GABA system in the prefrontal cortex involved in psychostimulant addiction.

Drug addiction is a chronic and relapse brain disorder. Psychostimulants such as cocaine and amphetamine are highly addictive drugs. Abuse drugs target various brain areas in the nervous system. Recent studies have shown that the prefrontal cortex (PFC) plays a key role in regulating addictive behaviors. The PFC is made up of excitatory glutamatergic cells and gamma-aminobutyric acid (GABAergic) interneurons. Recently, studies showed that GABA level was related with psychostimulant addiction. In this review, we will introduce the role and mechanism of GABA and γ-aminobutyric acid receptors (GABARs) of the PFC in regulating drug addiction, especially in psychostimulant addiction.

igRNA Prediction and Selection AI Models (igRNA-PS) for Bystander-less ABE Base Editing.

CRISPR derived base editing techniques tend to edit multiple bases in the targeted region, which impedes precise reversion of disease-associated single nucleotide variations (SNVs). We designed an imperfect gRNA (igRNA) editing strategy to achieve bystander-less single-base editing. To predict the performance and provide ready-to-use igRNAs, we employed a high-throughput method to edit 5000 loci, each with approximate 19 systematically designed ABE igRNAs. Through deep learning of the relationship of editing efficiency, original gRNA sequence and igRNA sequence, AI models were constructed and tested, designated igRNA Prediction and Selection AI models (igRNA-PS). The models have three functions, First, they can identify the major editing site from the bystanders on a gRNA protospacer with a near 90% accuracy. second, a modified single-base editing efficiency (SBE), considering both single-base editing efficiency and product purity, can be predicted for any given igRNAs. Third, for an editing locus, a set of 64 igRNAs derived from a gRNA can be generated, evaluated through igRNA-PS to select for the best performer, and provided to the user. In this work, we overcome one of the most significant obstacles of base editors, and provide a convenient and efficient approach for single-base bystander-less ABE base editing.

Epidemiology of carbapenem-resistant Klebsiella pneumoniae in China and the evolving trends of predominant clone ST11: a multicentre, genome-based study.

OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major nosocomial infectious pathogen with rapidly increasing prevalence. The genomic epidemiological characteristics of CRKP nationwide, especially the evolving trends within the predominant clones, should be evaluated clearly. METHODS: We collected 3415 K. pneumoniae strains from 28 hospitals across China. Antimicrobial susceptibility testing and WGS were performed. Subsequent genomic analyses, including sequence typing, K-locus (KL) identification, antimicrobial resistance gene screening, and virulence score assessment were performed. The phylogenetic relationship of clonal group 11 was determined based on core-genome analysis, and the presence of the pLVPK-like virulence plasmid in ST11 isolates was confirmed using plasmid core-gene analysis. Additionally, the trends of the ST11 lineage with different KL types on a global scale were investigated using Beast2. RESULTS: Of the K. pneumoniae strains, 708 were identified as CRKP isolates (20.7%), of which 97.7% were MDR. ST11 was the predominant clone, and KPC-2 was the prevalent carbapenemase in China, although the prevalence of specific clones and carbapenemases varied by geographic region. Among ST11 isolates, KL47 and KL64 were the predominant KL types, and KL64 gradually replaced KL47, with a higher percentage of KL64 isolates harbouring the pLVPK-like plasmid. Global genome data showed a significant increase in the effective population size of KL64 over the last 5 years. CONCLUSIONS: The prevalence of CRKP was very high in certain regions in China. The increasing convergence of virulence and resistance, particularly in ST11-KL64 isolates, should be given more attention and further investigation.

LILRB1-HLA-G axis defines a checkpoint driving natural killer cell exhaustion in tuberculosis.

Chronic infections, including Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), can induce host immune exhaustion. However, the key checkpoint molecules involved in this process and the underlying regulatory mechanisms remain largely undefined, which impede the application of checkpoint-based immunotherapy in infectious diseases. Here, through adopting time-of-flight mass cytometry and transcriptional profiling to systematically analyze natural killer (NK) cell surface receptors, we identify leukocyte immunoglobulin like receptor B1 (LILRB1) as a critical checkpoint receptor that defines a TB-associated cell subset (LILRB1+ NK cells) and drives NK cell exhaustion in TB. Mechanistically, Mtb-infected macrophages display high expression of human leukocyte antigen-G (HLA-G), which upregulates and activates LILRB1 on NK cells to impair their functions by inhibiting mitogen-activated protein kinase (MAPK) signaling via tyrosine phosphatases SHP1/2. Furthermore, LILRB1 blockade restores NK cell-dependent anti-Mtb immunity in immuno-humanized mice. Thus, LILRB1-HLA-G axis constitutes a NK cell immune checkpoint in TB and serves as a promising immunotherapy target.

