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Early rhythm control therapy mainly with antiarrhythmic drugs (AADs) for new-onset atrial fibrillation (AF) reduces major adverse cardiovascular events. However, negative dromotropic effects of AADs via ion channel blocking may cause bradyarrhythmias. This study aimed to evaluate the association between AAD use and the risk of pacemaker implantation or syncope in patients with new-onset AF receiving early rhythm control therapy with AADs. This study was based on data from the Korean National Health Insurance Service system. We screened all new-onset AF diagnoses that occurred from 2013 to 2019 and identified patients who were prescribed AADs within 1 year of AF diagnosis. The risk of pacemaker implantation or syncope was compared between AAD users and nonusers. A total of 770,977 new-onset AF cases were identified and 142,141 patients were prescribed AADs. After multivariate adjustment, use of AADs was associated with 3.5-, 2.0-, and 5.0-fold increased risk of pacemaker implantation or syncope, syncope, and pacemaker implantation, respectively. Propensity score–matched analysis revealed similar results, demonstrating a significant association between AAD use and the risk of pacemaker implantation or syncope. This association was consistent across various subgroups. Women were more susceptible to adverse effects of AADs than men. This study showed an association between AADs and risk of pacemaker implantation or syncope, a consistent finding across various subgroups. Precise evaluation of such risk should be undertaken before prescription of AADs. [Display omitted] [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) contributes to cardiovascular events. Therefore, we aimed to identify the association of MASLD, as indicated by the fatty liver index (FLI), on sudden cardiac arrest (SCA) in young adults. We analyzed data from adults aged 20–39 years, who underwent health examinations between 2009 and 2012, sourced from the Korean National Health Insurance Service database. The presence of MASLD was determined using the FLI, which was calculated based on an individual's body mass index, waist circumference, gamma-glutamyl transferase and triglyceride levels. The primary outcome was the occurrence of SCA during the follow-up period, until December 2020. Of the total 5,398,082 individuals analyzed, 4,021,056 (74.5 %) had a normal FLI (FLI <30), 837,943 (15.5 %) were within the intermediate range (30–60), and 539,083 (10.0 %) demonstrated a high FLI (≥60). Individuals with a high FLI were older, and comprised a higher proportion of men with hypertension, diabetes mellitus, dyslipidemia, heart failure, and myocardial infarction. During follow-up, SCA occurred in 4255 individuals (0.08 %). The group with a high FLI exhibited an increased incidence (incidence rate, 0.19) and elevated risk of SCA (hazard ratio, 3.04). Adjustment of covariates revealed a 55 % increased risk of SCA in the high FLI group (adjusted hazard ratio 1.55, 95 % confidence interval 1.41–1.70, p < 0.001). Moreover, the influence of a high FLI on SCA risk was more pronounced in women compared to men. Additionally, an increase in relevant cardiometabolic conditions was associated with an elevated risk of SCA. Among young adults, a high risk of MASLD, as indicated by the FLI, revealed an increased risk of SCA. Furthermore, the association of FLI with the risk of SCA varied by sex and cardiometabolic conditions. Summary of the study MASLD, metabolic dysfunction-associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease; SCA, sudden cardiac arrest; FLI, fatty liver index; CI, confidence interval. [Display omitted] • High FLI was associated with an increased risk of SCA in young adults. • Increase in cardiometabolic burden progressively elevated the risk of SCA. • Sexual dimorphism was observed in the linkage of MASLD and SCA. [ABSTRACT FROM AUTHOR]

Background: Electrical isolation of the left atrial appendage (LAA) is associated with a lower rate of atrial fibrillation (AF) recurrence in patients undergoing radiofrequency catheter ablation. However, LAA isolation can significantly impair LAA contractility.Objective: This study was performed to evaluate whether electrical isolation of the LAA is associated with an increased risk of ischemic stroke or transient ischemic attack (TIA).Methods: Consecutive patients with AF undergoing radiofrequency catheter ablation at Korea University Medical Center Anam Hospital were analyzed.Results: Of 2352 patients, 39 (1.7%) had LAA isolation. Patients with LAA isolation had a significantly higher rate of ischemic stroke or TIA than did those without LAA isolation (log-rank, P < .001; hazard ratio 23.6; P < .001). There were significant differences in the baseline characteristics of the 2 groups, including type of AF (34 [87.2%] and 911 [39.4%] patients with and without LAA isolation had nonparoxysmal AF, respectively). After multivariate adjustment, LAA isolation was found to be a significant risk factor for ischemic stroke or TIA (adjusted hazard ratio 11.3; P < .001). Propensity score-matched analysis also revealed an increased risk of ischemic stroke or TIA in patients with LAA isolation compared with those without LAA isolation (log-rank, P = .001). The LAA flow velocity of post-LAA isolation status was not significantly different between patients who did and did not experience ischemic stroke or TIA (30.3 ± 17.7 cm/s vs 33.9 ± 17.9 cm/s; P = .608).Conclusion: A significantly increased risk of ischemic stroke or TIA was observed in patients with electrical isolation of the LAA. In addition, postisolation LAA flow velocity is not a reliable marker to predict future ischemic events. [ABSTRACT FROM AUTHOR]

