Left Bundle Branch Area Pacing With or Without Conduction System Capture in Heart Failure Models.

BACKGROUND: Left bundle branch area pacing includes left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP), which is effective in patients with dyssynchronous heart failure (DHF). However, the basic mechanisms are unknown. OBJECTIVES: This study aimed to compare LBBP with LVSP and explore potential mechanisms underlying the better clinical outcomes of LBBP. METHODS: A total of 24 beagles were assigned to the following groups: 1) control group; 2) DHF group, left bundle branch ablation followed by 6 weeks of AOO pacing at 200 ppm; 3) LBBP group, DHF for 3 weeks followed by 3 weeks of DOO pacing at 200 ppm; and 4) LVSP with the same interventions in the LBBP group. Metrics of electrocardiogram, echocardiography, hemodynamics, and expression of left ventricular proteins were evaluated. RESULTS: Compared with LVSP, LBBP had better peak strain dispersion (44.67 ± 1.75 ms vs 55.50 ± 4.85 ms; P < 0.001) and hemodynamic effect (dP/dtmax improvement: 27.16% ± 7.79% vs 11.37% ± 4.73%; P < 0.001), whereas no significant differences in cardiac function were shown. The altered expressions of proteins in the lateral wall vs septum in the DHF group were partially reversed by LBBP and LVSP, which was associated with the contraction and adhesion process, separately. CONCLUSIONS: The animal study demonstrated that LBBP offered better mechanical synchrony and improved hemodynamics than LVSP, which might be explained by the reversed expression of contraction proteins. These results supported the potential superiority of left bundle branch area pacing with the capture of the conduction system in DHF model.

GSK3: A potential target and pending issues for treatment of Alzheimer's disease.

Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3ß subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aß aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aß formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity-driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.

The combined association of physical activity and alcohol use with long-term mortality: an age-stratified analysis.

BACKGROUND: The combined association of physical activity (PA) and alcohol use (AU) with long-term mortality is yet to be investigated. METHODS: For the current study, 12,621 participants aged ≥ 20 years were enrolled from the National Health and Nutrition Examination Survey (1999-2004). The study endpoint was all-cause mortality. Cox proportional hazards regression models were used to examine the combined effect of PA and AU on long-term mortality. RESULTS: The study population was divided into young (< 60 years, N = 8,258) and old (≥ 60 years, N = 4,363) groups. The median follow-up time was 203 months. In both young and old group, sedentary lifestyle combined with even minimal AU were associated with elevated risk of death (all P < 0.05). In young group, the integration of high volume AU with any degree of PA, including sedentary PA (HR = 2.35, 95% CI 1.24-4.44, P = 0.009), low PA (HR = 1.64, 95% CI 1.01-2.68, P = 0.047), and moderate-to-vigorous PA (HR = 1.99, 95% CI 1.03-3.84, P = 0.041), was associated with an increased risk of mortality. This relationship persisted as significant after adjusting for potential confounders (all P < 0.05). In old group, combining moderate-to-vigorous PA and low volume AU (HR = 0.59, 95% CI 0.37-0.94, P = 0.027) was associated with a reduction in mortality. After adjustment, the combination of moderate-to-vigorous PA and low volume AU was independently associated with favorable prognostic outcomes (all P < 0.05). CONCLUSIONS: In both age groups, combining sedentary lifestyle with even minimal AU was a risk factor for death. In young group, combining any level of PA with high volume AU was associated with increased mortality. In old group, combining moderate-to-vigorous PA with low volume AU was related to reduced mortality.

Bacterial persisters: molecular mechanisms and therapeutic development.