Potential causal association between serum vitamin D levels and intervertebral disc degeneration: A mendelian randomization study.

OBJECTIVES: Intervertebral disc degeneration (IDD) is a prevalent musculoskeletal disorder with substantial implications for disability and healthcare expenditures. The role of serum vitamin D (25-Hydroxyvitamin D, 25(OH)D) levels in the pathogenesis of various musculoskeletal conditions has been explored in prior observational studies, suggesting a potential association. While previous observational studies have suggested an association between the two conditions, it might confound the effect of 25(OH)D on IDD. This Mendelian randomization (MR) study seeks to elucidate the causal relationship between 25(OH)D and IDD. METHODS: We performed a MR analysis using summary-level data from genome-wide association studies (GWAS) of 25(OH)D (sample size = 441,291 European) and IDD (sample size = 336,439 (cases = 41,669, controls = 294,770) European). Single nucleotide polymorphisms (SNPs) significantly associated with 25(OH)D (p < 5 × 10-8) were selected as instrumental variables. The associations between genetically predicted 25(OH)D and IDD were estimated using the inverse-variance weighted (IVW) method, with sensitivity analyses employing the weighted median, MR-Egger, and MR-PRESSO approaches to assess the robustness of the findings. RESULTS: In the primary IVW analysis, genetically predicted 25(OH)D was unrelated associated with IDD (odds ratio (OR) = 0.9671, 95% confidence interval (CI): 0.8956-1.0444, p = 0.39). The results remained consistent across the sensitivity analyses, and no significant directional pleiotropy was detected (MR-Egger intercept: p = 0.64). CONCLUSIONS: This study found no obvious evidence that 25(OH)D is causally associated with IDD risks. We call for larger sample size studies to further unravel the potential causal relationship and the exact mechanism.

Clinical and laboratory insights into the threat of hypervirulent Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae (hvKP) typically causes severe invasive infections affecting multiple sites in healthy individuals. In the past, hvKP was characterized by a hypermucoviscosity phenotype, susceptibility to antimicrobial agents, and its tendency to cause invasive infections in healthy individuals within the community. However, there has been an alarming increase in reports of multidrug-resistant hvKP, particularly carbapenem-resistant strains, causing nosocomial infections in critically ill or immunocompromised patients. This presents a significant challenge for clinical treatment. Early identification of hvKP is crucial for timely infection control. Notably, identifying hvKP has become confusing due to its prevalence in nosocomial settings and the limited predictive specificity of the hypermucoviscosity phenotype. Novel virulence predictors for hvKP have been discovered through animal models or machine learning algorithms, while standardization of identification criteria is still necessary. Timely source control and antibiotic therapy have been widely employed for the treatment of hvKP infections. Additionally, phage therapy is a promising alternative approach due to escalating antibiotic resistance. In summary, this narrative review highlights the latest research progress in the development, virulence factors, identification, epidemiology of hvKP, and treatment options available for hvKP infection.

A Reliability Assessment Method for Complex Systems Based on Non-Homogeneous Markov Processes.

The Markov method is a common reliability assessment method. It is often used to describe the dynamic characteristics of a system, such as its repairability, fault sequence and multiple degradation states. However, the "curse of dimensionality", which refers to the exponential growth of the system state space with the increase in system complexity, presents a challenge to reliability assessments for complex systems based on the Markov method. In response to this challenge, a novel reliability assessment method for complex systems based on non-homogeneous Markov processes is proposed. This method entails the decomposition of a complex system into multilevel subsystems, each with a relatively small state space, in accordance with the system function. The homogeneous Markov model or the non-homogeneous Markov model is established for each subsystem/system from bottom to top. In order to utilize the outcomes of the lower-level subsystem models as inputs to the upper-level subsystem model, an algorithm is proposed for converting the unavailability curve of a subsystem into its corresponding 2×2 dynamic state transition probability matrix (STPM). The STPM is then employed as an input to the upper-level system's non-homogeneous Markov model. A case study is presented using the reliability assessment of the Reactor Protection System (RPS) based on the proposed method, which is then compared with the models based on the other two contrast methods. This comparison verifies the effectiveness and accuracy of the proposed method.

