism, and the frames in which the adrenal veins are presented are called key frames. Currently, the selection of key frames relies on the doctor's visual judgement which is time-consuming and laborious. This study proposes a key frame recognition algorithm based on deep learning. Firstly, wavelet denoising and multi-scale vessel-enhanced filtering are used to preserve the morphological features of the adrenal veins. Furthermore, by incorporating the self-attention mechanism, an improved recognition model called ResNet50-SA is obtained. Compared with commonly used transfer learning, the new model achieves 97.11% in accuracy, precision, recall, F1, and AUC, which is superior to other models and can help clinicians quickly identify key frames in adrenal veins.

Multicenter Evaluation of an MIC-Based Aztreonam and Ceftazidime-Avibactam Broth Disk Elution Test.

Due to limited therapeutic options, there is a clinical need to assess the in vitro activity of the combination of aztreonam (ATM) and ceftazidime-avibactam (CZA) to guide the therapeutic management of multidrug-resistant (MDR) Gram-negative organism infections. We set out to develop a practical MIC-based broth disk elution (BDE) method to determine the in vitro activity of the combination ATM-CZA using readily available supplies and compare it to reference broth microdilution (BMD). For the BDE method, a 30-µg ATM disk, a 30/20-µg CZA disk, both disks in combination, and no disks were added to 4 separate 5-mL cation-adjusted Mueller-Hinton broth (CA-MHB) tubes, using various manufacturers. Three testing sites performed both BDE and reference BMD testing of bacterial isolates in parallel from a single 0.5 McFarland standard inoculum and after overnight incubation, assessed them for growth (not susceptible) or no growth (susceptible) at a final concentration of 6/6/4 µg/mL ATM-CZA. During the first phase, the precision and accuracy of the BDE were analyzed by testing 61 Enterobacterales isolates at all sites. This testing yielded 98.3% precision between sites, with 98.3% categorical agreement and 1.8% major errors (ME). During the second phase, at each site, we evaluated unique, clinical isolates of metallo-ß-lactamase (MBL)-producing Enterobacterales (n = 75), carbapenem-resistant Pseudomonas aeruginosa (n = 25), Stenotrophomonas maltophilia (n = 46), and Myroides sp. (n = 1). This testing resulted in 97.9% categorical agreement, with 2.4% ME. Different results were observed for different disk and CA-MHB manufacturers, requiring a supplemental ATM-CZA-not-susceptible quality control organism to ensure the accuracy of results. The BDE is a precise and effective methodology for determining susceptibility to the combination ATM-CZA.

Comprehensive single-cell transcriptomic and proteomic analysis reveals NK cell exhaustion and unique tumor cell evolutionary trajectory in non-keratinizing nasopharyngeal carcinoma.

BACKGROUND: Nonkeratinizing nasopharyngeal carcinoma (NK-NPC) has a strong association with Epstein-Barr virus (EBV) infection. The role of NK cells and the tumor cell evolutionary trajectory in NK-NPC remain unclear. In this study, we aim to investigate the function of NK cell and the evolutionary trajectory of tumor cells in NK-NPC by single-cell transcriptomic analysis, proteomics and immunohistochemistry. METHODS: NK-NPC (n = 3) and normal nasopharyngeal mucosa cases (n = 3) were collected for proteomic analysis. Single-cell transcriptomic data of NK-NPC (n = 10) and nasopharyngeal lymphatic hyperplasia (NLH, n = 3) were obtained from Gene Expression Omnibus (GSE162025 and GSE150825). Quality control, dimension reduction and clustering were based on Seurat software (v4.0.2) process and batch effects were removed by harmony (v0.1.1) software. Normal cells of nasopharyngeal mucosa and tumor cells of NK-NPC were identified using copykat software (v1.0.8). Cell-cell interactions were explored using CellChat software (v1.4.0). Tumor cell evolutionary trajectory analysis was performed using SCORPIUS software (v1.0.8). Protein and gene function enrichment analyses were performed using clusterProfiler software (v4.2.2). RESULTS: A total of 161 differentially expressed proteins were obtained between NK-NPC (n = 3) and normal nasopharyngeal mucosa (n = 3) by proteomics (log2 fold change > 0.5 and P value < 0.05). Most of proteins associated with the nature killer cell mediated cytotoxicity pathway were downregulated in the NK-NPC group. In single cell transcriptomics, we identified three NK cell subsets (NK1-3), among which NK cell exhaustion was identified in the NK3 subset with high ZNF683 expression (a signature of tissue-resident NK cell) in NK-NPC. We demonstrated the presence of this ZNF683 + NK cell subset in NK-NPC but not in NLH. We also performed immunohistochemical experiments with TIGIT and LAG3 to confirm NK cell exhaustion in NK-NPC. Moreover, the trajectory analysis revealed that the evolutionary trajectory of NK-NPC tumor cells was associated with the status of EBV infection (active or latent). The analysis of cell-cell interactions uncovered a complex network of cellular interactions in NK-NPC. CONCLUSIONS: This study revealed that the NK cell exhaustion might be induced by upregulation of inhibitory receptors on the surface of NK cells in NK-NPC. Treatments for the reversal of NK cell exhaustion may be a promising strategy for NK-NPC. Meanwhile, we identified a unique evolutionary trajectory of tumor cells with active status of EBV-infection in NK-NPC for the first time. Our study may provide new immunotherapeutic targets and new sight of evolutionary trajectory involving tumor genesis, development and metastasis in NK-NPC.

