Ozone therapy mitigates parthanatos after ischemic stroke.

BACKGROUND: Stroke is a leading cause of death worldwide, with oxidative stress and calcium overload playing significant roles in the pathophysiology of the disease. Ozone, renowned for its potent antioxidant properties, is commonly employed as an adjuvant therapy in clinical settings. Nevertheless, it remains unclear whether ozone therapy on parthanatos in cerebral ischemia-reperfusion injury (CIRI). This study aims to investigate the impact of ozone therapy on reducing parthanatos during CIRI and to elucidate the underlying mechanism. METHODS: Hydrogen peroxide (H2O2) was utilized to mimic the generation of reactive oxygen species (ROS) in SH-SY5Y cell reperfusion injury in vitro, and an in vivo ischemic stroke model was established. Ozone saline was introduced for co-culture or intravenously administered to mice. Apoptosis and oxidative stress were assessed using flow cytometry and immunofluorescence. Western blotting was utilized to examine the expression of parthanatos signature proteins. The mechanism by which ozone inhibits parthanatos was elucidated through inhibiting PPARg or Nrf2 activity. RESULTS: The findings demonstrated that ozone mitigated H2O2-induced parthanatos by either upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) or activating peroxisome proliferator-activated receptorg (PPARg). Furthermore, through the use of calcium chelators and ROS inhibitors, it was discovered that ROS directly induced parthanatos and facilitated intracellular calcium elevation. Notably, a malignant feedback loop between ROS and calcium was identified, further amplifying the induction of parthanatos. Ozone therapy exhibited its efficacy by increasing PPARg activity or enhancing the Nrf2 translation, thereby inhibiting ROS production induced by H2O2. Concurrently, our study demonstrated that ozone treatment markedly inhibited parthanatos in stroke-afflicted mice. Additionally, ozone therapy demonstrated significant neuroprotective effects on cortical neurons, effectively suppressing parthanatos. CONCLUSIONS: These findings contribute valuable insights into the potential of ozone therapy as a therapeutic strategy for reducing parthanatos during CIRI, highlighting its impact on key molecular pathways associated with oxidative stress and calcium regulation.

Protective and Detoxifying Effects of Resveratrol on Zearalenone-Mediated Toxicity: A Review.

Zearalenone (ZEA) is a mycotoxin produced by Fusarium spp. fungi and is widely found in moldy corn, wheat, barley, and other grains. ZEA is distributed to the whole body via blood circulation after metabolic transformation in animals. Through oxidative stress, immunosuppression, apoptosis, autophagy, and mitochondrial dysfunction, ZEA leads to hepatitis, neurodegenerative diseases, cancer, abortion, and stillbirth in female animals, and decreased sperm motility in male animals. In recent years, due to the influence of climate, storage facilities, and other factors, the problem of ZEA pollution in global food crops has become particularly prominent, resulting in serious problems for the animal husbandry and feed industries, and threatening human health. Resveratrol (RSV) is a natural product with therapeutic activities such as anti-inflammatory, antioxidant, and anticancer properties. RSV can alleviate ZEA-induced toxic effects by targeting signaling pathways such as NF-κB, Nrf2/Keap1, and PI3K/AKT/mTOR via attenuating oxidative damage, inflammatory response, and apoptosis, and regulating cellular autophagy. Therefore, this paper provides a review of the protective effect of RSV against ZEA-induced toxicity and its molecular mechanism, and discusses the safety and potential clinical applications of RSV in the search for natural mycotoxin detoxification agents.

Oral colon-targeted pH-responsive polymeric nanoparticles loading naringin for enhanced ulcerative colitis therapy.

An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.

The role of pyroptosis in the occurrence and development of pregnancy-related diseases.

Pyroptosis is a form of programmed cell death that is crucial in the development of various diseases, including autoimmune diseases, atherosclerotic diseases, cancer, and pregnancy complications. In recent years, it has gained significant attention in national and international research due to its association with inflammatory immune overactivation and its involvement in pregnancy complications such as miscarriage and preeclampsia (PE). The mechanisms discussed include the canonical pyroptosis pathway of gasdermin activation and pore formation (caspase-1-dependent pyroptosis) and the non-canonical pyroptosis pathway (cysteoaspartic enzymes other than caspase-1). These pathways work on various cellular and factorial levels to influence normal pregnancy. This review aims to summarize and analyze the pyroptosis pathways associated with abnormal pregnancies and pregnancy complications. The objective is to enhance pregnancy outcomes by identifying various targets to prevent the onset of pyroptosis.

