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Abstract Background Gonorrhea, induced by Neisseria gonorrhoeae infection, stands as a prevalent sexually transmitted inflammatory disease globally. Our earlier research illuminated that N. gonorrhoeae-infected macrophages provoke inflammation by activating the intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, a pivotal regulator in inflammatory diseases governing the maturation and secretion of interleukin (IL)-1β and IL-18. Nevertheless, effective therapies addressing N. gonorrhoeae-mediated NLRP3 inflammasome activation and ensuing inflammation are currently lacking. This study delves into the impact of the angiotensin II receptor antagonist Candesartan (CS) on N. gonorrhoeae-infected macrophages. Methods The protein expression levels were examined through ELISA and Western blotting. Intracellular H2O2 levels, mitochondrial reactive oxygen species, and mitochondrial membrane integrity were evaluated using targeted fluorescent probes and analyzed via flow cytometry. NF-κB transcriptional activity was assessed using NF-κB reporter cells. LC3-knockdown cells were created using CRISPR/Cas9 technology. Results CS effectively inhibits the NLRP3 inflammasome, as indicated by the suppression of caspase-1 activation, IL-1β secretion, NLRP3 release, and the release of apoptosis-associated speck-like protein containing a CARD (ASC) in N. gonorrhoeae-infected J774A.1 macrophages. Additionally, CS selectively impedes IL-6 secretion and iNOS expression in both N. gonorrhoeae-infected J774A.1 and RAW264.7 macrophages. Mechanistic insights uncover the inhibition of NF-κB by CS in N. gonorrhoeae-infected J774A.1 macrophages, while intracellular H2O2 generation, mitogen-activated protein kinases phosphorylation, and mitochondrial damage remain unaffected. Notably, our study highlights that CS-induced autophagy contributes partially to its inhibitory effect on the NLRP3 inflammasome. Conclusions These results underscore the potential of CS as an anti-inflammatory drug for the treatment of gonorrhea, addressing a critical unmet medical need in combating N. gonorrhoeae-induced inflammation.

Abstract Background Worldwide, more than 125 million people are infected with Shigella each year and develop shigellosis. In our previous study, we provided evidence that Shigella sonnei infection triggers activation of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome in macrophages. NLRP3 inflammasome is responsible for regulating the release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 through the protease caspase-1. Researchers and biotech companies have shown great interest in developing inhibitors of the NLRP3 inflammasome, recognizing it as a promising therapeutic target for several diseases. The leaves of Cinnamomum osmophloeum kaneh, an indigenous tree species in Taiwan, are rich in cinnamaldehyde (CA), a compound present in significant amounts. Our aim is to investigate how CA affects the activation of the NLRP3 inflammasome in S. sonnei-infected macrophages. Methods Macrophages were infected with S. sonnei, with or without CA. ELISA and Western blotting were employed to detect protein expression or phosphorylation levels. Flow cytometry was utilized to assess H2O2 production and mitochondrial damage. Fluorescent microscopy was used to detect cathepsin B activity and mitochondrial ROS production. Additionally, colony-forming units were employed to measure macrophage phagocytosis and bactericidal activity. Results CA inhibited the NLRP3 inflammasome in S. sonnei-infected macrophages by suppressing caspase-1 activation and reducing IL-1β and IL-18 expression. CA also inhibited pyroptosis by decreasing caspase-11 and Gasdermin D activation. Mechanistically, CA reduced lysosomal damage and enhanced autophagy, while leaving mitochondrial damage, mitogen-activated protein kinase phosphorylation, and NF-κB activation unaffected. Furthermore, CA significantly boosted phagocytosis and the bactericidal activity of macrophages against S. sonnei, while reducing secretion of IL-6 and tumour necrosis factor following infection. Conclusion CA shows promise as a nutraceutical for mitigating S. sonnei infection by diminishing inflammation and enhancing phagocytosis and the bactericidal activity of macrophages against S. sonnei.