Heat-resistant super-dispersed oxide strengthened aluminium alloys.

Oxided-dispersion-strengthened (ODS) alloys are promising high-strength materials used in extreme environments such as high-temperature and radiation tolerance applications. Until now, ODS alloys have been developed for reducible metals by chemical processing methods, but there are no commercially available ODS alloys for unreducible metals, namely, Al, Mg, Ti, Zr and so on, owing to the challenge of uniformly dispersing oxide particles in these alloys by traditional techniques. Here we present a strategy to achieve ODS Al alloys containing highly dispersive 5 nm MgO nanoparticles by powder metallurgy, using nanoparticles that have in situ-grown graphene-like coatings and hence largely reduced surface energy. Notably, the densely dispersed MgO nanoparticles, which have a fully coherent relationship with an Al matrix, show effective suppression of interfacial vacancy diffusion, thus leading to unprecedented strength (~200 MPa) and creep resistance at temperatures as high as 500 °C. Our processing approach should enable the dispersion of ultrafine nanoparticles in a wide range of alloys for high-temperature-related applications.

Clinical application of nanopore-targeted sequencing technology in bronchoalveolar lavage fluid from patients with pulmonary infections.

The rapid and effective identification of pathogens in patients with pulmonary infections has posed a persistent challenge in medicine, with conventional microbiological tests (CMTs) proving time-consuming and less sensitive, hindering early diagnosis of respiratory infections. While there has been some research on the clinical performance of targeted sequencing technologies, limited focus has been directed toward bronchoalveolar lavage fluid (BALF). This study primarily evaluates the pathogen detection capabilities of nanopore-targeted sequencing (NTS) in BALF, providing a comprehensive analysis. The retrospective study, spanning from January 2022 to November 2023, includes 223 patients exclusively sourced from a single center. We conducted a detailed comparative analysis among NTS, targeted next-generation sequencing (tNGS), and CMTs. Initially, we compared the detection capabilities of NTS and tNGS and found no significant differences in their sensitivity and specificity. Specifically, we observed that the sensitivity of NTS was significantly higher than that of CMTs (74.83% vs 33.11%, P < 0.001). Furthermore, NTS exhibited a higher positivity rate in common pulmonary infections (62.88% vs. 23.48%) and in clinically suspected tuberculosis patients compared to CMTs (87.18% vs. 48.72%). Additionally, NTS showed less susceptibility to antibiotic interference, indicating a more sensitive detection capability, especially in detecting fastidious organisms. It complements GeneXpert in tuberculosis diagnosis and offers excellent advantages in identifying pathogens challenging for CMTs, such as non-tuberculous mycobacteria and viruses. Moreover, NTS significantly shortens the reporting time and is only a quarter of the cost of metagenomic next-generation sequencing. Clearly, NTS can facilitate faster and more cost-effective early diagnosis of respiratory infections.IMPORTANCEThis study holds paramount significance in advancing the field of respiratory infection diagnostics. By assessing the pathogen detection capabilities in bronchoalveolar lavage fluid (BALF) of patients with pulmonary infections, we illuminate the promising potential of nanopore-targeted sequencing (NTS). The findings underscore NTS as a comparable yet distinct alternative to traditional methods like comprehensive conventional microbiological tests (CMTs). Notably, NTS demonstrates a pivotal edge, expanding the spectrum of identified pathogens, particularly excelling in the detection of challenging entities like non-tuberculous mycobacteria and viruses. The study also highlights the complementary role of NTS alongside GeneXpert in the identification of tuberculosis, providing a comprehensive overview of the diagnostic landscape for respiratory infections. This insight carries significant implications for clinicians seeking rapid, cost-effective, and accurate diagnostic tools in the realm of pulmonary infections.

Prevalence and characteristics of ertapenem-mono-resistant isolates among carbapenem-resistant Enterobacterales in China.