Persisters refer to genetically drug susceptible quiescent (non-growing or slow growing) bacteria that survive in stress environments such as antibiotic exposure, acidic and starvation conditions. These cells can regrow after stress removal and remain susceptible to the same stress. Persisters are underlying the problems of treating chronic and persistent infections and relapse infections after treatment, drug resistance development, and biofilm infections, and pose significant challenges for effective treatments. Understanding the characteristics and the exact mechanisms of persister formation, especially the key molecules that affect the formation and survival of the persisters is critical to more effective treatment of chronic and persistent infections. Currently, genes related to persister formation and survival are being discovered and confirmed, but the mechanisms by which bacteria form persisters are very complex, and there are still many unanswered questions. This article comprehensively summarizes the historical background of bacterial persisters, details their complex characteristics and their relationship with antibiotic tolerant and resistant bacteria, systematically elucidates the interplay between various bacterial biological processes and the formation of persister cells, as well as consolidates the diverse anti-persister compounds and treatments. We hope to provide theoretical background for in-depth research on mechanisms of persisters and suggest new ideas for choosing strategies for more effective treatment of persistent infections.

Association between triglyceride-glucose index and the risk of heart failure hospitalization in older diabetic patients received right ventricular pacing: a retrospective cohort study.

BACKGROUND: The prognostic value of triglyceride-glucose (TyG) index is not yet known for older diabetic patients received right ventricular pacing (RVP). We aimed to investigate the association between TyG index and the risk of heart failure hospitalization (HFH) in older diabetic patients received RVP. METHODS: This study was conducted between January 2017 and January 2018 at Fuwai Hospital, Beijing, China, and included older (age ≥ 65 years) diabetic patients that received RVP for the first time. TyG index were obtained before implantation. The primary endpoint was HFH. RESULTS: A total of 231 patients were divided into three groups according to the tertiles of TyG index: < 8.5 (T1, N = 77), 8.5-9.1 (T2, N = 77), and > 9.1 (T3, N = 77). T3 group had higher rate of HFH (Log-rank = 11.7, P = 0.003). Multivariate analyses showed that, TyG index served as an independent predictor for HFH, both as numerical variable (HR = 1.94, 95% CI 1.21-3.11, P = 0.006), and as categorical variable (HR = 2.31, 95% CI 1.09-4.89, P = 0.03). RCS demonstrated that the risk of HFH was relatively low until TyG index exceeded 8.8, beyond which the risk began to increase rapidly (P-non-linear = 0.006). CONCLUSION: Preimplantation TyG index emerges as a robust, independent predictor for HFH in older diabetic patients received RVP, and TyG index > 8.8 might be the optimal cut-off value.

Bias-Free Cardiac Monitoring Capsule.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Patients often fail to recognize the early signs of CVDs, which display irregularities in cardiac contractility and may ultimately lead to heart failure. Therefore, continuously monitoring the abnormal changes in cardiac contractility may represent a novel approach to long-term CVD surveillance. Here, a zero-power consumption and implantable bias-free cardiac monitoring capsule (BCMC) is introduced based on the triboelectric effect for cardiac contractility monitoring in situ. The output performance of BCMC is improved over 10 times with nanoparticle self-adsorption method. This device can be implanted into the right ventricle of swine using catheter intervention to detect the change of cardiac contractility and the corresponding CVDs. The physiological signals can be wirelessly transmitted to a mobile terminal for analysis through the acquisition and transmission module. This work contributes to a new option for precise monitoring and early diagnosis of CVDs.

Genetically predicted biomarkers of iron homeostasis and risk of non-ischemic cardiomyopathy: A mendelian randomization study.

BACKGROUND AND AIMS: Both iron overload and iron deficiency have been associated with cardiovascular diseases in observational studies. Previous Mendelian Randomization (MR) studies discovered a protective effect of higher iron status on coronary atrial disease, while a neutral effect on all-cause heart failure. Using two-sample MR, we evaluated how genetically predicted systemic iron status affects the risk of non-ischemic cardiomyopathy and different phenotypes. METHODS AND RESULTS: Two-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR, 1.17; 95% CI, 1.13-1.38) when using nine separately selected genetic instruments. An increase in genetically determined serum iron (odds ratio [OR] per standard deviation [SD], 1.25; 95% confidence interval [CI], 1.13-1.38) and ferritin (OR, 1.49; 95% CI, 1.02-2.18) were associated with an increased risk of cardiomyopathy. Total iron binding capacity, a marker of reduced iron status, was inversely linked with cardiomyopathy (OR, 0.80; 95% CI, 0.65-0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure. CONCLUSIONS: These analyses support the causal effect of increased systemic iron status on a higher risk of non-ischemic cardiomyopathy. A screening test for cardiomyopathy should be considered in patients with evidence of iron overload. Future study is needed for exploring the mechanism of these causal variants on cardiomyopathy.