Abstract Police officers often face emotionally challenging interpersonal situations and numerous studies have demonstrated that policing is a stressful occupation. A study revealed a significant positive correlation between emotional demands among police officers and emotional dissonance, as well as burnout. Health-promoting behaviors can contribute to better overall health outcomes and reduce the risk of developing health problems, but there is limited research evaluating the association of job strain and health behaviors with mental health outcomes in police officers. The objective of this study was to assess the job strain associated with mental health mediated by health behaviors in Taiwanese police officers. This was a cross-sectional quantitative study conducted in Oct 2016. A total of 41,871 police officers (response rate was 79.7%) participated questionnaire that consisted of demographic information, job characteristics, health behaviors, and mental component summary (MCS) scores of the Short-Form Health Survey. Independent t-tests and one-way analysis of variance (One-way ANOVA) were conducted to assess the differences in mean MCS scores across various demographics, health behavior, and job characteristics. Multivariate regression analyses were used to assess the relationship between job strain and health behaviors with mental health outcomes. MCS scores were associated with job characteristics and health behaviors among police officers except for gender. After adjusting for covariates, multivariate analysis indicated that police officers with high job demands and high job strain index exhibited poor MCS scores. Job strain was significantly associated with MCS mediated by health behaviors (consumption of fruits and vegetables, and physical activity) in Taiwanese police officers. Since regular physical activity and increased vegetable and fruit consumption might alleviate the effects of job strain on mental health status, it is recommended that institutional policies be established to promote health-enhancing behaviors among police officers.

Abstract Background/Objective Limited evidence exists regarding the socioeconomic inequalities in cerebrovascular disease (CBD) mortality at different urbanization levels. Therefore, this study was conducted to assess the socioeconomic inequalities and urbanization levels in township-based CBD mortality in Taiwan. Methods Socioeconomic variables, including the percentages of low-income households, individuals with a university education and above, and tax payments, were measured at the township level from 2011 to 2020. Urbanization was also determined by the national survey and divided into seven levels. Age-standardized mortality rate (ASMR) of CBD was calculated using a Geographic Information System (GIS) in 358 townships. The effects of socioeconomic variables and urbanization levels on relative and absolute inequalities in township-based CBD mortality rates were examined. Results Significant differences in ASMR of CBD were observed across all socioeconomic status indicators over the years. Higher proportions of low-income households were associated with higher ASMR of CBD. Conversely, there were negative correlations between higher proportions of individuals with a university education and above and tax payments with ASMR of CBD. The regression analysis indicated significant impacts of relative and absolute socioeconomic inequalities on ASMR of CBD. Additionally, a moderation effect of socioeconomic variables and urbanization on CBD mortality rates was observed, with rural areas showing sensitivity to these factors. Conclusion Although ASMR of CBD showed significant decreases over time, socioeconomic inequalities in CBD mortality rates persist. Interventions targeting socioeconomic inequalities in health outcomes, especially in rural areas, are needed to address this issue.

With rapid urbanization in Taiwan, the green space has become a key factor in modifiable cardiovascular disease (CVD) risks. We investigated the relationships between socioeconomic status (SES), green space, and cerebrovascular disease (CBD) at the township level in Taiwan, focusing on urban–rural disparities. Analyzing data from 358 townships (2011–2020), we examined SES indicators (e.g., low-income households, education levels, median tax payments), green space (Normalized Difference Vegetation Index—NDVI), and CBD mortality rates using the pooled ordinary least squares (OLS) and random-effect models (REM) in panel regression. Additionally, we explored the mediating role of the NDVI in the SES-CBD mortality association. CBD mortality decreased more in urban areas over the decade, with consistent NDVI patterns across regions. Rural areas experienced a decline in low-income households, contrasting with an increase in urban areas. SES variables, NDVI, and time significantly affected CBD mortality in rural areas but not urban ones. Notably, the NDVI had a stronger impact on CBD mortality in rural areas. Mediation analysis revealed the NDVI’s indirect effects, especially in rural areas. Despite overall declines in CBD mortality in Taiwan, urban–rural disparities in SES and green space persist. Addressing these disparities is critical for understanding and developing interventions to mitigate health inequalities.