Ceftazidime-avibactam resistance in KPC-producing Klebsiella pneumoniae accompanied hypermucoviscosity acquisition.

BACKGROUND: Antimicrobial resistance and bacterial hypermucoviscosity, associated with escalating production of capsules, constitute major challenges for the clinical management of Klebsiella pneumoniae (K. pneumoniae) infections. This study investigates the association and underlying mechanism between ceftazidime-avibactam (CAZ-AVI) resistance and bacterial hypermucoviscosity in Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp). RESULTS: The proportion of CAZ-AVI-sensitive clinical isolates exhibiting the hypermucoviscous phenotype was significantly lower than that of the resistant strains (5.6% vs. 46.7%, P < 0.001). To further verify the correlation and molecular mechanism between CAZ-AVI resistance and hypermucoviscosity, 10 CAZ-AVI-resistant isolates were generated through in vitro resistance selection from CAZ-AVI-sensitive KPC-Kp. The results showed the same association as it showed in the clinical isolates, with four out of ten induced CAZ-AVI-resistant isolates transitioning from negative to positive in the string tests. Comparative genomic analysis identified diverse mutations in the wzc gene, crucial for capsule polysaccharide (CPS) synthesis, in all four CAZ-AVI-resistant hypermucoviscous KPC-Kp strains compared to the parent strains. However, these mutations were absent in the other six KPC-Kp strains that did not exhibit induced hypermucoviscosity. Cloning of the wzc gene variants and their expression in wild-type strains confirmed that mutations in the wzc gene can induce bacterial hypermucoviscosity and heightened virulence, however, they do not confer resistance to CAZ-AVI. CONCLUSIONS: These results indicated that resistance to CAZ-AVI in KPC-Kp isolates may be accompanied by the acquisition of hypermucoviscosity, with mutations in the wzc gene often involving in this process.

Understanding the role of ten-eleven translocation family proteins in kidney diseases.

Epigenetic mechanisms play a critical role in the pathogenesis of human diseases including kidney disorders. As the erasers of DNA methylation, Ten-eleven translocation (TET) family proteins can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thus leading to passive or active DNA demethylation. Similarly, TET family proteins can also catalyze the same reaction on RNA. In addition, TET family proteins can also regulate chromatin structure and gene expression in a catalytic activity-independent manner through recruiting the SIN3A/HDAC co-repressor complex. In 2012, we reported for the first time that the genomic 5-hydroxymethylcytosine level and the mRNA levels of Tet1 and Tet2 were significantly downregulated in murine kidneys upon ischemia and reperfusion injury. Since then, accumulating evidences have eventually established an indispensable role of TET family proteins in not only acute kidney injury but also chronic kidney disease. In this review, we summarize the upstream regulatory mechanisms and the pathophysiological role of TET family proteins in major types of kidney diseases and discuss their potential values in clinical diagnosis and treatment.

Deleting fibroblast growth factor 2 in macrophages aggravates septic acute lung injury by increasing M1 polarization and inflammatory cytokine secretion.

Septic lung injury is strongly associated with polarization of M1 macrophages and excessive cytokine release. Fibroblast growth factor (FGF) signaling plays a role in both processes. However, the impact of FGF2 deficiency on macrophage polarization and septic acute lung injury remains unclear. To investigate this, we obtained macrophages from FGF2 knockout mice and examined their polarization and inflammatory cytokine expression. We also eliminated endogenous macrophages using clodronate liposomes and administered FGF2 knockout or WT macrophages intravenously in conjunction with cecal ligation and puncture (CLP) surgery to induce sepsis. In vitro analysis by flow cytometry and real-time PCR analysis demonstrated that FGF2 deficiency resulted in increased expression of M1 markers (iNOS and CD86) and inflammatory cytokines (CXCL1, IL1ß, and IL6), especially after LPS stimulation. Additionally, immunofluorescence demonstrated increased nuclear translocation of p65 NF-κB in FGF2 knockout macrophages and RNA-seq analysis showed enrichment of differentially expressed genes in the IL17 and TNFα inflammatory signaling pathways. Furthermore, in vivo experiments revealed that depletion of FGF2 in macrophages worsened sepsis-induced lung inflammation, lung vascular leak, and lung histological injury, accompanied by an increase in CD86-positive cells and apoptosis. Our study suggests that FGF2 deficiency in macrophages plays a critical role in the pathogenesis of septic ALI, possibly because of the enhanced M1 macrophage polarization and production of proinflammatory cytokines. These findings provide empirical evidence for potential therapeutic interventions targeting FGF2 signaling to modulate the polarization of M1 and M2 macrophages in the management of sepsis-induced acute lung injury.