Types of Septic Cardiomyopathy: Prognosis and Influencing Factors - A Clinical Study.

Objective: To explore the prognostic outcomes associated with different types of septic cardiomyopathy and analyze the factors that exert an influence on these outcomes. Methods: The data collected within 24 hours of ICU admission included cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP); SOFA (sequential organ failure assessment) scores, and the proportion of vasopressor use. Based on echocardiographic outcomes, septic cardiomyopathy was categorized into left ventricular (LV) systolic dysfunction, LV diastolic dysfunction, and right ventricular (RV) systolic dysfunction. Differences between the mortality and survival groups, as well as between each cardiomyopathy subgroup and the non-cardiomyopathy group were compared, to explore the influencing factors of cardiomyopathy. Results: A cohort of 184 patients were included in this study, with LV diastolic dysfunction having the highest incidence rate (43.5%). The mortality group had significantly higher SOFA scores, vasopressor use, and cTnI levels compared to the survival group; the survival group had better LV diastolic function than the mortality group (p < 0.05 for all). In contrast to the non-cardiomyopathy group, each subgroup within the cardiomyopathy category exhibited elevated levels of cTnI. The subgroup with left ventricular diastolic dysfunction demonstrated a higher prevalence of advanced age, hypertension, diabetes mellitus, coronary artery disease, and an increased mortality rate; the RV systolic dysfunction subgroup had higher SOFA scores and NT-proBNP levels, and a higher mortality rate (P < 0.05 for all); the LV systolic dysfunction subgroup had a similar mortality rate (P > 0.05). Conclusion: Patients with advanced age, hypertension, diabetes mellitus, or coronary artery disease are more prone to develop LV diastolic dysfunction type of cardiomyopathy; cardiomyopathy subgroups had higher levels of cTnI. The RV systolic dysfunction cardiomyopathy subgroup had higher SOFA scores and NT-proBNP levels. The occurrence of RV systolic dysfunction in patients with sepsis significantly increased the mortality rate.

Implication of geriatric nutritional risk index on treatment response and long-term prognosis in patients with cardiac resynchronization therapy.

PURPOSE: Geriatric Nutritional Risk Index (GNRI) is a simple tool for assessing the nutritional status of the aging population. This study aims to explore the clinical implication of GNRI on treatment response and long-term clinical outcomes in heart failure (HF) patients receiving cardiac resynchronization therapy (CRT). METHODS: Patients who underwent CRT implantation or upgrade at our hospital were retrospectively included. The association of GNRI and its tertiles with the echocardiographic response, all-cause mortality or heart transplantation, and the first hospitalization due to HF were investigated. RESULTS: Totally, 647 patients were enrolled, with a median age of 60 [Interquartile Range (IQR): 52-67] years and mean score of GNRI at 107.9 ± 23.7. Super-response rates increased significantly among the GNRI T1, T2, and T3 groups (25.1%, 29.8% vs. 41.1%, P = 0.002). Patients with higher GNRI were more likely to have better LVEF improvement after multiple adjustments (OR = 1.13, 95% CI: 1.04-1.23, P = 0.010). Higher GNRI was independently associated with a lower risk of all-cause mortality or heart implantation (HR = 0.95, 95% CI: 0.93-0.96, P < 0.001) and HF hospitalization (HR = 0.96, 95% CI: 0.95-0.98, P < 0.001). The inclusion of GNRI enhanced the predictability of all-cause mortality based on traditional model, including sex, New York Heart Association functional class, left bundle branch block, QRS reduction, and N-terminal pro-B-type natriuretic peptide level (C statistics improved from 0.785 to 0.813, P = 0.007). CONCLUSION: Higher GNRI was associated with better treatment response and long-term prognosis in HF patients with CRT. Evaluation of nutritional status among CRT population is necessary for individualized choice of potential responders.