Carbapenem-resistant Enterobacterales (CRE), specifically those resistant to only ertapenem among carbapenems (ETP-mono-resistant), are increasingly reported, while the optimal therapy options remain uncertain. To investigate the prevalence and characteristics of ETP-mono-resistant CRE, CRE strains were systematically collected from 102 hospitals across China between 2018 and 2021. A 1:1 randomized matching study was conducted with ETP-mono-resistant strains to meropenem- and/or imipenem-resistant (MEM/IPM-resistant) strains. Antimicrobial susceptibility testing, whole-genome sequencing, carbapenem-hydrolysing activity and the expression of carbapenemase genes were determined. In total, 18.8% of CRE strains were ETP-mono-resistant, with relatively low ertapenem MIC values. ETP-mono-resistant strains exhibited enhanced susceptibility to ß-lactams, ß-lactam/ß-lactamase inhibitor combinations, levofloxacin, fosfomycin, amikacin and polymyxin than MEM/IPM-resistant strains (P < 0.05). Phylogenetic analysis revealed high genetic diversity among ETP-mono-resistant strains. Extended-spectrum ß-lactamases (ESBLs) and/or AmpC, as well as porin mutations, were identified as potential major mechanisms mediating ETP-mono-resistance, while the presence of carbapenemases was found to be the key factor distinguishing the carbapenem-resistant phenotypes between the two groups (P < 0.001). Compared with the MEM/IPM-resistant group, limited carbapenemase-producing CRE (CP-CRE) strains in the ETP-mono-resistant group showed a significantly lower prevalence of ESBLs and porin mutations, along with reduced expression of carbapenemase. Remarkably, spot assays combined with modified carbapenem inactivation method indicated that ETP-mono-resistant CP-CRE isolates grew at meropenem concentrations eightfold above their corresponding MIC values, accompanied by rapidly enhanced carbapenem-hydrolysing ability. These findings illustrate that ETP-mono-resistant CRE strains are relatively prevalent and that caution should be exercised when using meropenem alone for treatment. The detection of carbapenemase should be prioritized.

Poly(d-amino acid) Nanoparticles Target Staphylococcal Growth and Biofilm Disassembly by Interfering with Peptidoglycan Synthesis.

d-Amino acids are signals for biofilm disassembly. However, unexpected metabolic pathways severely attenuate the utilization of d-amino acids in biofilm disassembly, resulting in unsatisfactory efficiency. Herein, three-dimensional poly(d-amino acid) nanoparticles (NPs), which possess the ability to block intracellular metabolism, are constructed with the aim of disassembling the biofilms. The obtained poly(α-N-acryloyl-d-phenylalanine)-block-poly(ß-N-acryloyl-d-aminoalanine NPs (denoted as FA NPs) present α-amino groups and α-carboxyl groups of d-aminoalanine on their surface, which guarantees that FA NPs can effectively insert into bacterial peptidoglycan (PG) via the mediation of PG binding protein 4 (PBP4). Subsequently, the FA NPs trigger the detachment of amyloid-like fibers that connect to the PG and reduce the number of polysaccharides and proteins in extracellular polymeric substances (EPS). Finally, FA NPs damage the structural stability of EPS and lead to the disassembly of the biofilm. Based on this feature, FA NPs significantly enhance the killing efficacy of encapsulated sitafloxacin sesquihydrate (Sita) by facilitating the penetration of Sita within the biofilm, achieving complete elimination of Staphylococcal biofilm in mice. Therefore, this study strongly demonstrates that FA NPs can effectively improve biofilm disassembly efficacy and provide great potential for bacterial biofilm infection treatment.

TRIM27 elicits protective immunity against tuberculosis by activating TFEB-mediated autophagy flux.

Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a promising strategy for infection treatment through targeting host immunity. However, the limited understanding of the function and regulatory mechanism of host factors involved in immune defense against infections has impeded HDT development. Here, we identify the ubiquitin ligase (E3) TRIM27 (tripartite motif-containing 27) as a host protective factor against Mtb by enhancing host macroautophagy/autophagy flux in an E3 ligase activity-independent manner. Mechanistically, upon Mtb infection, nuclear-localized TRIM27 increases and functions as a transcription activator of TFEB (transcription factor EB). Specifically, TRIM27 binds to the TFEB promoter and the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity toward TFEB, eventually inducing autophagy-related gene expression as well as autophagy flux activation to clear the pathogen. Furthermore, TFEB activator 1 can rescue TRIM27 deficiency-caused decreased autophagy-related gene transcription and attenuated autophagy flux, and accordingly suppressed the intracellular survival of Mtb in cell and mouse models. Taken together, our data reveal that TRIM27 is a host defense factor against Mtb, and the TRIM27-CREB1-TFEB axis is a potential HDT-based TB target that can enhance host autophagy flux.Abbreviations: ATG5: autophagy related 5; BMDMs: bone marrow-derived macrophages; CFU: colony-forming unit; ChIP-seq: chromatin immunoprecipitation followed by sequencing; CREB1: cAMP responsive element binding protein 1; CTSB: cathepsin B; E3: ubiquitin ligase; EMSA: electrophoretic mobility shift assay; HC: healthy control; HDT: host-directed therapy; LAMP: lysosomal associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TPR cation channel 1; Mtb: Mycobacterium tuberculosis; NLS: nuclear localization signal; PBMCs: peripheral blood mononuclear cells; PRKA/PKA: protein kinase cAMP-activated; qRT-PCR: quantitative real-time PCR; RFP: RET finger protein; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TRIM: tripartite motif; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.

Long-term outcomes of left atrial appendage closure with or without concomitant pulmonary vein isolation:a propensity score matching analysis based on CLACBAC study.

BACKGROUND: The combined procedure of left atrial appendage closure (LAAC) with concomitant pulmonary vein isolation (PVI) has demonstrated its efficacy and safety. However, there is still a lack of comparative investigations regarding the long-term benefits of the combined procedure when compared to LAAC alone. Our study aims to assess the long-term outcomes of combined procedure of LAAC with concomitant PVI in comparison with a propensity matched LAAC alone group. METHODS: Propensity score matching (PSM) was employed to rectify covariate imbalances, resulting in the inclusion of 153 comparable patients from the initial cohort of 333 non-valvular atrial fibrillation (AF) patients. Clinical outcomes, encompassing thrombotic events, major cardiocerebrovascular adverse events (MACCE), re-hospitalization due to cardiovascular disease (CVD), and atrial tachycardia (AT), were juxtaposed between the two groups. Bleeding events and peri-device complications, such as residual flow, device-related thrombus, and device replacement, were also compared. Additionally, a patients group underwent PVI alone was included for comparing AF recurrence rates between the PVI alone group and the combined group. RESULTS: Following PSM, 153 patients (mean age 70.3 ± 8.9, 62.7% men) were included, with 102 undergoing the combined procedure and 51 undergoing LAAC alone. No significant differences were found in baseline characteristics between the two groups. The mean follow-up time was 37.6 ± 7.9 months, and two patients were lost to follow-up in the combined procedure group. Thrombotic events were observed in 4 (7.8%) patients in the LAAC alone group and 4 (4.0%) in the combined group (Log-rank p = 0.301). The proportion of patients experiencing MACCE, re-hospitalization due to CVD, and AT between the two groups was comparable, as were bleeding events and peri-device complications. Among patients from the combined procedure group without AF recurrence, a significant difference was noted in prior-procedure left ventricular ejection fraction (LVEF) and LVEF at the 12th month after the procedure (57.2% ± 7.1% vs. 60.5% ± 6.5%, p = 0.002). CONCLUSION: The concomitant PVI and LAAC procedure did not increase procedure-related complications, nor did it confer significant benefits in preventing thrombotic events or reducing other cardiovascular events. However, the combined procedure improved heart function, suggesting potential long-term benefits.

TREM2 gene induces differentiation of induced pluripotent stem cells into dopaminergic neurons and promotes neuronal repair via TGF-ß activation in 6-OHDA-lesioned mouse model of Parkinson's disease.

OBJECTIVE: Induced pluripotent stem cells (iPSCs) hold a promising potential for rescuing dopaminergic neurons in therapy for Parkinson's disease (PD). This study clarifies a TREM2-dependent mechanism explaining the function of iPSC differentiation in neuronal repair of PD. METHODS: PD-related differentially expressed genes were screened by bioinformatics analyses and their expression was verified using RT-qPCR in nigral tissues of 6-OHDA-lesioned mice. Following ectopic expression and depletion experiments in iPSCs, cell differentiation into dopaminergic neurons as well as the expression of dopaminergic neuronal markers TH and DAT was measured. Stereotaxic injection of 6-OHDA was used to develop a mouse model of PD, which was injected with iPSC suspension overexpressing TREM2 to verify the effect of TREM2 on neuronal repair. RESULTS: TREM2 was poorly expressed in the nigral tissues of 6-OHDA-lesioned mice. In the presence of TREM2 overexpression, the iPSCs showed increased expression of dopaminergic neuronal markers TH and DAT, which facilitated the differentiation of iPSCs into dopaminergic neurons. Mechanistic investigations indicated that TREM2 activated the TGF-ß pathway and induced iPSC differentiation into dopaminergic neurons. In vivo data showed that iPSCs overexpressing TREM2 enhanced neuronal repair in 6-OHDA-lesioned mice. CONCLUSION: This work identifies a mechanistic insight for TREM2-mediated TGF-ß activation in the regulation of neuronal repair in PD and suggests novel strategies for neurodegenerative disorders.