Advances in nanoparticle-based therapeutics for ischemic stroke: Enhancing drug delivery and efficacy.

Ischemic stroke, characterized by vascular occlusion, has recently emerged as one of the primary causes of mortality and disability worldwide. Conventional treatment modalities, such as thrombolytic and neuroprotective therapies, face numerous challenges, including limited bioavailability, significant neurotoxicity, suboptimal targeting, short half-life, and poor blood-brain barrier (BBB) penetration. Nanoparticle-based drug delivery systems present distinct advantages, such as small size, enhanced lipophilicity, and modifiability, which can potentially address these limitations. Utilizing nanoparticles for drug delivery in ischemic stroke therapy offers improved drug bioavailability, reduced neurotoxicity, enhanced targeted delivery, prolonged drug half-life, and better dissolution kinetics. This review aims to provide a comprehensive overview of current strategies in preclinical studies for managing or preventing ischemic stroke from a nanomaterial perspective, highlighting the advantages and limitations of each approach.

Therapeutic drug monitoring of linezolid in Chinese premature neonates: a population pharmacokinetic analysis and dosage optimization.

This study aimed to develop a pharmacokinetic model of linezolid in premature neonates and evaluate and optimize the administration regimen. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect the blood concentration data of 54 premature neonates after intravenous administration of linezolid, and the relevant clinical data were collected. The population pharmacokinetic (PPK) model was established by nonlinear mixed effects modeling. Based on the final model parameters, the optimal administration regimen of linezolid in premature neonates with different body surface areas (BSA) was simulated and evaluated. The pharmacokinetic properties of linezolid in premature neonates are best described by a single-compartment model with primary elimination. The population typical values for apparent volume of distribution and clearance were 0.783 L and 0.154 L/h, respectively. BSA was a statistically significant covariate with clearance (CL) and volume of distribution (Vd). Monte Carlo simulations showed that the optimal administration regimen for linezolid in premature neonates was 6 mg/kg q8h for BSA 0.11 m2, 7 mg/kg q8h for BSA 0.13 m2, and 9 mg/kg q8h for BSA 0.15 m2 with minimum inhibitory concentration (MIC) ≤1 mg/L, 7 mg/kg q8h for BSA 0.11 m2, 8 mg/kg q8h for BSA 0.13 m2, and 10 mg/kg q8h for BSA 0.15 m2 with MIC = 2 mg/L. A pharmacokinetic model was developed to predict the blood concentration on linezolid in premature neonates. Based on this model, the optimal administration regimen of linezolid in premature neonates needs to be individualized according to different BSA levels.

Easy access to amphiphilic nitrogenous block copolymers via switchable catalysis.

A key challenge in polymer synthesis is to develop new methods that enable block copolymers to be prepared from mixed monomer feedstock. The emerging switchable polymerization catalysis can generate block copolymers with well-defined structures and tunable properties from monomer mixtures. However, constrained by the reactivity of monomers and the incompatibility of different polymerization mechanisms, this method is usually confined to oxygenated monomers. In this work, the switchable polymerization was successfully applied to nitrogenous monomers for the first time, achieving the efficient copolymerization of N-substituted N-carboxyanhydrides (NNCAs) with epoxides and cyclic anhydrides. This leads to easy access towards amphiphilic nitrogenous copolymers, such as polyester-b-polypeptoids. Density functional theory calculations demonstrated that the reaction of cyclic anhydrides with the alkoxide terminal is thermodynamically more favorable than that of NNCAs. Characterization, using nuclear magnetic resonance spectroscopy, size exclusion chromatography and in situ infrared spectroscopy, has confirmed the well-defined block structure of the obtained copolymers. This switchable polymerization strategy is applicable to a range of monomer mixtures with different oxygenated monomers and NNCAs, providing a highly efficient synthetic route towards nitrogenous block copolymers. Most importantly, the easily accessed amphiphilic polyester-b-polypeptoids demonstrated excellent anti-protein adsorption capabilities and barely any cytotoxicity, showing great potential in the field of biomedicine.