Mueller matrix imaging of pathological slides with plastic coverslips.

Mueller matrix microscopy is capable of polarization characterization of pathological samples and polarization imaging based digital pathology. In recent years, hospitals are replacing glass coverslips with plastic coverslips for automatic preparations of dry and clean pathological slides with less slide-sticking and air bubbles. However, plastic coverslips are usually birefringent and introduce polarization artifacts in Mueller matrix imaging. In this study, a spatial frequency based calibration method (SFCM) is used to remove such polarization artifacts. The polarization information of the plastic coverslips and the pathological tissues are separated by the spatial frequency analysis, then the Mueller matrix images of pathological tissues are restored by matrix inversions. By cutting two adjacent lung cancer tissue slides, we prepare paired samples of very similar pathological structures but one with a glass coverslip and the other with a plastic coverslip. Comparisons between Mueller matrix images of the paired samples show that SFCM can effectively remove the artifacts due to plastic coverslip.

Non-Layered Te/In2 S3 Tunneling Heterojunctions with Ultrahigh Photoresponsivity and Fast Photoresponse.

A photodetector based on 2D non-layered materials can easily utilize the photogating effect to achieve considerable photogain, but at the cost of response speed. Here, a rationally designed tunneling heterojunction fabricated by vertical stacking of non-layered In2 S3 and Te flakes is studied systematically. The Te/In2 S3 heterojunctions possess type-II band alignment and can transfer to type-I or type-III depending on the electric field applied, allowing for tunable tunneling of the photoinduced carriers. The Te/In2 S3 tunneling heterojunction exhibits a reverse rectification ratio exceeding 104 , an ultralow forward current of 10-12 A, and a current on/off ratio over 105 . A photodetector based on the heterojunctions shows an ultrahigh photoresponsivity of 146 A W-1 in the visible range. Furthermore, the devices exhibit a response time of 5 ms, which is two and four orders of magnitude faster than that of its constituent In2 S3 and Te. The simultaneously improved photocurrent and response speed are attributed to the direct tunneling of the photoinduced carriers, as well as a combined mechanism of photoconductive and photogating effects. In addition, the photodetector exhibits a clear photovoltaic effect, which can work in a self-powered mode.

Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type Specific Manner.

Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposi's sarcoma associated virus (KSHV), and murine γ-herpesvirus 68 (MHV68), establish latent infection in B cells, macrophages, and non-lymphoid cells, and can induce both lymphoid and non-lymphoid cancers. Research on these viruses has relied heavily on immortalized B cell and endothelial cell lines. Therefore, we know very little about the cell type specific regulation of virus infection. We have previously shown that treatment of MHV68-infected macrophages with the cytokine interleukin-4 (IL-4) or challenge of MHV68-infected mice with an IL-4-inducing parasite leads to virus reactivation. However, we do not know if all latent reservoirs of the virus, including B cells, reactivate the virus in response to IL-4. Here we used an in vivo approach to address the question of whether all latently infected cell types reactivate MHV68 in response to a particular stimulus. We found that IL-4 receptor expression on macrophages was required for IL-4 to induce virus reactivation, but that it was dispensable on B cells. We further demonstrated that the transcription factor, STAT6, which is downstream of the IL-4 receptor and binds virus gene 50 N4/N5 promoter in macrophages, did not bind to the virus gene 50 N4/N5 promoter in B cells. These data suggest that stimuli that promote herpesvirus reactivation may only affect latent virus in particular cell types, but not in others.Importance Herpesviruses establish life-long quiescent infections in specific cells in the body, and only reactivate to produce infectious virus when precise signals induce them to do so. The signals that induce herpesvirus reactivation are often studied only in one particular cell type infected with the virus. However, herpesviruses establish latency in multiple cell types in their hosts. Using murine gammaherpesvirus-68 (MHV68) and conditional knockout mice, we examined the cell type specificity of a particular reactivation signal, interleukin-4 (IL-4). We found that IL-4 only induced herpesvirus reactivation from macrophages, but not from B cells. This work indicates that regulation of virus latency and reactivation is cell type specific. This has important implications for therapies aimed at either promoting or inhibiting reactivation for the control or elimination of chronic viral infections.

Mediators of neutrophil-lymphocyte ratio in the relationship between ondansetron pre-treatment and the mortality of ICU patients on mechanical ventilation: Causal mediation analysis from the MIMIC-IV database.