Background: Coronary artery calcification (CAC) is a well-validated parameter reflecting the extent of subclinical atherosclerosis. Atherosclerosis manifestations are commonly presented in atrial fibrillation (AF) patients. Nevertheless, the long-term cardiovascular risks in AF patients with concomitant CAC are limited. Aim: The aim of this study is to identify the prognostic impact of CAC in patients with AF. Methods: A total of 646 eligible patients who underwent noncontrast coronary computed tomography (nCCT) from January 2012 to December 2018 were evaluated and retrospectively followed up for 2 years. The patients were assessed for cardiovascular outcomes, including nonfatal myocardial infarction, nonfatal stroke, late coronary revascularization, major adverse cardiovascular event (MACE), and total coronary and total composite events, by a multivariable Cox regression hazards model with adjusting for significant confounding factors. Results: AF patients with severe CAC (CAC score [CACS] >400 Agatston units) had significantly higher risks of composite cardiovascular outcomes, including MACEs (adjusted hazard ratio [HR]: 57.18, 95% confidence interval [CI]: 2.28–1434.41, P = 0.014), total coronary events (adjusted HR: 16.48, 95% CI: 1.21–224.15, P = 0.035), and total composite events (adjusted HR: 26.35, 95% CI: 2.45–283.69, P = 0.007), than sinus rhythm patients without CAC. Moreover, severe CAC in AF patients was a significant predictor of total composite events (adjusted HR: 59.1, 95% CI: 2.16–1616.33, P = 0.016). Conclusion: Severe CAC in AF patients may cause significantly higher cardiovascular risks, highlighting the role of nCCT in determining CACs for early risk evaluation to facilitate aggressive risk modification and thereby to prevent subsequent cardiovascular events. Further, large, prospective studies are needed to validate the impact of CAC in patients with AF.

Abstract Aims Sacubitril/valsartan (SAC/VAL) has been used in patients with heart failure and reduced ejection fraction (HFrEF), and cardiac resynchronization therapy (CRT) could benefit the HFrEF patients with wide QRS durations. This study aimed to evaluate the clinical impacts of SAC/VAL on reverse cardiac remodelling in CRT‐eligible and CRT‐ineligible HFrEF patients with different QRS durations. Methods and results The TAROT‐HF study was a multicentre, observational study enrolling patients who initiated SAC/VAL from 10 hospitals since 2017. Patients with baseline left ventricular ejection fraction (LVEF) ≤ 35% were classified into two groups: (i) Group 1: CRT‐eligible group, patients with left bundle branch block (LBBB) morphology plus QRS duration ≥130 ms or non‐LBBB morphology plus QRS duration ≥150 ms; and (ii) Group 2: CRT‐ineligible group. Propensity score matching was performed to adjust for confounders, and 1168 patients were analysed. Baseline characteristics were comparable between the two groups. The improvements in LVEF and left ventricular end‐systolic volume index (LVESVi) were more significant in Group 2 than in Group 1 after 1 year SAC/VAL treatment (LVEF: 8.4% ± 11.3% vs. 4.5% ± 8.1%, P