Rapamycin improves the long-term T-cell memory and protective efficacy of tuberculosis subunit vaccine.

The formation of long-lived T-cell memory is a critical goal of vaccines against intracellular pathogens like Mycobacterium tuberculosis (M. tuberculosis). In this study, to access the adjuvant effect of rapamycin on tuberculosis subunit vaccine, we treated mice with rapamycin during the course of vaccination and then monitored the vaccine-specific long-term memory T cell recall responses and protective ability against mycobacterial organisms. Compared with the mice that received vaccine alone, rapamycin treatment enhanced the vaccine induced long-term IFN-γ and IL-2 recall responses, promoted the development of TCM (central memory) like cells and improved the long-term proliferative ability of lymphocytes. Long-duration (total 53 days) of low-dose rapamycin (75 µg/kg/day) treatment generated stronger vaccine-specific memory T cell responses than short-duration treatment (total 25 days). Moreover, rapamycin improved the vaccine's long-term protective efficacy, which resulted in a better reduction of 0.89-log10 CFU of mycobacterial organisms in the lungs compared with control without rapamycin treatment. These findings suggest that rapamycin may be considered in designing TB subunit vaccine regimens or as potential adjuvant to enhance vaccine-induced T cell memory response and to prolong the longevity of vaccine's protective efficacy.

Dyssynchronous heart failure models in canines: New insights into electrocardiographic, echocardiographic and histological features.

BACKGROUND: We investigated the similarities and differences between two experimental approaches using tachy-pacing technology to induce desynchronized heart failure in canines. METHODS: A total of eight dogs were included in the experiment, four were tachy-paced in right ventricle apex (RVAP) and 4 were paced in right atrium after the ablation of left bundle branch to achieve left bundle branch block (RAP+LBBB). Three weeks of follow-up were conducted to observe the changes in cardiac function and myocardial staining was performed at the end of the experiment. RESULTS: Both experimental approaches successfully established heart failure with reduced ejection fraction models, with similar trends in declining cardiac function. The RAP+LBBB group exhibited a prolonged overall ventricular activation time, delayed left ventricular activation, and lesser impact on the right ventricle. The RVAP approach led to a reduction in overall right ventricular compliance and right ventricular enlargement. The RAP+LBBB group exhibited significant reductions in left heart compliance (LVGLS, %: RAP+LBBB -12.60 ± 0.12 to -5.93 ± 1.25; RVAP -13.28 ± 0.62 to -8.05 ± 0.63, p = 0.023; LASct, %: RAP+LBBB -15.75 ± 6.85 to -1.50 ± 1.00; RVAP -15.75 ± 2.87 to -10.05 ± 6.16, p = 0.035). Histological examination revealed more pronounced fibrosis in the left ventricular wall and left atrium in the RAP+LBBB group while the RVAP group showed more prominent fibrosis in the right ventricular myocardium. CONCLUSION: Both approaches establish HFrEF models with comparable trends. The RVAP group shows impaired right ventricular function, while the RAP+LBBB group exhibits more severe decreased compliance and fibrosis in left ventricle.

A self-powered intracardiac pacemaker in swine model.

Harvesting biomechanical energy from cardiac motion is an attractive power source for implantable bioelectronic devices. Here, we report a battery-free, transcatheter, self-powered intracardiac pacemaker based on the coupled effect of triboelectrification and electrostatic induction for the treatment of arrhythmia in large animal models. We show that the capsule-shaped device (1.75 g, 1.52 cc) can be integrated with a delivery catheter for implanting in the right ventricle of a swine through the intravenous route, which effectively converts cardiac motion energy to electricity and maintains endocardial pacing function during the three-week follow-up period. We measure in vivo open circuit voltage and short circuit current of the self-powered intracardiac pacemaker of about 6.0 V and 0.2 µA, respectively. This approach exhibits up-to-date progress in self-powered medical devices and it may overcome the inherent energy shortcomings of implantable pacemakers and other bioelectronic devices for therapy and sensing.