Background: The electrophysiological features and roles of persistent left superior vena cava (PLSVC) in supraventricular tachycardia (SVT) are not known.Objective: The purpose of this study was to elucidate the electrophysiological features and roles of PLSVC in patients with SVT.Methods: We included 37 patients with PLSVC (mean age 43.5 ± 17.1 years; 35.1% men) and 510 patients without PLSVC (mean age 43.9 ± 18.8 years; 48.2% men) who underwent an electrophysiology study for SVT. The number of induced tachycardias, location of the slow pathway (SP) or accessory pathway (AP), and radiofrequency catheter ablation (RFCA) outcomes were compared between patients with and without PLSVC. During RFCA of the left AP, a coronary sinus (CS) catheter was placed into the left superior vena cava (left superior vena cava group) or the great cardiac vein (great cardiac vein group). The RFCA outcomes were compared between the groups.Results: In patients with PLSVC, 40 tachycardias were induced: atrioventricular nodal reentrant tachycardia (AVNRT) (n = 19), atrioventricular reentrant tachycardia (n = 17), and focal atrial tachycardia (n = 4). Among patients with AVNRT, an SP in the CS was significantly more frequent in patients with PLSVC than in those without PLSVC (47.4% vs 3.8%; P < .001). In patients with the left AP, the number of RFCA attempts and recurrence were lower in the great cardiac vein group than in the left superior vena cava group.Conclusion: An SP in the CS is prevalent in patients with AVNRT and PLSVC. It is useful to place a CS catheter into the great cardiac vein in patients with a left AP and PLSVC. [ABSTRACT FROM AUTHOR]

Background: VerifyNow P2Y12 assay is used widely to evaluate residual platelet reactivity in patients taking P2Y12 receptor antagonists. However, a laboratory association between VerifyNow P2Y12 reaction unit (PRU) and hemoglobin, which might lead to wrong interpretation of the data, is reported. We performed these systematic review and meta-analysis to clearly define the relationship between PRU and hemoglobin and to elucidate whether the relationship, if any, is a true biological association or is just a laboratory error.Methods: Through a comprehensive electronic and manual search, 10 studies were selected for the cohort level meta-analysis. Among 10 studies, we were able to retrieve the raw data of 5 studies, and a patient-level meta-analysis was performed. Potential publication bias was searched by funnel plot analysis and was actively adjusted, if present, by trim and fill method.Results: The pooled analysis revealed a significant inverse correlation between PRU and hemoglobin (r=-0.349; P<.001; 10 studies with 4,793 patients). VerifyNow P2Y12 base unit, which reflects off-drug platelet reactivity, was also inversely correlated with hemoglobin (r=-0.526; P<.001; 8 studies with 4,395 patients). % Inhibition (r=0.081; P=.059; 6 studies with 3,832 patients) and ΔPRU (r=-0.037; P=.188; 5 studies with 3,521 patients) were not associated with hemoglobin. A significant inverse association between PRU and hemoglobin was also observed in the patient-level meta-analysis (3,533 patients pooled from 5 studies; r=-0.335; P<.001). Light transmission aggregometry (r=0.160; P=.072; 4 studies with 1,144 patients) and multiple electrode platelet aggregometry (r=-0.029; P=.394; 3 studies with 7,645 patients) showed no significant association with hemoglobin.Conclusions: A significant inverse association was observed between PRU and hemoglobin which is likely to be a laboratory error. Clinicians should be aware that this association might lead to wrong interpretation of the data. [ABSTRACT FROM AUTHOR]