Motion-Aware Memory Network for Fast Video Salient Object Detection.

Previous methods based on 3DCNN, convLSTM, or optical flow have achieved great success in video salient object detection (VSOD). However, these methods still suffer from high computational costs or poor quality of the generated saliency maps. To address this, we design a space-time memory (STM)-based network that employs a standard encoder-decoder architecture. During the encoding stage, we extract high-level temporal features from the current frame and its adjacent frames, which is more efficient and practical than methods reliant on optical flow. During the decoding stage, we introduce an effective fusion strategy for both spatial and temporal branches. The semantic information of the high-level features is used to improve the object details in the low-level features. Subsequently, spatiotemporal features are methodically derived step by step to reconstruct the saliency maps. Moreover, inspired by the boundary supervision prevalent in image salient object detection (ISOD), we design a motion-aware loss that predicts object boundary motion, and simultaneously perform multitask learning for VSOD and object motion prediction. This can further enhance the model's capability to accurately extract spatiotemporal features while maintaining object integrity. Extensive experiments on several datasets demonstrate the effectiveness of our method and can achieve state-of-the-art metrics on some datasets. Our proposed model does not require optical flow or additional preprocessing, and can reach an impressive inference speed of nearly 100 FPS.

Glycosylase-based base editors for efficient T-to-G and C-to-G editing in mammalian cells.

Base editors show promise for treating human genetic diseases, but most current systems use deaminases, which cause off-target effects and are limited in editing type. In this study, we constructed deaminase-free base editors for cytosine (DAF-CBE) and thymine (DAF-TBE), which contain only a cytosine-DNA or a thymine-DNA glycosylase (CDG/TDG) variant, respectively, tethered to a Cas9 nickase. Multiple rounds of mutagenesis by directed evolution in Escherichia coli generated two variants with enhanced base-converting activity-CDG-nCas9 and TDG-nCas9-with efficiencies of up to 58.7% for C-to-A and 54.3% for T-to-A. DAF-BEs achieve C-to-G/T-to-G editing in mammalian cells with minimal Cas9-dependent and Cas9-independent off-target effects as well as minimal RNA off-target effects. Additional engineering resulted in DAF-CBE2/DAF-TBE2, which exhibit altered editing windows from the 5' end to the middle of the protospacer and increased C-to-G/T-to-G editing efficiency of 3.5-fold and 1.2-fold, respectively. Compared to prime editing or CGBEs, DAF-BEs expand conversion types of base editors with similar efficiencies, smaller sizes and lower off-target effects.

Liquid Nitrogen Cryoballoon Ablation System for Paroxysmal Atrial Fibrillation: A Multicenter, Prospective, Single-Arm Clinical Trial.

Background: Cryoballoon ablation (CBA) has emerged as an effective treatment for atrial fibrillation (AF). Objectives: This study sought to assess the performance of a novel liquid nitrogen-driven CBA system and evaluate its safety and efficacy in the treatment of drug-resistant paroxysmal atrial fibrillation (PAF). Methods: This was a prospective multicenter single-arm clinical trial with 10 participating tertiary hospitals enrolling 176 patients with PAF. All participants received liquid nitrogen-driven CBA developed by the Cryofocus Medtech Company. Scheduled follow-up was performed before discharge and 3 months, 6 months, and 12 months after CBA. The primary endpoints were defined as 1) treatment success (freedom from antiarrhythmic drugs and atrial tachycardia at 12 months after CBA); and 2) immediate success rate of pulmonary vein isolation. The safety endpoint was the incidence of device- and procedure-related adverse events (AEs) and all-cause mortality. Results: A total of 172 participants were included, with an average age of 59.22 ± 9.25 years and 99 (57.56%) of them men. Immediate success rate was 97.67% (95% CI: 94.15%-99.36%) and 12-month treatment success rate was 82.56% (95% CI: 76.89%-88.23%), including a late recurrence rate of 13.61%. Incidences of device- and procedure-related AEs were 2.27% and 25.00%, respectively. Phrenic nerve palsy (PNP) occurred in 6 patients, of which 5 recovered during follow-up. Although the incidence of total severe AEs was 17.05%, including an all-cause mortality of 0.57%, only 1 case of permanent PNP was related to the CBA procedure. Conclusions: This premarketing prospective multicenter single-arm clinical trial demonstrated that the liquid nitrogen cryoablation system is safe and effective in the treatment of PAF.