Effect of short-term cardiac function changes after cardiac resynchronization therapy on long-term prognosis in heart failure patients with and without diabetes.

Background: The relationship between short-term cardiac function changes and long-term outcomes in heart failure (HF) patients undergoing cardiac resynchronization therapy (CRT) remains uncertain, especially when stratified by diabetes status. Objectives: This study aims to assess the association between short-term cardiac function changes and outcomes such as all-cause mortality and HF hospitalization in patients undergoing CRT, stratified by diabetes status. Design: This is a cohort longitudinal retrospective study. Methods: A total of 666 HF patients, treated with CRT between March 2007 and March 2019, were included in this study. Among them, 166 patients (24.9%) were diagnosed with diabetes. Cardiac function was assessed at baseline and again at 6 months, incorporating evaluations of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left atrial diameter (LAD), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and QRS duration. The QRS duration represents the time required for a stimulus to spread through the ventricles (ventricular depolarization). The primary endpoints of the study were all-cause mortality and HF-related hospitalization. Results: During a median follow-up of 2.51 years, 172 (25.8%) patients died and 197 (29.6%) were hospitalized for HF. Changes in LVEF, LVEDD, and LAD within 6 months had similar effects on adverse outcomes in both diabetic and nondiabetic patients. However, the presence of diabetes significantly modified the association between changes in NT-proBNP and QRS duration and adverse outcomes. Short-term changes in NT-proBNP and QRS duration were positively associated with all-cause mortality and HF hospitalization in patients without diabetes. However, the relationship between short-term changes in NT-proBNP and QRS duration and adverse outcomes was non-linear in diabetic patients. Conclusion: Improvement of cardiac function after CRT implantation can reduce long-term risk of all-cause mortality and HF hospitalization in HF patients. However, the presence of diabetes may affect the association between short-term changes in NT-proBNP and QRS duration and adverse outcomes.

Metabolomics Profiling Predicts Ventricular Arrhythmia in Patients with an Implantable Cardioverter Defibrillator.

Implantable cardioverter defibrillators (ICDs) reduce sudden cardiac death (SCD) when patients experience life-threatening ventricular arrhythmias (LTVA). However, current strategies determining ICD patient selection and risk stratification are inefficient. We used metabolomics to assess whether dysregulated metabolites are associated with LTVA and identify potential biomarkers. Baseline plasma samples were collected from 72 patients receiving ICDs. Over a median follow-up of 524.0 days (range 239.0-705.5), LTVA occurred in 23 (31.9%) patients (22 effective ICD treatments and 1 SCD). After confounding risk factors adjustment for age, smoking, secondary prevention, and creatine kinase MB, 23 metabolites were significantly associated with LTVA. Pathway analysis revealed LTVA associations with disrupted metabolism of glycine, serine, threonine, and branched chain amino acids. Pathway enrichment analysis identified a panel of 6 metabolites that potentially predicted LTVA, with an area under the receiver operating characteristic curve of 0.8. Future studies are necessary on biological mechanisms and potential clinical use.

Construction and evaluation of a novel multi-antigenic Mycobacterium tuberculosis subunit vaccine candidate BfrB-GrpE/DPC.

Tuberculosis poses a significant threat to human health due to the lack of an effective vaccine. Although promising progress has been made in the development of tuberculosis vaccines, new vaccines that broaden the antigenic repertoire need to be developed to eradicate this illness. In this study, we used Mycobacterium tuberculosis ferritin BfrB and heat-shock protein GrpE to construct a novel multi-antigenic fusion protein, BfrB-GrpE (BG). BG protein was stably overexpressed in the soluble form in Escherichia coli at a high yield and purified via sequential salt fractionation and hydrophobic chromatography. Purified BG was emulsified in an adjuvant containing N, N'-dimethyl-N, N'-dioctadecylammonium bromide, polyinosinic-polycytidylic acid, and cholesterol (DPC) to construct the BG/DPC vaccine, which stimulated strong cellular and humoral immune responses in mice. Moreover, combination of BG with our previously developed vaccine, Mtb10.4-HspX (MH), containing antigens from both the proliferating and dormant stages, significantly reduced the bacterial counts in the lungs and spleens of M. tuberculosis-infected mice. Importantly, mice that received BG + MH/DPC after M. tuberculosis H37Rv infection survived slightly better (100% survival) than those that received the BCG vaccine (80% survival), although the difference was not statistically significant. Our findings can aid in the selection of antigens and optimization of vaccination regimens to improve the efficacy of tuberculosis vaccines.

