Association between the triglyceride-glucose index and all-cause and CVD mortality in the young population with diabetes.

BACKGROUND: Although studies have demonstrated the value of the triglyceride-glucose (TyG) index for cardiovascular disease (CVD) and cardiovascular mortality, however, few studies have shown that the TyG index is associated with all-cause or CVD mortality in young patients with diabetes. This study aimed to investigate the association between the TyG index and all-cause and CVD mortality in young patients with diabetes in the United States. METHODS: Our study recruited 2440 young patients with diabetes from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Cox regression modeling was used to investigate the association between TyG index and mortality in young patients with diabetes. The nonlinear association between TyG index and mortality was analyzed using restricted cubic splines (RCS), and a two-segment Cox proportional risk model was constructed for both sides of the inflection point. RESULTS: During a median follow-up period of 8.2 years, 332 deaths from all causes and 82 deaths from cardiovascular disease were observed. Based on the RCS, the TyG index was found to have a U-shaped association with all-cause and CVD mortality in young patients with diabetes, with threshold values of 9.18 and 9.16, respectively. When the TyG index was below the threshold value (TyG index < 9.18 in all-cause mortality and < 9.16 in CVD mortality), its association with all-cause and CVD mortality was not significant. When the TyG index was above the threshold (TyG index ≥ 9.18 in all-cause mortality and ≥ 9.16 in CVD mortality), it showed a significant positive association with all-cause mortality and CVD mortality (HR 1.77, 95% CI 1.05-2.96 for all-cause mortality and HR 2.38, 95% CI 1.05-5.38 for CVD mortality). CONCLUSION: Our results suggest a U-shaped association between TyG index and all-cause and CVD mortality among young patients with diabetes in the United States, with threshold values of 9.18 and 9.16 for CVD and all-cause mortality, respectively.

Cell Crosstalk in Alveolar Microenvironment: From Lung Injury to Fibrosis.

Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions between these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions between the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. Additionally, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aimed to reveal new insights into the molecular mechanisms that drive lung injury towards fibrosis and identify potential targets for therapeutic intervention. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Single-Nuclei Characterization of Lacrimal Gland in Scopolamine-Induced Dry Eye Disease.

Purpose: The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq). Methods: Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining. Results: The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells. Conclusions: Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.

Polystyrene microplastic-induced endoplasmic reticulum stress contributes to growth plate endochondral ossification disorder in young rat.

BACKGROUND: Previous studies on the effects of microplastics (MPs) on bone in early development are limited. This study aimed to investigate the adverse effects of MPs on bone in young rats and the potential mechanism. METHODS: Three-week-old female rats were orally administered MPs for 28 days, and endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) and ER stress agonist tunicamycin (TM) were added to evaluate the effect of ER stress on toxicity of MPs. The indicators of growth and plasma markers of bone turnover were evaluated. Tibias were analyzed using micro-computed tomography (micro-CT). Histomorphological staining of growth plates was performed, and related gene expression of growth plate chondrocytes was tested. RESULTS: After exposure of MPs, the rats had decreased growth, shortened tibial length, and altered blood calcium and phosphorus metabolism. Trabecular bone was sparse according to micro-CT inspection. In the growth plate, the thickness of proliferative zone substantial reduced while the thickness of hypertrophic zone increased significantly, and the chondrocytes were scarce and irregularly arranged according to tibial histological staining. The transcription of the ER stress-related genes BIP, PERK, ATF4, and CHOP dramatically increased, and the transcription factors involved in chondrocyte proliferation, differentiation, apoptosis, and matrix secretion were aberrant according to RT-qPCR and western blotting. Moreover, the addition of TM showed higher percentage of chondrocyte death. Administration of SAL alleviated all of the MPs-induced symptoms. CONCLUSION: These results indicated that MPs could induce growth retardation and longitudinal bone damage in early development. The toxicity of MPs may attribute to induced ER stress and impaired essential processes of the endochondral ossification after MPs exposure.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

A novel therapeutic outlook: Classification, applications and challenges of inhalable micron/nanoparticle drug delivery systems in lung cancer (Review).