Objectives The authors performed this analysis to examine whether the enhanced clopidogrel responsiveness in current smokers is maintained after adjusting the influence of hemoglobin on VerifyNow P2Y12 reaction unit (PRU). Background PRU is consistently reported to be lower in current smokers. However, PRU has a significant inverse relationship with hemoglobin level, and smokers have higher hemoglobin levels. Because the association between PRU and hemoglobin is likely to be an in vitro phenomenon, we hypothesized that the observed difference in PRU between nonsmokers and current smokers is the result of confounding effect of hemoglobin rather than true difference in platelet reactivity. Methods Three cohorts were combined for the analysis (SNUBH [Seoul National University Bundang Hospital], n = 459; CILON-T [influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation], n = 715; HOST-ASSURE [Harmonizing Optimal Strategy for Treatment of coronary artery stenosis – sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen], n = 1,357). The final combined cohort consisted of 1,314 patients who underwent percutaneous coronary intervention and had VerifyNow P2Y12 assay results. General linear model (analysis of covariance) was used to control the effect of hemoglobin on PRU. Results A significant inverse correlation was observed between PRU and hemoglobin ( r = -0.389; p < 0.001). Current smokers showed a significantly higher hemoglobin level (13.5 ± 1.6 vs. 14.4 ± 1.5; p < 0.001) but lower PRU level (230.1 ± 90.7 vs. 212.2 ± 83.6; p < 0.001). After adjusting the influence of hemoglobin on PRU, there was no difference in PRU between nonsmokers and current smokers (224.1 [95% confidence interval: 218.7 to 229.5] vs. 225.3 [95% confidence interval: 217.2 to 233.3]; p = 0.813). Conclusions The observed difference in PRU between nonsmokers and current smokers is largely attributable to the difference in hemoglobin level. Enhanced clopidogrel responsiveness in cigarette smokers is not confirmed in this study and the concept of the smokers’ paradox needs further validation. [ABSTRACT FROM AUTHOR]

Clostridioides difficile causes nosocomial antibiotic-associated diarrhea on a global scale. Susceptibility to C. difficile infection (CDI) is influenced by the composition and metabolism of gut microbiota, which in turn are affected by diet. However, the mechanism underlying the interplay between diet and gut microbiota that modulates susceptibility to CDI remains unclear. Here, we show that a soy protein diet increases the mortality of antibiotic-treated, C. difficile -infected mice while also enhancing the intestinal levels of amino acids (aas) and relative abundance of Lactobacillus genus. Indeed, Ligilactobacillus murinus -mediated fermentation of soy protein results in the generation of aas, thereby promoting C. difficile growth, and the process involves the anchored cell wall proteinase PrtP. Thus, mutual interaction between dietary protein and the gut microbiota is a critical factor affecting host susceptibility to CDI, suggesting that dietary protein sources can be an important determinant in controlling the disease. [Display omitted] • A soy protein diet increases the susceptibility to C. difficile infection • A soy protein diet increases the gut amino acids, which promote C. difficile growth • A soy protein diet enhances the relative abundance of Lactobacillus genus • Lactobacillus supplies gut amino acids by digestion of soy protein Susceptibility to Clostridioides difficile infection is influenced by gut microbiota and diet. Yakabe et al. demonstrate that soy protein promotes the growth of C. difficile by enhancing the intestinal levels of amino acids (aas). Furthermore, soy protein enhances the relative abundance of Lactobacillus , which digests soy protein to generate aas. [ABSTRACT FROM AUTHOR]

Gut microbiota act beyond the gastrointestinal tract to regulate the physiology of the host. However, their contribution to the antioxidant capacity of the host remains largely understudied. In this study, we observe that gut bacteria increase the steady-state plasma levels of high-antioxidant molecules, reactive sulfur species (RSS), such as hydrogen sulfide and cysteine persulfide (CysSSH), in the host. Moreover, gut bacteria utilize cystine as a substrate to enzymatically produce CysSSH. Administration of cystine to mice increases their plasma levels of RSS and suppresses the concanavalin-A-induced oxidative stress and liver damage in a gut-microbiota-dependent manner. We find that gut bacteria belonging to the Lachnospiraceae and Ruminococcaceae families have a high capacity to produce RSS, requiring pyridoxal 5′-phosphate for their enzymatic reactions. Collectively, our data demonstrate that gut microbiota enhance the antioxidant capacity of the host through the generation of RSS. [Display omitted] • Gut microbiota increase the levels of reactive sulfur species in the host • Gut bacteria utilize cystine as a substrate to produce cysteine persulfide • Reactive sulfur species levels are increased in mice given cystine via gut microbiota • Administration of cystine to mice suppresses concanavalin-A-induced oxidative stress Host physiology is regulated by the gut microbiota. Uchiyama et al. demonstrate that gut bacteria increase an antioxidant reactive sulfur species in the host and they contribute to suppression of oxidative stress. Gut bacteria belonging to the Lachnospiraceae and Ruminococcaceae families have a high capacity to produce reactive sulfur species. [ABSTRACT FROM AUTHOR]

