Salmonella Typhimurium exploits host polyamines for assembly of the type 3 secretion machinery.

Bacterial pathogens utilize the factors of their hosts to infect them, but which factors they exploit remain poorly defined. Here, we show that a pathogenic Salmonella enterica serovar Typhimurium (STm) exploits host polyamines for the functional expression of virulence factors. An STm mutant strain lacking principal genes required for polyamine synthesis and transport exhibited impaired infectivity in mice. A polyamine uptake-impaired strain of STm was unable to inject effectors of the type 3 secretion system into host cells due to a failure of needle assembly. STm infection stimulated host polyamine production by increasing arginase expression. The decline in polyamine levels caused by difluoromethylornithine, which inhibits host polyamine production, attenuated STm colonization, whereas polyamine supplementation augmented STm pathogenesis. Our work reveals that host polyamines are a key factor promoting STm infection, and therefore a promising therapeutic target for bacterial infection.

Atrial fibrillation and risk of sudden cardiac arrest in young adults.

AIMS: Evidence of an association between atrial fibrillation (AF) and sudden cardiac arrest (SCA) in young adults is limited. In this study, we aim to evaluate this association in a general population aged between 20 and 39 years. METHODS AND RESULTS: Young adults who underwent health check-ups between 2009 and 2012 were screened from a nationwide healthcare database in South Korea. A history of AF diagnosis before the health check-ups was identified based on the relevant International Classification of Diseases, 10th edition codes reported in the database. Associations between an established diagnosis of AF and the risk of SCA during follow-up were examined. A total of 6 345 162 young people were analysed with a mean follow-up duration of 9.4 years. The mean age was 30.9 ± 5.0 years, and 5875 (0.09%) individuals were diagnosed with AF. During follow-up, SCA occurred in 5352 (0.08%) individuals, and the crude incidence was 0.56 and 0.09 events per 1000 person-years for participants with and without AF, respectively. Individuals with AF had a 3.0-fold higher risk in a multivariate model adjusted for age, sex, lifestyle, anthropometric data, and medical comorbidities (adjusted hazard ratio 2.96, 95% confidence interval 1.99-4.41, P < 0.001). Both incident and prevalent AFs were associated with an increased risk of SCA, with no significant differences between the two groups. CONCLUSION: Atrial fibrillation was associated with a significantly higher risk of SCA developing in healthy young adults. Whether the rate or rhythm control influences the risk of SCA in young patients with AF remains to be examined.

Association of fatty liver index with sudden cardiac arrest in young adults.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Sufficient water intake maintains the gut microbiota and immune homeostasis and promotes pathogen elimination.

Water is the most abundant substance in the human body and plays a pivotal role in various bodily functions. While underhydration is associated with the incidence of certain diseases, the specific role of water in gut function remains largely unexplored. Here, we show that water restriction disrupts gut homeostasis, which is accompanied by a bloom of gut microbes and decreased numbers of immune cells, especially Th17 cells, within the colon. These microbial and immunological changes in the gut are associated with an impaired ability to eliminate the enteric pathogen Citrobacter rodentium. Moreover, aquaporin 3, a water channel protein, is required for the maintenance of Th17 cell function and differentiation. Taken together, adequate water intake is critical for maintaining bacterial and immunological homeostasis in the gut, thereby enhancing host defenses against enteric pathogens.

Association of Antiarrhythmic Drug Therapy With Syncope and Pacemaker Implantation in Patients With Atrial Fibrillation.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Alcohol and the risk of all-cause death, atrial fibrillation, ventricular arrhythmia, and sudden cardiac arrest.

The risk of having atrial fibrillation (AF) is associated with alcohol intake. However, it is not clear whether sudden cardiac arrest (SCA) and ventricular arrhythmia (VA) including ventricular tachycardia, flutter, or fibrillation have similar associations with alcohol. We aimed to evaluate the association of alcohol intake with all-cause death, new-onset AF, VA, and SCA using single cohort with a sufficient sample size. A total of 3,990,373 people without a prior history of AF, VAs, or SCA was enrolled in this study based on nationwide health check-up in 2009. We classified the participants into four groups according to weekly alcohol consumption, and evaluated the association of alcohol consumption with each outcome. We observed a significant association between mild (hazard ratio [HR] = 0.826; 95% confidence interval [CI] = 0.815-0.838) to moderate (HR = 0.930; 95% CI = 0.912-0.947) drinking with decreased risk of all-cause mortality. However heavy drinking (HR = 1.108; 95% CI = 1.087-1.129) was associated with increased all-cause death. The risk of new-onset AF was significantly associated with moderate (HR = 1.129; 95% CI = 1.097-1.161) and heavy (HR = 1.298; 95% CI = 1.261-1.337) drinking. However, the risk of SCA showed negative association with all degrees of alcohol intake: 20% (HR = 0.803; 95% CI = 0.769-0.839), 15% (HR = 0.853; 95% CI = 0.806-0.902), and 8% (HR = 0.918; 95% CI = 0.866-0.974) lower risk for mild, moderate, and heavy drinkers, respectively. Mild drinking was associated with reduced risk of VA with moderate and heavy drinking having no associations. In conclusion, the association between alcohol and various outcomes in this study were heterogeneous. Alcohol might have different influences on various cardiac disorders.

Association of temporal change in body mass index with sudden cardiac arrest in diabetes mellitus.