Abstract Background TGF-β superfamily signaling is indispensable for bone homeostasis. However, the global expression profiles of all the genes that make up this signaling module in bone and bone-related diseases have not yet been well characterized. Methods Transcriptomic datasets from human bone marrows, bone marrow-derived mesenchymal stem cells (MSCs) and MSCs of primary osteoporotic patients were used for expression profile analyses. Protein treatments, gene quantification, reporter assay and signaling dissection in MSC lines were used to clarify the interactive regulations and feedback mechanisms between TGF-β superfamily ligands and antagonists. Ingenuity Pathway Analysis was used for network construction. Results We identified TGFB1 in the ligand group that carries out SMAD2/3 signaling and BMP8A, BMP8B and BMP2 in the ligand group that conducts SMAD1/5/8 signaling have relatively high expression levels in normal bone marrows and MSCs. Among 16 antagonist genes, the dominantly expressed TGF-β superfamily ligands induced only NOG, GREM1 and GREM2 via different SMAD pathways in MSCs. These induced antagonist proteins further showed distinct antagonisms to the treated ligands and thus would make up complicated negative feedback networks in bone. We further identified TGF-β superfamily signaling is enriched in MSCs of primary osteoporosis. Enhanced expression of the genes mediating TGF-β-mediated SMAD3 signaling and the genes encoding TGF-β superfamily antagonists served as significant features to osteoporosis. Conclusion Our data for the first time unveiled the transcription landscape of all the genes that make up TGF-β superfamily signaling module in bone. The feedback mechanisms and regulatory network prediction of antagonists provided novel hints to treat osteoporosis. Video Abstract

Abstract Background Since the policy of “keeping trash off of the ground” in Taiwan, long-term exposure to repetitive motion in waste collection process results in high risk of upper extremity musculoskeletal disorders (UEMDs). Thus, we assessed the moderation and mediation effects of job-related stress and job support on work-related UEMDs among municipal waste collectors. Methods A cross-sectional study was conducted in two cities located at northern Taiwan during 2018–2019. 626 municipal waste collectors voluntarily participated and anonymously filled out a structured questionnaire. The moderation and mediation effects of effort-reward imbalance (ERI) and social support on UEMDs were analyzed by Haye’s Process Macro Model. Results Prevalence of UEMDs in municipal waste collectors were 43.4% for neck, 56.0% for shoulder, 24.1% for upper back, and 33.1% for hand/wrist. There was high prevalence of shoulder (72.2%), neck (48%), and upper back (30%) in female workers compared to male, most significantly in shoulders. In univariate and multivariate analysis, high ERI and low job support were significantly associated with ORs of 3.11 (95% CI:1.58–6.13) for elbow, 2.79 (95% CI:1.39–5.56) for shoulder, 3.39 (95% CI:1.64–7.00) for upper back and 3.83 (95% CI:1.98–7.41) for hand/wrist. Prevalent UEMDs were positively associated with high ERI in municipal waste collectors but negatively with job support. The moderation effects of ERI and job support on UEMDs, of which the measured synergy index exceeded one, were 18.24 for shoulder, 3.32 for elbow, and 2.45 for hand/wrist, but mediation effects were not significant. Conclusions This study found municipal waste collectors with work-related upper extremity disorders were significantly associated with work-related psychological risk factors. Therefore, waste collection cannot only to be improved by semi-automatic and automatic processes but immediate intervention programs for the reduction of psychological risk factors is needed promptly.

Objectives Work-related stress (WRS) is significantly associated with health-related quality of life (HRQoL), but the amounts of evidence on differences of effort-reward imbalance (ERI) and job strain index (JSI) remain sparse and have limited generalizability. Therefore, we aimed to assess the association between ERI and JSI with HRQoL and assess the mediation effect of social support (JS) and over-commitment (OC) on this association in Taiwan’s civil servants. Material and Methods A cross-sectional national survey was given to registered civil servants in Taiwan – 20 046 civil servants from 647 institutions were enrolled using multistage stratified random cluster sampling. A web-questionnaire collected demographic information, job characteristics, and different indexes of ERI and job-control-demand-support (JCDS) models. Structural equation model (SEM) was used to examine the association between ERI and JSI with HRQoL, and the mediation effect of JS and OC on the associations. Results In the ERI model, ERI and OC were consistently negatively associated with the mental component score (MCS) (r = –0.46 and r = –0.37) and physical component score (PCS) (r = –0.45 and r = –0.34), which were higher than job demand (r = –0.28 and r = –0.22) and JSI (r = –0.38 and r = –0.29). Using hierarchical multiple regression analyses, ERI was significantly correlated with MCS and PCS, which was consistently higher than JSI. The ERI and JSI were significantly correlated with MCS (β = –0.170 and β = –0.140) and PCS (β = –0.150 and β = –0.082) using SEM analysis, whereas ERI was considerably higher than in JSI. In addition, OC and JS mediated the association between The ERI and JSI with HRQoL. Conclusions We found the ERI index is significantly correlated with HRQoL superior to JSI, in particular among Taiwan civil servants. Further longitudinal studies are needed to determine the causality and spatiotemporal relation of these differences. Int J Occup Med Environ Health. 2022;35(4):425–36