Lung cancer represents a marked global public health concern. Despite existing treatment modalities, the average 5­year survival rate for patients with patients with lung cancer is only ~20%. As there are numerous adverse effects of systemic administration routes, there is an urgent need to develop a novel therapeutic strategy tailored specifically for patients with lung cancer. Non­invasive aerosol inhalation, as a route of drug administration, holds unique advantages in the context of respiratory diseases. Nanoscale materials have extensive applications in the field of biomedical research in recent years. The present study provides a comprehensive review of the classification, applications summarized according to existing clinical treatment modalities for lung cancer and challenges associated with inhalable micron/nanoparticle drug delivery systems (DDSs) in lung cancer. Achieving localized treatment of lung cancer preclinical models through inhalation is deemed feasible. However, further research is required to substantiate the efficacy and long­term safety of inhalable micron/nanoparticle DDSs in the clinical management of lung cancer.

Real-world effectiveness of nirmatrelvir-ritonavir versus azvudine in hospitalized patients with COVID-19 during the omicron wave in Beijing: a multicenter retrospective cohort study.

BACKGROUND AND AIM: Two oral antivirals (Nirmatrelvir- ritonavir and Azvudine) are widely used in China practice during the Omicron wave of the pandemic. However, little evidence regarding the real-world effectiveness of these two oral antivirals in in-hospital patients. We aimed to evaluate the clinical effectiveness of nirmatrelvir-ritonavir versus azvudine among adult hospitalized patients with COVID-19. METHODS: This retrospective cohort study used data from three Chinese PLA General Hospital medical centres. Hospitalized patients with COVID-19 treated with azvudine or nirmatrelvir-ritonavir from Dec 10, 2022, to February 20, 2023, and did not require invasive ventilation support on admission were eligible for inclusion. RESULTS: After exclusions and propensity-score matching, the final analysis included 486 azvudine recipients and 486 nirmatrelvir-ritonavir recipients. By 28 days of initiation of the antivirus treatment, the crude incidence rate of all-cause death was similar in both types of antivirus treatment (nirmatrelvir-ritonavir group 2.8 events 1000 person-days [95% CI, 2.1-3.6] vs azvudine group 3.4 events/1000 person-days [95% CI, 2.6-4.3], P = 0.38). Landmark analysis showed that all-cause death was lower in the nirmatrelvir-ritonavir (3.5%) group than the azvudine (6.8%, P = 0.029) within the initial 10-day admission period, while no significant difference was observed for results between 10 and 28 days follow-up. There was no significant difference between the nirmatrelvir-ritonavir group and the azvudine group in cumulative incidence of the composite disease progression event (8.6% with nirmatrelvir-ritonavir vs. 10.1% with azvudine, HR, 1.22; 95% CI 0.80-1.86, P = 0.43). CONCLUSION: Among patients hospitalized with COVID-19 during the omicron wave in Beijing, similar in-hospital clinical outcomes on 28 days were observed between patients receiving nirmatrelvir-ritonavir and azvudine. However, it is worth noticing that nirmatrelvir-ritonavir appears to hold an advantage over azvudine in reducing early mortality. Further randomized controlled trials are needed to verify the efficacy of those two antivirus medications especially in early treatment.

Nosocomial surveillance of multidrug-resistant Acinetobacter baumannii: a genomic epidemiological study.

Acinetobacter baumannii is a major opportunistic pathogen causing hospital-acquired infections, and it is imperative to comprehend its evolutionary and epidemiological dynamics in hospitals to prevent and control nosocomial transmission. Here, we present a comprehensive genomic epidemiological study involving the genomic sequencing and antibiotic resistance profiling of 634 A. baumannii strains isolated from seven intensive care units (ICUs) of a Chinese general hospital over 2 consecutive years. Our study reveals that ST2 is highly dominant (90.54%) in the ICUs, with 98.90% of the ST2 exhibiting multidrug resistant or extensively drug resistant. Phylogenetic analyses of newly sequenced genomes and public data suggest that nosocomial isolates originated outside the hospital but evolved inside. The major lineages appear to be stable, with 9 of the 28 identified nosocomial epidemic clones infecting over 60% of the affected patients. However, outbreaks of two highly evolved clones have been observed in different hospitals, suggesting significant inter-hospital transmission chains. By coupling patient medical records and genomic divergence of the ST2, we found that cross-ward patient transfer played a crucial role in pathogen's nosocomial transmission. Additionally, we identified 831 potential adaptive evolutionary loci and 44 associated genes by grouping and comparing the genomes of clones with different prevalence. Overall, our study provides a comprehensive and contemporary survey on the epidemiology and genomic evolution of A. baumannii in a large Chinese general hospital. These findings shed light on the nosocomial evolution and transmission of A. baumannii and offers valuable information for transmission prevention and antibiotic therapy.IMPORTANCEThis study delved into the genomic evolution and transmission of nosocomial Acinetobacter baumannii on a large scale, spanning both an extended time period and the largest sample size to date. Through molecular epidemiological investigations based on genomics, we can directly trace the origin of the pathogen, detecting and monitoring outbreaks of infectious diseases in a timely manner, and ensuring public health safety. In addition, this study also collects a large amount of genomic and antibiotic resistance detection data, which is helpful for phenotype prediction based on genomic sequencing. It enables patients to receive personalized antibiotic treatment quickly, helps doctors select antibiotics more accurately, and contributes to reducing the use of antibiotics and lowering the risk of antibiotic resistance development.