BACKGROUND: Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus. METHODS: Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005-2008) were retrospectively analyzed. BMI was measured at baseline (2005-2008) and 4-year follow-up health examination (2009-2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA. RESULTS: A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval [2.25-3.00], sustained non-underweight as a reference), followed by newly developed underweight (2.42, [2.15-2.74]), and previous underweight (2.12, [1.77-2.53]). CONCLUSIONS: In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA.

[Supersulfides to Regulate Electrophilic Stress].

Environmental electrophiles modify thiol groups of proteins in organs, disrupting cellular functions carried out by the modified proteins and increasing the risk of various diseases. The transcription factor NF-E2-related factor 2 (Nrf2) plays a crucial role in detoxifying electrophiles by forming glutathione adducts and subsequently excreting them into extracellular spaces. Supersulfides such as cysteine persulfides (CysSSH) produced by cystathionine γ-lyase (CSE) capture environmental electrophiles through sulfur adduct formation. However, the Nrf2 and CSE contributions to blocking environmental electrophile-mediated toxicity have yet to be evaluated. Therefore, we assessed the individual and combined roles of Nrf2 and CSE in suppressing toxicity induced by environmental electrophiles using Nrf2 knockout (KO), CSE KO, and Nrf2/CSE double KO (DKO) mice. Our findings indicate that CSE/Nrf2 DKO mice are more sensitive to environmental electrophiles compared to their single KO counterparts, highlighting the distinct mechanisms through which both pathways mitigate the toxic effects of reactive electrophiles. Moreover, diverse metabolites produced by symbiotic gut bacteria in the human body are known to exert various effects on host organ functions beyond the intestinal tract. We observed reduced blood supersulfide levels in mice lacking gut microflora compared to normal mice. Furthermore, we identified intestinal bacteria belonging to the families Ruminococcaceae and Lachnospiraceae as high CysSSH-producing bacteria. This suggests that the gut microbiota serves as a source of in vivo supersulfide molecules. These findings suggest that supersulfide derived from gut bacteria may act protectively against environmental electrophilic exposure in the host.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Temporal elevation of blood pressure is associated with increased risk of sudden cardiac arrest.

Hypertension is a known risk factor for sudden cardiac arrest (SCA). However, the role of temporal changes in blood pressure on the risk of SCA is not fully understood. This study was conducted to determine whether a temporal increase or decrease in blood pressure is associated with the risk of SCA. This study was based on nationwide healthcare insurance data. Individuals who underwent nationwide health check-ups in 2009 and 2011 were analyzed. A total of 2,801,153 individuals were evaluated for 8100 SCA events during the 17, 740, 420 person-years of follow-up. In a multivariate analysis, there were linear association between the degree of temporal elevation of systolic blood pressure (SBP) and the risk of SCA: (i) adjusted-hazard ratio (HR) 1.11 (p = 0.001) in 10 ≤ ΔSBP < 20 (mmHg) group; (ii) adjusted-HR 1.40 (p < 0.001) in 20 ≤ ΔSBP < 40 group; and (iii) adjusted-HR 1.88 (p < 0.001) in 40 ≤ ΔSBP group as compared with the reference group (- 10 ≤ ΔSBP < 10). Temporal increase in diastolic blood pressure (DBP) also a showed significant association with SCA risk with the highest risk observed in ∆DBP ≥ 25 group (adjusted-HR 1.61; p < 0.001) as compared with the reference group (- 5 ≤ ΔDBP < 5). The association between SBP and SCA was not affected by age, sex, presence of diabetes mellitus, or baseline SBP. In conclusion, a temporal increase in blood pressure was significantly associated with the occurrence of SCA, and this association was consistent across all subgroups. However, a temporary decrease in blood pressure does not reduce the risk of SCA. Prevention of elevated blood pressure may play an important role in preventing SCA.

Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19.

Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

Association of typical atrial flutter and cavotricuspid isthmus ablation on clinical recurrence after cryoballoon ablation for atrial fibrillation.

Typical atrial flutter commonly occurs in patients with atrial fibrillation (AF). Limited information exists regarding the effects of concurrent atrial flutter on the long-term outcomes of rhythm control. This study investigated the association between concurrent typical atrial flutter and cavotricuspid isthmus (CTI) ablation and the recurrence of atrial arrhythmia. The data were obtained from a multicenter registry of cryoballoon ablation for AF (n = 2,689). Patients who were screened for typical atrial flutter were included in the analysis (n = 1,907). All the patients with typical atrial flutter underwent CTI ablation. The primary endpoint was the late recurrence of atrial arrhythmia, including AF, atrial flutter, and atrial tachycardia. Among the 1,907 patients, typical atrial flutter was detected in 493 patients (25.9%). Patients with concurrent atrial flutter had a lower incidence of persistent AF and a smaller size of the left atrium. Patients with atrial flutter had a significantly lower recurrence rate of atrial arrhythmia (19.7% vs. 29.9%, p < 0.001). In patients with atrial flutter, the recurrence rate of atrial tachycardia or atrial flutter was more frequent (7.3% vs. 4.7%, p = 0.028), but the recurrence rate of AF was significantly lower (17.0% vs. 29.4%, p < 0.001). Atrial flutter has been identified as an independent predictor of the primary endpoint (adjusted hazard ratio, 0.704; 95% confidence interval, 0.548-0.906; p = 0.006). Typical atrial flutter in patients with AF may serve as a positive marker of the recurrence of atrial arrhythmia, and performing CTI ablation in this population is associated with a reduced likelihood of AF recurrence. Performing routine screening and ablation procedures for coexisting atrial flutter may improve the clinical outcomes of AF.