Abstract Objectives The choice of optimal antithrombotic therapy in atrial fibrillation (AF) patients with acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains controversial. The aim of this longitudinal cohort study is to investigate the prescribing pattern of antithrombotic regimen in different cohorts and its subsequent impact. Setting and design Longitudinal data from the Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry, between January 2016 and August 2018 was screened. Participants and method Patients with prior history of nonvalvular AF, who had ACS presentation or underwent PCI were selected, and these patients were divided into cohort 1 and cohort 2, according to the index date of antithrombotic prescription before and after the PIONEER AF-PCI study. Primary and secondary outcomes The primary safety endpoints were composites of major bleeding and/or clinically relevant non-major bleeding. The secondary efficacy endpoints included the occurrence of all-cause mortality, stroke/systemic embolization, nonfatal myocardial infarction (MI), and >30-days coronary revascularization. Results A total of 121 patients were included into analysis (cohort 1=35; cohort 2=86). Comparing with cohort 1, the prescription rate of triple antithrombotic therapy (TAT) increased from 17.1 to 38.4%, especially the regimen with dual antiplatelet therapy (DAPT) plus low-dose non-vitamin-K dependent oral anticoagulation (NOAC). However, the prescription rate of dual antithrombotic therapy (DAT) decreased (14.3–10.5%), as well as the prescription rate of DAPT (68.6–51.2%). These changes of antithrombotic prescription across different cohorts were not associated with risk of adverse safety (HR= 0.87; 95% CI, 0.42-1.80, p=0.710) and efficacy outcomes (HR=0.96; 95% CI, 0.40-2.32, p=0.930). Conclusions Entering the NOAC era, the prescription of TAT increased alongside the decrease in DAT. As the prescription rate of DAPT without anticoagulation remained high, future efforts are mandatory to improve the implementation of guidelines and clinical practice.

Abstract Aims Ivabradine has been used in patients who have chronic heart failure (HF) with reduced ejection fraction (HFrEF) and concomitant sinus heart rate ≥70 bpm. This administration for acute HFrEF remains a concern. This study used a real‐world multicentre database to investigate the effects of ivabradine among patients with acute decompensated HFrEF before discharge. Methods and results This study retrospectively identified patients with acute decompensated HFrEF who were administered ivabradine at discharge from two multicentre HF databases. Propensity score matching was performed to adjust for confounders. Cardiovascular mortality, all‐cause mortality, and recurrent HF rehospitalization risks were then compared between those with and without ivabradine treatment. After 1:2 propensity score matching, 876 patients (age, 60.7 ± 14.6 years; female, 23.2%; left ventricular ejection fraction, 28.2% ± 7.8%; and heart rate at discharge, 84.3 ± 13.8 bpm) were included in the final analysis, including 292 and 584 patients with and without ivabradine treatment at discharge, respectively. No significant differences were observed in baseline characteristics between the two groups. At 1 year follow‐up, patients in the ivabradine group had significantly lower heart rates (77.6 ± 14.7 vs. 81.1 ± 16.3 bpm; P = 0.005) and lower HF severity symptoms (New York Heart Association Functional class, 2.1 ± 0.7 vs. 2.3 ± 0.9; P