Abstract: Probiotic bacteria are microorganisms that benefit the host through improvement of the balance of intestinal microflora and possibly by augmentation of host defense systems. We examined the mechanisms for the up-regulation of innate immune responses by a probiotic Lactobacillus casei ATCC27139, in vivo. Using mouse models of systemic Listeria monocytogenes infection and MethA fibrosarcoma tumorigenesis in combination with BALB/c and SCID mice, we found that parenteral administration of L. casei ATCC27139 confers a protective effect against L. monocytogenes infection and anti-tumor activity against MethA fibrosarcoma by activation of innate immunity, while L. casei ATCC27139-J1R strains, which are J1 phage-resistant strains that have been selected from MNNG-treated clones, lacked these activities. Substantial differences between ATCC27139 and ATCC27139-J1R strains were observed in the capacity to induce innate cytokines such as TNF-α, IL-12, IL-18, and IFN-γ, and pathogen-associated molecular pattern receptors, TLR2 and Nod2, by spleen cells. In addition, although phosphorylation of NF-κB p65 in spleen was equally enhanced in the ATCC27139- and the ATCC27139-J1R-treated groups, phosphorylation of both p38 MAPK and MAPKAPK-2 was significantly induced only by ATCC27139. Furthermore, inhibitors of NF-κB (sulfasalazine) and p38 MAPK (SB203580) significantly reduced cytokine production by the spleen cells of the mice treated with L. casei ATCC27139, suggesting that both NF-κB and p38 MAPK signaling pathways play important roles in the augmentation of innate immunity by the probiotic L. casei. [Copyright &y& Elsevier]

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) (nucleotide-binding domain leucine-rich repeat containing) family of proteins has been demonstrated to function as regulators of innate immune response against microbial pathogens. Stimulation of NOD1 and NOD2, two prototypic NLRs, results in the activation of MAPK and NF-κB. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of an inflammasome. This review discusses recent findings regarding the signaling pathways utilized by NLR proteins in the control of caspase-1 and NF-κB activation, as well as the nonredundant role of NLRs in pathogen clearance. The review also covers advances regarding the cellular localization of these proteins and the implications this may have on pathogen sensing and signal transduction. [Copyright &y& Elsevier]

Methylmercury (MeHg) is a prevalent toxic metal that readily modifies protein thiols. Reactive persulfides that play a role in redox homeostasis are able to inactivate this metal through sulfur adduct formation. Although humans are exposed to other metals that could consume reactive persulfides on a daily basis, the health effects of combined exposure to MeHg and other metals remain unexplored. This study aimed to examine potential MeHg toxicity during exposure to MeHg with other metals capable of consuming reactive persulfides. We designed a simple system to assess the risk of combined exposure to metals based on reactivity to reactive persulfides and mercury accumulation. Among the metals examined in a cell-free system, copper, cadmium, nickel, and MeHg consumed Na 2 S 2 , used as a model of reactive persulfides, whereas zinc, iron, lithium, strontium, tin, and aluminum did not. In HepG2 cells, binary exposure to MeHg and copper, but not aluminum, increased the consumption of extracellular reactive persulfides. Binary exposure exacerbated MeHg-induced cytotoxicity by promoting the modification of intracellular proteins by MeHg. In a mouse model, binary exposure to MeHg and copper resulted in elevated mercury accumulation in the fetuses and placenta of pregnant mice, as well as the brain and liver of non-pregnant mice. Our study suggests that MeHg sensitivity can be increased by combined exposure with other electrophilic metals. In particular, binary exposure to MeHg and copper during pregnancy exacerbated mercury accumulation in offspring. [Display omitted] • Combined exposure to methylmercury with other metals was assessed in vitro and in vivo. • Na 2 S 2 was consumed by several metals, including methylmercury and copper. • Copper potentiated methylmercury-induced Hg accumulation and its cytotoxicity. • Binary exposure to methylmercury and copper enhanced Hg accumulation in vivo. [ABSTRACT FROM AUTHOR]

Highlights: [•] Trapezoidal metal with high aspect ratio and dense pitch was formed. [•] Trapezoidal metal reduced optical shadowing and electrical resistive losses. [•] Ion implantation was used for the front junction, contact and back surface field. [•] Selective front base contact was formed by self-aligned spacer technology. [•] Low resistive metal silicide contact was formed to reduce series resistance. [Copyright &y& Elsevier]

The identification of several families of innate pattern recognition receptors has greatly enhanced our understanding of the host innate immune response against a variety of pathogens. One such family of innate receptors is the nucleotide-binding domain and leucine rich repeat containing receptors (NLRs). NOD2 has been characterized as a cytosolic sensor of bacteria peptidoglycan (PGN). For almost 10 years, NOD2 was assigned with the function of mediating the RICK- and nuclear factor-κB induced proinflammatory response triggered by PGN. Recent studies have extended the biological activity of NOD2 to include the induction of autophagy and antiviral responses, as well as mediating direct T cell activation. Here, we highlight and discuss these new findings in the context of immune activation and pathogen detection. [Copyright &y& Elsevier]