Joint association of sedentary behavior and vitamin D status with mortality among cancer survivors.

BACKGROUND: Sedentary behavior and vitamin D deficiency are independent risk factors for mortality in cancer survivors, but their joint association with mortality has not been investigated. METHODS: We analyzed data from 2914 cancer survivors who participated in the National Health and Nutrition Examination Survey (2007-2018) and followed up with them until December 31, 2019. Sedentary behavior was assessed by self-reported daily hours of sitting, and vitamin D status was measured by serum total 25-hydroxyvitamin D (25(OH)D) levels. RESULTS: Among 2914 cancer survivors, vitamin D deficiency was more prevalent in those with prolonged daily sitting time. During up to 13.2 years (median, 5.6 years) of follow-up, there were 676 deaths (cancer, 226; cardiovascular disease, 142; other causes, 308). The prolonged sitting time was associated with a higher risk of all-cause and noncancer mortality, and vitamin D deficiency was associated with a higher risk of all-cause and cancer mortality. Furthermore, cancer survivors with both prolonged sitting time (≥ 6 h/day) and vitamin D deficiency had a significantly higher risk of all-cause (HR, 2.05; 95% CI: 1.54-2.72), cancer (HR, 2.33; 95% CI, 1.47-3.70), and noncancer mortality (HR, 1.91; 95% CI, 1.33-2.74) than those with neither risk factor after adjustment for potential confounders. CONCLUSIONS: In a nationally representative sample of U.S. cancer survivors, the joint presence of sedentary behavior and vitamin D deficiency was significantly associated with an increased risk of all-cause and cancer-specific mortality.

High antipersister activity of a promising new quinolone drug candidate in eradicating uropathogenic Escherichia coli persisters and persistent infection in mice.

AIMS: To develop more potent drugs that eradicate persister bacteria and cure persistent urinary tract infections (rUTIs). METHODS AND RESULTS: We synthesized eight novel clinifloxacin analogs and measured minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the time-kill curves in uropathogenic Escherichia coli (UPEC) UTI89, and applied the candidate drugs and combinations against biofilm bacteria in vitro and in mice. Transcriptomic analysis was performed for UPEC after candidate drug treatment to shed light on potential mechanism of action. We identified Compound 2, named Qingdafloxacin (QDF), which was more potent than clinafloxacin and clinically used levofloxacin and moxifloxacin, with an MIC of < 0.04 µg ml-1 and an MBC of 0.08∼0.16 µg ml-1. In drug combination studies, QDF + gentamicin + nitrofuran combination but not single drugs completely eradicated all stationary phase bacteria containing persisters and biofilm bacteria, and all bacteria in a persistent UTI mouse model. Transcriptome analysis revealed that the unique antipersister activity of QDF was associated with downregulation of genes involved in bacterial stress response, DNA repair, protein misfolding repair, pyrimidine metabolism, glutamate, and glutathione metabolism, and efflux. CONCLUSIONS: QDF has high antipersister activity and its drug combinations proved highly effective against biofilm bacteria in vitro and persistent UTIs in mice, which may have implications for treating rUTIs.

Effectiveness of adding a defibrillator with cardiac resynchronization therapy in heart failure according to the modified Model for End-stage Liver Disease-Albumin score.