ObjectiveThe aim of this study was to investigate the application of sacubitril/valsartan in clinical practice and the utility of PREDICT-HF score for outcome prediction in Asian heart failure patients with difference risk profiles.MethodsThe TAROT-HF study was a multicenter, single-arm, observational study. Totally 1,187 outpatients with HFrEF treated with sacubitril/valsartan were enrolled and categorized by: (1) high-risk group with ≥1 of the following three risk factors: old age (≥80 years), low baseline systolic blood pressure (

Abstract Aims Ivabradine and sacubitril/valsartan are second‐line therapies for patients with heart failure and reduced ejection fraction (HFrEF) based on guideline recommendations. We aimed to evaluate the synergistic effects of these two medications. Methods and results Patients' data were extracted from a multicentre database between 2016 and 2018. Patients were classified into (1) Simultaneous group: simultaneous prescription of ivabradine and sacubitril/valsartan within 6 weeks; (2A) Sequential group, ivabradine‐first: ivabradine was prescribed first, followed by sacubitril/valsartan; and (2B) Sequential group, sacubitril/valsartan‐first: sacubitril/valsartan was prescribed first, followed by ivabradine. A total of 464 patients with HFrEF were enrolled. Cardiovascular death and/or unplanned re‐hospitalizations for HF were less frequent (28.6% vs. 44.8%, P = 0.01), and the improvement of left ventricular ejection fraction (LVEF) was significantly greater in patients from the Simultaneous group than those from the Sequential group (∆LVEF 12.8 ± 12.9% vs. 9.3 ± 12.6%, P = 0.007). Among Sequential subgroups, the ivabradine‐first treatment decreased heart rate and increased systolic blood pressure (SBP) compared with sacubitril/valsartan‐first treatment (∆heart rate −9.1 ± 12.9 b.p.m. vs. 2.6 ± 16.0 b.p.m., P

Abstract. Ectopic pregnancy is the most common cause of maternal mortality in the first trimester of pregnancy. The aim of this study was to find risk factors and clinical characteristics associated with ruptured ectopic pregnancies at a medical center in eastern Taiwan in a 19-year period. This was a retrospective observational study that included patients diagnosed with ectopic pregnancy between August 1999 and December 2018. Data about the demographic variables, initial presentation, pre-treatment beta-human chorionic gonadotropin levels, treatment routes (laparoscopy or laparotomy), surgical methods (salpingostomy or salpingectomy), operation time, blood loss amount, the status of ectopic pregnancy (ruptured or unruptured), the requirement for transfusion, and duration of hospital stay were collected. The categorical and continuous variables were analyzed using the correlation coefficients. This study included 225 women who were diagnosed as having an ectopic pregnancy. There were 49 and 176 women with unruptured and ruptured ectopic pregnancies, respectively. The beta-human chorionic gonadotropin levels, history of previous ectopic pregnancy, pelvic inflammatory disease, tubal surgery, abdominal history, and vaginal bleeding were not significantly different between the 2 groups. The ratio of women with abdominal pain was significantly higher in the ruptured ectopic pregnancy group than in the unruptured group (89.1% vs. 63.8%, respectively, P

Aberrant activation of the NLRP3 inflammasome promotes the pathogenesis of many inflammatory diseases. The development of the NLRP3 inflammasome inhibitors from existing drugs for new therapeutic purposes is becoming more important. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug; however, the inhibitory potential of candesartan on the NLRP3 inflammasome has not yet been investigated. We demonstrated that candesartan significantly inhibited the NLRP3 inflammasome and pyroptosis in macrophages. Mechanistic analysis revealed that candesartan inhibited the expression of NLRP3 and proIL-1β by suppressing NF-κB activation and reducing the phosphorylation of ERK1/2 and JNK1/2. Candesartan reduced mitochondrial damage and inhibited the NLRP3 inflammasome assembly by suppressing NLRP3 binding to PKR, NEK7 and ASC. In addition, candesartan inhibited IL-1β secretion partially through autophagy induction. Furthermore, oral administration of candesartan reduced peritoneal neutrophil influx, NLRP3 and ASC expression in peritoneal cells, and lavage fluid concentrations of active caspase-1, IL-1β, IL-6 and MCP-1 in uric acid crystal-injected mice. These results indicated that candesartan has board anti-inflammatory effects and has the potential to be repositioned to ameliorate inflammatory diseases or NLRP3-associated complications.