The role of corneal endothelium in macular corneal dystrophy development and recurrence.

Macular corneal dystrophy (MCD) is a progressive, bilateral stromal dystrophic disease that arises from mutations in carbohydrate sulfotransferase 6 (CHST6). Corneal transplantation is the ultimate therapeutic solution for MCD patients. Unfortunately, postoperative recurrence remains a significant challenge. We conducted a retrospective review of a clinical cohort comprising 102 MCD patients with 124 eyes that underwent either penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK). Our results revealed that the recurrence rate was nearly three times higher in the DALK group (39.13%, 9/23 eyes) compared with the PKP group (10.89%, 11/101 eyes), suggesting that surgical replacement of the corneal endothelium for treating MCD is advisable to prevent postoperative recurrence. Our experimental data confirmed the robust mRNA and protein expression of CHST6 in human corneal endothelium and the rodent homolog CHST5 in mouse endothelium. Selective knockdown of wild-type Chst5 in mouse corneal endothelium (ACsiChst5), but not in the corneal stroma, induced experimental MCD with similar extracellular matrix synthesis impairments and corneal thinning as observed in MCD patients. Mice carrying Chst5 point mutation also recapitulated clinical phenotypes of MCD, along with corneal endothelial abnormalities. Intracameral injection of wild-type Chst5 rescued the corneal impairments in ACsiChst5 mice and retarded the disease progression in Chst5 mutant mice. Overall, our study provides new mechanistic insights and therapeutic approaches for MCD treatment by high-lighting the role of corneal endothelium in MCD development.

iNOS inhibitor S-methylisothiourea alleviates smoke inhalation-induced acute lung injury by suppressing inflammation and macrophage infiltration.

OBJECTIVE: We investigated the effects of the inducible NO synthase (iNOS) inhibitor, S-methylisothiourea (SMT), in a mouse model of smoke inhalation-induced acute lung injury (ALI) and explored the underlying molecular mechanism. METHODS AND ANALYSIS: A mouse model of smoke inhalation-induced ALI was established. RNA-sequencing (seq) analysis was conducted to identify the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed for functional annotation of DEGs. Moreover, an immunofluorescence assay using macrophage marker F4/80 was performed to assess macrophage infiltration. A hypoxia-induced HUVEC model was used to mimic smoke inhalation-induced injury in endothelial cells. Finally, a transwell assay was used to analyze the chemoattractive effects of endothelial cells on macrophages. RESULTS: SMT markedly alleviated the pulmonary pathological symptoms, edema, and inflammatory response in the mouse smoke inhalation-induced ALI model. RNA-seq analysis revealed that SMT may diminish lung injury by regulating the levels of genes associated with inflammatory responses, cell chemokines, and adhesion. In vivo data revealed that the protective effects of SMT against smoke inhalation-induced ALI were partly achieved by inhibiting the production of adhesion molecules and infiltration of macrophages. Furthermore, in vitro data from the hypoxia-induced HUVEC model revealed that SMT reduced macrophage chemotaxis by inhibiting the production of chemokines and adhesion molecules in endothelial cells. CONCLUSION: iNOS inhibitor SMT protects the lungs from smoke inhalation-induced ALI by reducing the production of pro-inflammatory cytokines, adhesion molecules, and chemokines in endothelial cells, thereby inhibiting inflammation and macrophage infiltration.

Effects of THE PEEP-ZEEP Maneuver in Adults Receiving Mechanical Ventilation: A Systematic Review with Meta-Analysis.