Current guidelines lack clear recommendations between the implantation of cardiac resynchronization therapy (CRT) with defibrillator (CRT-D) and CRT with pacemaker (CRT-P). We hypothesized that modified model for end-stage liver disease score including albumin (MELD-Albumin score), could be used to select patients who may not benefit from CRT-D. We consecutively included patients with CRT-P or CRT-D implantation between 2010 and 2022. The primary endpoint was the composite of all-cause mortality or worsening heart failure. We performed multivariable-adjusted Cox proportional hazard regression. We assessed the interaction between the MELD-Albumin score and the effect of adding a defibrillator with CRT.A total of 752 patients were included in this study, with 291 implanted CRT-P. During a median follow-up of 880 days, 205 patients reached the primary endpoint. MELD-Albumin score was significantly associated with the primary endpoint in the CRT-D group [HR 1.16 (1.09-1.24); P < 0.001] but not in the CRT-P group [HR 1.03 (0.95-1.12); P = 0.49]. There was a significant interaction between the MELD-Albumin score and the effect of CRTD (P = 0.013). The optimal cut-off value of the MELD-Albumin score was 12. For patients with MELD-Albumin ≥ 12, CRT-D was associated with a higher occurrence of the primary endpoint [HR 1.99 (1.10-3.58); P = 0.02], whereas not in patients with MELD-Albumin < 12 [HR 1.19 (0.83-1.70); P = 0.35). Our findings suggest that CRT-D is associated with an excess risk of composite clinical endpoints in HF patients with higher MELD-Albumin score.

Glutamate Transporters GltS, GltP and GltI Are Involved in Escherichia coli Tolerance In Vitro and Pathogenicity in Mouse Urinary Tract Infections.

To verify the roles of GltS, GltP, and GltI in E. coli tolerance and pathogenicity, we quantified and compared the relative abundance of gltS, gltP, and gltI in log-phase and stationary-phase E. coli and constructed their knockout mutant strains in E. coli BW25113 and uropathogenic E. coli (UPEC) separately, followed by analysis of their abilities to tolerate antibiotics and stressors, their capacity for adhesion to and invasion of human bladder epithelial cells, and their survival ability in mouse urinary tracts. Our results showed that gltS, gltP, and gltI transcripts were higher in stationary phase E. coli than in log-phase incubation. Furthermore, deletion of gltS, gltP, and gltI genes in E. coli BW25113 results in decreased tolerance to antibiotics (levofloxacin and ofloxacin) and stressors (acid pH, hyperosmosis, and heat), and loss of gltS, gltP, and gltI in uropathogenic E. coli UTI89 caused attenuated adhesion and invasion in human bladder epithelial cells and markedly reduced survival in mice. The results showed the important roles of the glutamate transporter genes gltI, gltP, and gltS in E. coli tolerance to antibiotics (levofloxacin and ofloxacin) and stressors (acid pH, hyperosmosis, and heat) in vitro and in pathogenicity in mouse urinary tracts and human bladder epithelial cells, as shown by reduced survival and colonization, which improves our understanding of the molecular mechanisms of bacterial tolerance and pathogenicity.

Effects of donepezil treatment on plasma and urine metabolites in amyloid beta-induced Alzheimer's disease rats.

Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the brain function and behavior of various central nervous system diseases such as Alzheimer's disease (AD). In this study, metabolic profiling was used to investigate changes in plasma and urine metabolites following stereotactic injection of amyloid ß (Aß) and treatment with donepezil in rats. Aß causes cognitive impairment, while donepezil treatment successfully improves memory impairment. Donepezil improves Aß-induced plasma fatty acid and bile acid metabolism disorders, as well as Aß-induced urine phenylalanine and tryptophan metabolism disorders in rats. More specifically, the plasma fatty acids improved by donepezil include alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, arachidonic acid, oleic acid, and palmitic acid, among others. Additionally, donepezil significantly restored the downregulation of bile acids such as ursodeoxycholic acid, cholic acid, and glycocholic acid caused by Aß. As for urine metabolites, phenylacetylglycine, epinephrine, and other phenylalanine metabolites, as well as kynurenic acid, xanthurenic acid, and other tryptophan metabolites, were worsened by Aß and improved by donepezil. These findings suggest that the cognitive impairment induced by Aß and the improvement by donepezil are associated with changes in metabolic disorders in rats. This study provides basic data for the effects of Aß and donepezil on plasma and urine metabolites in Aß-induced AD rat models.