Predictive value of stress hyperglycemia ratio on one-year mortality in chronic kidney disease patients admitted to intensive care unit.

BACKGROUND: Stress Hyperglycemia Ratio (SHR) reflects the acute blood glucose variation in critically ill conditions. However, its prognostic value in chronic kidney disease (CKD) remains understudied. This study aimed to investigate the association between SHR and one-year mortality in CKD patients hospitalized in the Intensive Care Unit (ICU). METHODS: Patients with diagnosis of CKD in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were enrolled. Incidence of all-cause mortality within one-year follow-up was used as the primary endpoint. RESULTS: 1825 CKD patients were included in the study. A "U-shaped" relationship between SHR and one-year mortality as identified using multivariate restricted cubic spline (RCS) analysis. Then study population were categorized into three groups: Group 1 (SHR < 0.70), Group 2 (0.70 ≤ SHR ≤ 0.95) and Group 3 (SHR > 0.95). Group 2 showed significantly better one-year outcomes compared to the other two groups (p = 0.0031). This survival benefit persisted across subgroup analyses stratified by age, sex, CKD stage, anemia and various clinical conditions. CONCLUSION: SHR proved to be a meaningful biomarker for predicting one-year mortality in ICU-admitted CKD patients, with a "U-shaped" correlation. The identification of the optimal SHR range (0.70-0.95) provided clinicians with a valuable tool for detecting high-risk populations.

Advances in the study of metal-organic frameworks and their biomolecule composites for osteoporosis therapeutic applications.

With the population aging, osteoporosis (OP) is becoming more and more common, seriously affecting patients' quality of life and their families, and how to prevent and treat osteoporosis has become a hot topic. However, the current conventional method of treating OP is oral anti-osteoporosis medication, which has drawbacks such as first-pass elimination and gastrointestinal adverse effects. At the same time, osteoporosis can lead to microbial infections and the need to promote angiogenesis for bone healing, among other needs that often cannot be met with conventional treatments, and there is a risk of resistance to oral antibiotics for microbial infections. Metal-organic frameworks (MOFs) having a high specific surface area, high porosity, controlled degradation, and variable composition; they can not only be used as a carrier to control drug release, but can also play multiple roles in the treatment of OP and microbial infections by releasing metal ions, etc., so they have inherent advantages for OP, which is a disease that requires long-term treatment. Therefore, this paper reviews the research progress of MOFs and their biomacromolecular composites in therapeutic applications for osteoporosis, categorized by MOF type, and briefly describes the mechanism of osteoporosis, and different synthesis methods of MOFs and MOF-based composites, and finally presents the main existing problems and future perspectives, aiming to make MOFs more helpful for OP treatment.

Time to positivity of blood cultures in paediatric patients.

AIM: Continuous monitoring of blood culture (BC) systems allows rapid detection of microbial growth. We aimed to determine differences in time to positivity (TTP) in BACTEC BC between organisms and whether a 36-h period was sufficient to detect all relevant pathogenic bacteria for children admitted to a tertiary care paediatric hospital. METHODS: This was a retrospective audit of positive aerobic (AE) and anaerobic (AN) BC from paediatric inpatients with available TTP from 1 August 2016 to 2 January 2019. First positive BC per bacteraemia episode was analysed. RESULTS: Overall, 649 BC were positive, of which 480 first positive BC were analysed: 246 AE (51.3%) only, 216 paired (45%) (108 AE and 108 AN) and 18 AN (3.8%) only. There were 372 episodes of bacteraemia in 340 patients. Median age was 19 months (interquartile range (IQR): 1.25-60). Median TTP for AE and AN cultures was 13.20 (IQR: 9.84-18.48) and 13.92 h (IQR: 10.32-17.04), respectively. Organisms were GNR 49.7%, GPC 29.6%, contaminants 14.5%, mixed 3.0%, other 2.4% and yeast 0.8%. Streptococcus agalactiae had the fastest median TTP in AE and AN cultures, followed by Escherichia coli (AE 8.88 vs. 10.20 h). For paired AE and AN cultures, TTP was faster for AE versus AN cultures (13.36 vs. 14.52 h, P = 0.001). A 36-h cut-off time captured 97.7% AE BC and 99.1% AN BC with pathogens, and 86.5% AE BC and 91.7% AN BC with contaminants, respectively. CONCLUSIONS: GNR were the commonest pathogens in paediatric BC and faster growth was detected in AE versus AN cultures. By 36 h, >97.7% of BC were positive for pathogens versus 86.5% for contaminants.