Gut microbiota play a key role in health maintenance and disease pathogenesis in animals. Dietary phytochemicals are crucial factors shaping gut bacteria. Here, we investigated the function and mechanism of a phytogenic formulation, EUBIO-BPSG (BP), in laying hens. We found that BP dose-dependently improved health and egg production in 54-week-old hens. Furthermore, BP was correlated with increased fecal Lactobacillus, decreased Escherichia coli and Salmonella enterica, and reduced antibiotic resistance (AR) and antibiotic resistance genes (ARG) in chicken stools. The 16S rDNA data showed that BP increased seven genera of probiotics and reduced 13 genera of pathogens in chicken feces. In vitro co-culture experiments showed that BP at 4 µg/mL and above promoted growth of L. reuteri while large 100- and 200-fold higher doses suppressed growth of E. coli and S. enterica, respectively. Mechanistic studies indicated that L. reuteri and its supernatants antagonized growth of E. coli and S. enterica but not vice-versa. Five short-chain fatty acids and derivatives (SCFA) produced from L. reuteri directly killed both pathogens via membrane destruction. Furthermore, BP inhibited conjugation and recombination of ARG via interference with conjugation machinery and integrase activity in E. coli. Collectively, this work suggests that BP promotes host health and reproductive performance in laying hens through regulation of gut microbiota through increasing probiotics and decreasing pathogens and spreading ARG.

Cardiovascular events such as myocarditis following mRNA COVID-19 vaccination are increasing. We present a 67-year-old postmenopausal woman with Takotsubo Syndrome and Graves’ disease after mRNA COVID-19 vaccination. She developed chest pain and shortness of breath one week after vaccination. An electrocardiogram revealed ST elevation in the precordial leads. Coronary angiography revealed the absence of obstructive coronary artery disease, and the left ventriculography showed a typical feature with apical ballooning. Laboratory workup showed the elevation of free T4 and thyrotropin receptor antibodies. It was presumed that Takotsubo Syndrome and Graves’ disease were probably related to the COVID-19 mRNA vaccination. The patient was treated with low-dose bisoprolol, diuretics, carbimazole, and steroid and discharged uneventfully. The mRNA COVID-19 vaccination is still safe and effective to defend against COVID-19 pandemic. However, clinicians should be aware of the possible cardiovascular adverse events other than myocarditis following vaccination.

Abstract Background Although enterovirus 71 (EV71) is an important public health threat, especially in the Asia-Pacific region, there are still no effective drugs or vaccines to treat and prevent EV71 infection. Therefore, it is critical to develop prophylactic and therapeutic agents against EV71. Rosmarinic acid (RA), a phytochemical, has been discovered to possess a broad spectrum of biological activities. Methods The virucidal effects of RA on EV71 were determined by MTT, western blot, median cell culture infectious dose, apoptosis detection, plaque reduction, semi-quantitative real-time polymerase chain reaction, immunofluorescence detection, molecular docking analysis, and mouse protection assay. Results RA showed a strong protective effect against EV71 infection in human rhabdomyosarcoma cells when the multiplicity of infection was 1, with a low IC50 value (4.33 ± 0.18 μM) and high therapeutic index (340). RA not only protected cells from EV71-induced cytopathic effects, but also from EV71-induced apoptosis. The results of time-of-addition analysis demonstrated that the inhibitory activity of RA was highest at the early stage of viral infection. Consistent with this, the infectivity of EV71 in the early stage of viral infection also was observed to be limited in neonatal mice treated with RA. Further, molecular docking predicts that RA could replace the natural pocket factor within the VP1 capsid-binding hydrophobic pocket. Conclusions This study suggests that RA has the potential to be developed as an antiviral agent against initial EV71 infection to prevent or reduce EV71-induced pathogenesis and complications, since RA can effectively reduce EV71 infection in the early stages of viral infection.