Taurine alleviates high-fat-high-glucose-induced pancreatic islet ß-cell oxidative stress and apoptosis in rat.

The effect of taurine (TAU) as a specific regulatory mediator on pancreatic function in obese rats induced by a high-fat-high-glucose (HFHG) diet was investigated. We fed male Sprague-Dawley rats under different conditions, namely the control, HFHG, TAU, and HFHG + TAU treatment groups for 4 months. Compared with the HFHG group, TAU supplementation significantly reduced malondialdehyde levels and increased superoxide dismutase, total antioxidant capacity, and glutathione levels in the rat pancreas. In addition, TAU significantly decreased the level of reactive oxygen species, and markedly increased the activity of heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP-1), and nuclear factor erythrocyte-2-related factor 2 (Nrf2) in the rat pancreas. Notably, HFHG diet could induce pancreatic injury in the rats through the Nrf2/HO-1 signaling pathway and activate the mitochondrial channel-mediated apoptotic signaling pathway. The addition of TAU significantly improved the pancreatic tissue injury induced by the HFHG diet in the rats and reduced the protein expression of Caspase-3, Cleaved-caspase-3, Caspase-9 and Bcl-2 associated protein X (BAX), and increased the protein expression of B-cell lymphoma-2 (Bcl-2). In conclusion, this experiment confirmed that TAU could alleviate the oxidative stress and apoptosis induced by the HFHG diet in rat pancreatic ß-cells.

Predictive value of admission red cell distribution width-to-platelet ratio for 30-day death in patients with spontaneous intracerebral hemorrhage: an analysis of the MIMIC database.

Aim: Prognostic assessment plays an important role in the effective management of patients with spontaneous intracerebral hemorrhage (ICH). The study aimed to investigate whether elevated red cell distribution width-to-platelet ratio (RPR) at admission was related to 30-day death in patients with spontaneous intracerebral hemorrhage (ICH). Methods: This retrospective cohort study included 2,823 adult patients with ICH from the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) III and IV databases between 2001 and 2019. The Cox proportional hazard model was utilized to evaluate the relationship between RPR levels and 30-day death risk. The area under receiver-operating characteristic curve (AUC) was used to assess the predictive ability of RPR for 30-day death in patients with ICH. Results: At the end of the 30-day follow-up, 799 (28.30%) patients died, and the median RPR level was 0.066 (0.053, 0.087). After adjusting for confounders, the tertile 3 of RPR levels [hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.15-1.64] were associated with a higher risk of 30-day death in patients with ICH compared with tertile 1. In the stratified analyses, elevated RPR levels were found to be associated with an increased risk of 30-day death in patients aged <65 years (HR = 1.77, 95%CI: 1.29-2.43), aged ≥65 years (HR = 1.30, 95%CI: 1.05-1.61), with Glasgow Coma Score (GCS) <14 (HR = 1.65, 95%CI: 1.27-2.14), with Charlson comorbidity index (CCI) ≥4 (HR = 1.45, 95%CI: 1.17-1.80), with (HR = 1.66, 95%CI: 1.13-2.43) or without sepsis (HR = 1.32, 95%CI: 1.08-1.61), and female patients (HR = 1.75, 95%CI: 1.35-2.26) but not in male patients (P = 0.139) and patients with GCS ≥14 (P = 0.058) or CCI <4 (P = 0.188). The AUC for RPR to predict 30-day death in patients with ICH was 0.795 (95%CI: 0.763-0.828) in the testing set, indicating a good predictive ability. Conclusion: Elevated RPR levels were correlated with an increased risk of 30-day death in patients with ICH, and RPP levels showed good predictive ability for 30-day death.