Exploring charge transfer and schottky barrier modulation at monolayer Ge2Sb2Te5-metal interfaces.

Monolayer Ge2Sb2Te5exhibits great potential in non-volatile memory technology due to its excellent electronic properties and phase-change characteristics, while the fundamental nature of Ge2Sb2Te5-metal contacts has not been well understood yet. Here, we provide a comprehensiveab initiostudy of the electronic properties between monolayer Ge2Sb2Te5and Pt, Pd, Au, Cu, Cr, Ag, and W contacts based on first-principles calculations. We find that the strong interaction interfaces formed between monolayer Ge2Sb2Te5and Pt, Pd, Cr, and W contacts show chemical bonding and strong charge transfer. In contrast, no apparent chemical bonding and weak charge transfer are observed in the weak interaction interfaces formed with Au, Cu, and Ag. Additionally, our study reveals the presence of a pronounced Fermi level pinning effect between monolayer Ge2Sb2Te5and metals, with pinning factors ofSn=0.325andSp=0.350. By increasing the interlayer distance, an effective transition fromn-type Ohmic contact ton-type Schottky contact is facilitated because the band edge of Ge2Sb2Te5is shifted upwards. Our study not only provides a theoretical basis for selecting suitable metal electrodes in Ge2Sb2Te5-based devices but also holds significant implications for understanding Schottky barrier height modulation between semiconductors and metals.

Optimizing the hemodynamics of hand injections in neuroangiography.

PURPOSE: Optimizing the preparation of a 10 ml syringe for manual injection of contrast media can help operators obtain easier and faster injections. This study aims to compare the flow rates of different contrast media injection methods. METHODS: Different contrast media solutions were compared: 100% contrast (10 ml contrast), mixed contrast solution (8:2 contrast/saline), and layered contrast below saline ("Parfait") in different volumes. Contrast media were injected at room temperature (20°C) and after heating (37°C). Four operators injected 10 ml syringes filled with different mediums through 5-French angiographic catheters. The average flow rate was used to compare different contrast injection mediums. The Kruskal-Wallis test with post-hoc pairwise comparisons using Bonferroni correction or Mann-Whitney U-tests were employed depending on the type of comparison. RESULTS: Compared to the 100% contrast solution, every Parfait media and mixed contrast solution demonstrated significantly higher flow rates (p < 0.001). The 5 ml saline Parfait had the highest flow rate among the Parfait solutions. The 5 ml saline Parfait and the mixed solution had comparable flow rates (p = 0.237). Higher flow rates were observed upon heating both 100% contrast (p < 0.001) and mixed contrast solutions (p < 0.001) in comparison to their flow rates at room temperature. CONCLUSION: This study demonstrates the capability of the Parfait and mixed contrast injections to achieve higher flow rates than the 100% contrast solutions. Heating the contrast media to 37°C also proves to be a viable strategy for further enhancing the flow rates for 100% and mixed contrast solutions.

Emerging trends and hotspots in peptic ulcer from 2008 to 2023: A bibliometric analysis.

Peptic ulcer (PU) is a common digestive disorder in the gastroduodenal. Although bibliometrics has become very popular in the medical field, a bibliometric analysis of research related to PU has yet to be reported. Therefore, this research aims to analyze the trends and hotspots of PU in the last 15 years. Literature data related to PU retrieved from the Web of Science Core Collection database from 2008 to 2023 were visualized and analyzed using CiteSpace 6.1.6.msi, VOSviewer 1.6.19, and SCImago Graphica Beta 1.0.35. Six thousand four hundred ninety-one papers were collected based on inclusion and exclusion criteria. The country with the highest number of publications was China. The institution with the highest number of publications was Baylor College of Medicine. The most prolific author was Yamaoka Yoshio. Malfertheiner Peter had the highest number of citations. The journal with the most publications is World Journal of Gastroenterology. The most cited Journal is Gastroenterology. The most cited reference was published by Marshall B. J. et al in 1984. The article with the highest burst strength was published in 2012 by Malfertheiner Peter. The keyword with the highest burst strength was "oxidative stress." Our research provides a bibliometric analysis of PU research to reveal the trends and hotspots of PU for 2008 to 2023. Our findings will help researchers to quickly understand the current state of research and provide a reference for in-depth studies in this area to foster the development of PU research.