AIMS: The mortality of critically ill patients undergoing mechanical ventilation (MV) is high and few strategies are available. We explored the relationship between ondansetron pre-treatment, the neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR), and mortality of ventilated patients in the intensive care unit. METHODS: We developed a retrospective cohort study that involved patients undergoing MV in the Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database. Causal mediation analysis was conducted to assess the relationship of ondansetron use and mortality and to explore the potential causal pathway mediated by the NLR or PLR. The primary outcome was 28-day mortality. RESULTS: A total of 17 927 eligible patients took part in the study (5665 had taken ondansetron before MV initiation and 12 262 patients had not). The odds ratio (OR) for 28-day mortality for ondansetron use uncorrelated with the mediator (NLR, PLR) was 0.72 (95% confidence interval [CI] = 0.64-0.81, P < .001). Ondansetron was also associated with a reduction in 28-day mortality after controlling for the mediator of NLR (OR = 0.98, 95% CI = 0.97-0.99, P < .01). For the indirect effect, the NLR could explain 13.47% (95% CI = 8.59-20.54%, P < .01) of the impact of ondansetron use on 28-day mortality. The proportion mediated increased to 21.50% (95% CI = 12.36-47.44%, P < .01) for 90-day mortality. Adjusted mediation analysis revealed no suggestion of a causal mediation pathway for this effect by the PLR (P = .12). CONCLUSIONS: NLR may play substantial roles in the relationship between ondansetron pre-treatment before initiation of mechanical ventilation and the reduction of death risk in ventilated patients.

C/EBP-α induces autophagy by binding to Beclin1 through its own acetylation modification in activated hepatic stellate cells.

The activation of hepatic stellate cells (HSCs) plays a key role in the occurrence of liver fibrosis，and promoting the apoptosis of activated HSCs or reducing the number of activated HSCs can reverse the development of liver fibrosis. In our previous studies, we have demonstrated that the CCAAT/enhancer binding protein α (C/EBP-α) played an important role in promoting the apoptosis of activated HSCs, thereby exerting an anti-liver fibrosis effect. Unlike apoptosis, autophagy, as a caspase-independent programmed cell death, can promptly remove the abnormal accumulation of substances or damaged organelles in cells and play a key role in regulating the homeostasis of intracellular environment. However, it is still unclear whether C/EBP-α participates in the occurrence of autophagy in HSCs. Therefore, in this study, we firstly used the methods of Western blot and immunofluorescence to characterize the consequence of C/EBP-α overexpression on the expression of proteins LC3B, P62, ATG5 and Beclin1 which were related to autophagy in HSCs. Subsequently, we performed Western blot and site-directed mutagenesis methods to clarify the type and related mechanism of autophagy which was induced by C/EBP-α. Here we show that C/EBP-α promotes the occurrence of autophagy in HSCs and the autophagy induced by C/EBP-α belongs to mitophagy. The stability of C/EBP-α protein regulates the level of autophagy in HSCs. In addition, acetylation of C/EBP-α also regulates the occurrence of autophagy in HSCs. Acetylation of lysine at positions K298, K302 and K326 of C/EBP-α promotes its binding to Beclin1. In conclusion, our study uncovers the role of C/EBP-α in regulating autophagy in HSCs, thereby providing a new strategy for clinical treatment of liver fibrosis.

Making Mouse Models That Reflect Human Immune Responses.

Humans are infected with a variety of acute and chronic pathogens over the course of their lives, and pathogen-driven selection has shaped the immune system of humans. The same is likely true for mice. However, laboratory mice we use for most biomedical studies are bred in ultra-hygienic environments, and are kept free of specific pathogens. We review recent studies that indicate that pathogen infections are important for the basal level of activation and the function of the immune system. Consideration of these environmental exposures of both humans and mice can potentially improve mouse models of human disease.

The influence of a community intervention on influenza vaccination knowledge and behavior among diabetic patients.

BACKGROUND: This study was conducted to evaluate the impact of a comprehensive community intervention on cognition and inoculation behaviors of diabetic patients immunized with influenza vaccine. METHODS: A total of 1538 diabetic patients aged 35 years and above for outpatient visits and follow-up treatments were selected from six community health service centers (three for the experimental group, and the other three for the control group) in Chaoyang District, Beijing. Comprehensive interventions applied to the experimental group include patient intervention and community climate interventions. We compared the total awareness of influenza vaccine knowledge and influenza vaccination rates between the two groups before and after the intervention. RESULTS: Before the intervention, the total awareness rate of influenza vaccine in the experimental group and the control group was similar (50.6 and 50.2%, respectively. P = 0.171). After the intervention, the awareness rate of influenza vaccine in the experimental group and the control group increased. The amplitude of the increase was similar (70.3 and 70.1%, respectively. P = 0.822,). Before the intervention, there was no significant difference in the influenza vaccination rate between the experimental group and the control group (29.0 and 26.8%, respectively. P = 0.334). After the intervention, the vaccination rate of the experimental group was higher than that of the control group. The difference was statistically significant (The vaccination rate 45.8 and 27.4% for the experimental group and the control group, respectively. P < 0.001). CONCLUSION: Comprehensive community interventions had a positive effect on vaccination in diabetic patients. TRIAL REGISTRATION: ChiCTR1900025194, registered in Aug,16th, 2019. Retrospectively registered.