INTRODUCTION: It is important to clarify the secretion clearance and lung-related effects of the PEEP-ZEEP maneuver in adults undergoing mechanical ventilation (MV). There is no published comprehensive meta-analysis of the effects of PEEP-ZEEP in adults receiving MV. OBJECTIVES: The aim of this study was to analyze published randomized controlled trials, investigating the effects of the PEEP-ZEEP maneuver in adults undergoing mechanical ventilation. METHODS: We searched Embase, PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from the date of inception of the databases until 6 May 2023. Quality assessment was using the Cochrane Systematic Assessment Handbook. The GRADE system was used to grade the quality of the evidence. RESULTS: A total of 12 trials were included, and the results of the meta-analysis showed that PEEP-ZEEP was not superior to bag squeezing for the removal of bronchial secretions. One study showed a significant increase in the amount of secretion retrieved with the PEEP-ZEEP when compared with tracheal suctioning. Additionally, PEEP-ZEEP was more effective than bag squeezing at improving oxygen saturation. However, one trial showed that bag squeezing was better at improving dynamic compliance. No other differences were found between PEEP-ZEEP and other techniques, except for one study showing more frequent changes in diastolic blood pressure with PEEP-ZEEP compared with ventilator hyperinflation. CONCLUSION: PEEP-ZEEP was not superior to bag squeezing in removing bronchial secretions. However, it improves oxygen saturation when compared to bag squeezing, and no adverse effects on patients' respiratory systems have yet been observed.

A Versatile Hydrogel with Antibacterial and Sequential Drug-Releasing Capability for the Programmable Healing of Infectious Keratitis.

Hydrogels have attracted tremendous attention as favorable corneal substitutes for treating severe infectious keratitis (IK). However, current hydrogel-based corneal substitutes were majorly designed to promote the single stage of corneal regeneration, which falls short in meeting the clinical management needs of severe IK including the multiple phases of corneal wound healing. Herein, we introduce a versatile hybrid hydrogel (SQPV) composed of silk fibroin and chitosan, which exhibits spatiotemporal properties for drug release. The SQPV is fabricated by incorporating verteporfin-loaded poly(lactic-co-glycolic)-polyethylene glycol-o-nitrobenzene micelles into a hydrogel network, which is formed from methacrylate silk fibroin and glycidyl methacrylate functionalized quaternized chitosan containing polydeoxyribonucleotide. This double network approach results in a material with exceptional anti-inflammatory, antibacterial, and proliferative stimulation and tissue remodeling regulation capabilities. Furthermore, SQPV showcases mechanical strength and transparency akin to those of native cornea. Extensive in vitro and in vivo studies validate SQPV's ability to effectively eliminate residual bacteria, mitigate inflammation, foster regeneration of corneal epithelium and stroma, prevent corneal scarring, and ultimately expedite wound healing. In summary, the SF/CS-based hybrid hydrogel may represent a promising substitute for comprehensive corneal repair and regeneration in severe IK.

MicroRNA­200c­3p regulates seawater­induced acute lung injury via ANGII and ACE2/ANG1­7 pathways.

Apoptosis is a main characteristic of seawater aspiration-induced acute lung injury (ALI). The local angiotensin (ANG) system angiotensin converting enzyme (ACE)-2/ANG1-7/Mas axis and ANGII/angiotensin II receptor type 1 (AT1) play an important role in apoptosis. MicroRNA (miR)-200c-3p is involved in the regulation of the ACE-2 pathway, but its role and mechanism in seawater-induced ALI remain to be elucidated. In the present study, seawater-ALI lung tissue and cell model was established and apoptosis-related proteins, ACE2, ANGII, ANG1-7 were detected by western blotting following downregulation of miR-200c-3p. In addition, miR-200c-3p was detected by reverse transcription-quantitative PCR. The target relationship between miR-200c-3p and ACE2 was confirmed by dual-luciferase reporter assay. Seawater stimulation increased the expression of miR-200c-3p, ANGII and decreased ACE-2/ANG1-7 expression and induced changes of apoptosis-related protein expression. Apoptosis can be inhibited by AT1 blocker and abrogated by addition of ANG1-7 following seawater stimulation. In addition, inhibition of miR-200c-3p suppressed apoptosis and decreased the expression of ANGII, but increased the ACE-2/ANG1-7 expression. These results suggested that increased expression of miR-200c-3p was an important cause in seawater-induced ALI and this phenomenon was through inhibition of ACE2/ANG1-7 pathway.

Metatranscriptome of human lung microbial communities in a cohort of mechanically ventilated COVID-19 Omicron patients.

The Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infected a substantial proportion of Chinese population, and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment. We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles, plus viral, bacterial, and fungal content, as well as virulence factors and examined their relationships to 28-day mortality were examined. In addition, the bronchoalveolar lavage fluid (BALF) samples from invasive ventilated hospital/community-acquired pneumonia patients (HAP/CAP) sampled in 2019 were included for comparison. Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages, with no difference in 28-day mortality between them. Compared to HAP/CAP cohort, invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract; and in the COVID-19 non-survivors, we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane, higher abundance of opportunistic pathogens including bacterial Alloprevotella, Caulobacter, Escherichia-Shigella, Ralstonia and fungal Aspergillus sydowii and Penicillium rubens. Correlational analysis further revealed significant associations between host immune responses and microbial compositions, besides synergy within viral, bacterial, and fungal pathogens. Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients, providing the basis for future clinical treatment and reduction of fatality.

Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in platelets.

Platelets are highly involved in inflammation and organ injury under pathological conditions. The mitophagy in platelets may restrict hyperactivation of the inflammasome and relieve acute kidney injury (AKI). Cecal ligation puncture (CLP)/LPS-induced AKI Triggering receptor expressed on myeloid cells (TREM-1)-knockout mice models were established. Additionally, septic patients with AKI were also included. TREM-1 expression in platelets and inflammasome activation were examined. Platelet transfer assays were performed to investigate the contribution of platelet TREM-1 to renal injury. Mitophagy was evaluated in the context of inflammation. BNIP3L/Nix knockout mice were used to examine the relationship between platelet mitophagy and inflammatory activation. The results showed that the level of TREM-1 was increased and the platelet inflammasome was hyperactivated in CLP mice and septic patients, and TREM-1 activated platelet inflammasomes. TREM-1 deletion significantly abrogated hyperactivation of the platelet inflammasome and dramatically reduced AKI, whereas ablation of the mitophagy receptor BNIP3L/Nix induced the accumulation of damaged mitochondria and hyperactivation of platelet inflammasomes in CLP mice. BNIP3L/Nix controlled platelet inflammasome activation, and an amplification loop of platelet inflammasome activation and dysfunctional mitochondria controlled sepsis-related AKI. Therefore, targeting TREM-1 and NLRP3/BNIP3L in platelets may represent a novel therapeutic strategy for treating septic AKI.

Macrophage-based delivery of anti-fibrotic proteins alleviates bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by chronic, progressive, and fibrotic lung injury. Although remarkable progress has been made toward understanding the pathogenesis of PF, finding more effective treatments for this fatal disease remains a challenge. In this study, we describe an innovative macrophage-based approach to deliver anti-fibrotic protein to the lung and inhibit PF in a mouse model of bleomycin (BLM)-induced lung injury. We engineered macrophages to continuously secrete three types of proteins: interleukin-10, which prevents inflammation; TGFRcFc, a soluble truncated TGF-ßR2 that blocks TGF-ß; and CD147, which induces matrix metalloproteinases (MMPs) and causes collagen degradation. Infusing these engineered macrophages into the lungs of BLM-induced PF mouse models in an optimal pattern significantly ameliorated PF in mice. Specifically, the most effective therapeutic outcome was achieved by infusing IL-10-secreting macrophages on day 1, followed by TGFRcFc-secreting macrophages on day 7 and CD147-secreting macrophages on day 14 into the same mice after BLM treatment. Our data suggest that macrophage-based delivery of anti-fibrotic proteins to the lungs is a promising therapy for fibrotic lung disorders.

VNN1 as a potential biomarker for sepsis diagnosis and its implications in immune infiltration and tumor prognosis.

Background: This study explored novel biomarkers for diagnosing sepsis, a severe disease prevalent in clinical settings, particularly threatening to elderly patients. Methods: Using microarray gene expression datasets and fatty acid metabolism signatures, we identified differentially expressed genes between sepsis and healthy control groups. Correlations between candidate genes, immune cells, and immune function were assessed. Logistic regression analysis and single-gene GSEA analysis were performed to identify potential biomarkers. The biomarkers' association with different types of tumors was investigated. Results: Twelve genes related to fatty acid metabolism were excluded. CA4, OLAN, and VNN1 were found relevant to immune cells and function. Among these, only VNN1 showed statistical significance (p < 0.05), with a strong area under the ROC curve (0.995). High VNN1 expression indicated activation of certain metabolic pathways, while low expression suggested potential autoimmune responses. VNN1 was up-regulated in eight tumors and down-regulated in eight others. High VNN1 expression was linked to poor prognosis in six types of tumors, and low expression was linked to poor prognosis in four types of tumors. VNN1 expression showed correlations with stromal scores, immune scores, and cancer purity in different types of tumors. Conclusion: VNN1 holds promise as a potential biomarker for sepsis diagnosis and is significant in identifying immune infiltration in tumor tissue and predicting tumor prognosis.