Fungtion: A Server for Predicting and Visualizing Fungal Effector Proteins.

Fungal pathogens pose significant threats to plant health by secreting effectors that manipulate plant-host defences. However, identifying effector proteins remains challenging, in part because they lack common sequence motifs. Here, we introduce Fungtion (Fungal effector prediction), a toolkit leveraging a hybrid framework to accurately predict and visualize fungal effectors. By combining global patterns learned from pretrained protein language models with refined information from known effectors, Fungtion achieves state-of-the-art prediction performance. Additionally, the interactive visualizations we have developed enable researchers to explore both sequence- and high-level relationships between the predicted and known effectors, facilitating effector function discovery, annotation, and hypothesis formulation regarding plant-pathogen interactions. We anticipate Fungtion to be a valuable resource for biologists seeking deeper insights into fungal effector functions and for computational biologists aiming to develop future methodologies for fungal effector prediction: https://step3.erc.monash.edu/Fungtion/.

Cu0-based nanoparticles boost anti-tumor efficacy via synergy of cuproptosis and ferroptosis enhanced by cuproptosis-induced glutathione synthesis disorder.

Apoptotic resistance of tumor often leads to poor efficacy from mono-therapy based on apoptosis. Cuproptosis, a new type of non-apoptotic cell death related to mitochondrial dysfunction, can alter metabolism and enhance ferroptosis, providing a promising strategy for effective synergistic cancer treatment. In this work, Cu0-based nanoparticles (denoted as HA-ZCu) were successfully developed to improve anti-tumor efficacy by combining cuproptosis with enhanced ferroptosis, which was achieved by cuproptosis-induced glutathione synthesis disorder. In vitro studies revealed that HA-ZCu effectively induced cuproptosis and ferroptosis in HepG2 cells. Moreover, HA-ZCu induced mitochondrial dysfunction and decreased intracellular adenosine triphosphate (ATP), glutamate, and glutathione, demonstrating the effective synergy. In vivo studies further approved the synergistic therapeutic efficacy of HA-ZCu, where the inhibition rate of tumor growth reached 83.2 %. This work represents the first example of enhanced anti-tumor efficacy via cuproptosis and ferroptosis synergy through cuproptosis-induced glutathione synthesis disorder.

Comparison of Hypervirulent and Non-Hypervirulent Carbapenem-Resistant Acinetobacter baumannii Isolated from Bloodstream Infections: Mortality, Potential Virulence Factors, and Combination Therapy In Vitro.

Hypervirulent carbapenem-resistant Acinetobacter baumannii (hv-CRAB) has emerged in bloodstream infections (BSI). Cases of BSI caused by hv-CRAB (hv-CRAB-BSI) had posed a significant threat to hospitalized patients. In this study, 31 CRAB strains isolated from Chinese BSI patients were analyzed, of which 24 were identified as hv-CRAB-BSI and 7 as non-hv-CRAB-BSI, using the Galleria mellonella infection model. Patients with hv-CRAB-BSI had higher rates of septic shock (79.2% vs. 14.3%, p = 0.004) and mortality (66.7% vs. 14.3%, p = 0.028). All strains were resistant to most antibiotics but sensitive to colistin. Hv-CRAB-BSI showed lower resistance to minocycline than non-hv-CRAB-BSI (54.2% vs. 100%, p = 0.03). Whole-genome sequencing revealed that the detection rates of immune modulation genes ptk and epsA in hv-CRAB-BSI were significantly higher than in non-hv-CRAB-BSI (91.7% vs. 28.6%, p = 0.002). Additionally, all ST457 hv-CRAB-BSI lacked abaR, and all ST1486 non-hv-CRAB-BSI lacked adeG. The checkerboard dilution method assessed the efficacies of various antibiotic combinations, revealing that although synergism was rarely observed, the combination of colistin and minocycline showed the best efficacy for treating CRAB-BSI, regardless of whether the infections were hv-CRAB-BSI or non-hv-CRAB-BSI. These findings highlight the importance of analyzing molecular characteristics and exploring effective treatment strategies for hv-CRAB-BSI.