The emergence of influenza B as a major respiratory pathogen in the absence of COVID-19 during the 2021-2022 flu season in China.

BACKGROUND: The emergence of COVID-19 and the implementation of preventive measures and behavioral changes have led to a significant decrease in the prevalence of other respiratory viruses. However, the manner in which seasonal viruses will reemerge in the absence of COVID-19-related restrictions remains unknown. METHODS: Patients presenting with influenza-like illness in two hospitals in Beijing were subjected to testing for COVID-19, influenza A, and influenza B to determine the causative agent for viral infections. The prevalence of influenza B across China was confirmed using data from the Centers for Disease Control, China (China CDC). Clinical characteristics, laboratory findings, imaging results, and mortality data were collected for a cohort of 70 hospitalized patients with confirmed influenza B from 9 hospitals across China. RESULTS: Starting from October 2021, a substantial increase in the number of patients visiting the designated fever clinics in Beijing was observed, with this trend continuing until January 2022. COVID-19 tests conducted on these patients yielded negative results, while the positivity rate for influenza rose from approximately 8% in October 2021 to over 40% by late January 2022. The cases started to decline after this peak. Data from China CDC confirmed that influenza B is a major pathogen during the season. Sequencing of the viral strain revealed the presence of the Victoria-like lineage of the influenza B strain, with minor variations from the Florida/39/2018 strain. Analysis of the hospitalized patients' characteristics indicated that severe cases were relatively more prevalent among younger individuals, with an average age of 40.9 ± 24.1 years. Among the seven patients who succumbed to influenza, the average age was 30 ± 30.1 years. These patients exhibited secondary infections involving either bacterial or fungal pathogens and displayed elevated levels of cell death markers (such as LDH) and coagulation pathway markers (D-dimer). CONCLUSION: Influenza B represents a significant infection threat and can lead to substantial morbidity and mortality, particularly among young patients. To mitigate morbidity and mortality rates, it is imperative to implement appropriate vaccination and other preventive strategies.

Protocol of a multicenter, single-blind, randomized, parallel controlled trial evaluating the effect of microbiological rapid on-site evaluation (M-ROSE) guiding anti-infection treatment in patients with severe hospital-acquired pneumonia.

INTRODUCTION: The mortality rate of hospitalized patients with severe hospital-acquired pneumonia (SHAP) remains high. Empirical broad-spectrum antibiotic coverage and the misuse of high-grade antibiotics could lead to the emergence of multi-drug and even pandrug-resistant bacteria. In addition to metagenomic next-generation sequencing (mNGS), microbiological rapid on-site evaluation (M-ROSE) might be a useful technique to identify the pathogens in the early stage; however, the effect of M-ROSE guiding anti-infection treatment on prognostic outcomes of SHAP patients is still unclear. METHODS/DESIGN: This is a multicenter, single-blind, prospective, randomized controlled trial to evaluate the effect of M-ROSE guiding anti-infection treatment in SHAP patients, which will provide new strategies for the prevention and control of clinical multi-drug resistance bacteria. A total of 166 patients with SHAP, aged 18 years and over, will be recruited from seven centers in Beijing and randomly assigned to the intervention group (M-ROSE combined with mNGS) or the control group (mNGS only) in a 1:1 ratio using the central randomization system. Patients in the intervention group will accept M-ROSE and mNGS analysis, and the control group will accept mNGS analysis. Individualized anti-infective treatment and routine treatment will be selected according to the analysis results. The primary outcome is the ICU outcome (mortality). The safety of the intervention measures will be evaluated during the entire trial period. This trial will be the first randomized controlled trial to evaluate the effect of M-ROSE guiding treatment on mortality in patients with SHAP and may change the prevalence of multi-drug resistant bacteria. ETHICS AND DISSEMINATION: This trial adheres to the Declaration of Helsinki and guidelines of Good Clinical Practice. Signed informed consent will be obtained from all participants. The trial has been approved by the Chinese PLA General Hospital (Approval Number: 20220322001). TRIAL REGISTRATION: ClinicalTrials.gov NCT05300776. Registered on 25 March 2022.