Trichloroethylene (TCE) is commonly used in various industries. If wastewater in factories is not effectively treated, the inflow into and subsequent contamination of underground water is likely. Our study assessed the association of exposure to TCE in underground water with oxidative stress and renal tubule damage. We selected 579 residents from areas with underground water contaminated with TCE. Each participant was interviewed via a questionnaire. We also assessed their urinary trichloroacetic acid (TCA) levels by gas chromatography (GC)-FID. Urinary malondialdehyde (MDA) and N-acetyl-β-D-glucosaminidase (NAG) were taken as indicators of oxidative stress and renal tubule damage. We found about 73% of the residents to have consumed underground water. The average duration of consumption was 26 years, with an average of 1.6 L per day. Currently, only 1.5% of the residents still continuously consume underground water. The consumption of underground water positively correlated with heightened urinary TCA levels (r = 0.554). Heightened urinary TCA levels, in turn, were positively associated with NAG levels (r = 0.180) but negatively associated with MDA levels (r = −0.193). The results held even after we had segmented urinary TCA levels into three groups of different levels. The elimination of the source of heightened TCE levels from various industrial effluents is essential. Residents exposed to TCE-laden underground water should periodically undergo health inspections.

Gonorrhea is a type III legal communicable disease caused by Neisseria gonorrhoeae (NG), one of the most common sexually transmitted bacteria worldwide. NG infection can cause urethritis or systemic inflammation and may lead to infertility or other complications. The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is a protein complex composed of NLRP3, apoptosis-associated speck-like protein and caspase-1 and is an important part of the cellular machinery controlling the release of interleukin (IL)-1β and IL-18 and the pathogenesis of numerous infectious diseases. It has been reported that NG infection activates the NLRP3 inflammasome; however, the underlying mechanism remain unclear. In this report, the signaling pathways involved in the regulation of NG-mediated NLRP3 inflammasome activation in macrophages were studied. The results indicated that viable NG, but not heat-killed or freeze/thaw-killed NG, activated the NLRP3 inflammasome in macrophages through toll-like receptor 2, but not toll-like receptor 4. NG infection provided the priming signal to the NLRP3 inflammasome that induced the expression of NLRP3 and IL-1β precursor through the nuclear factor kappa B and mitogen-activated protein kinase pathways. In addition, NG infection provided the activation signal to the NLRP3 inflammasome that activated caspase-1 through P2X7 receptor-dependent potassium efflux, lysosomal acidification, mitochondrial dysfunction, and reactive oxygen species production pathways. Furthermore, we demonstrated that NLRP3 knockout increased phagocytosis of bacteria by macrophages and increases the bactericidal activity of macrophages against NG. These findings provide potential molecular targets for the development of anti-inflammatory drugs that could ameliorate NG-mediated inflammation.

The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the in vivo mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.

Background: Revascularization within a 90-min door-to-balloon time is a strict policy enacted in Taiwan. Prompt diagnosis is critical to avoid an unnecessary procedure and catheterization laboratory activation. This study was aimed to investigate the clinical and prognostic characteristics of the patients with ST-elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI) and normal coronary arteries found following coronary angiography (CAG). Materials and Methods: From October 2009 to December 2012, 216 consecutive patients with STEMI referred for primary PCI were enrolled. The data of clinical history, physical examination, laboratory results, electrocardiography, echocardiography, CAG findings, diagnosis, and outcomes were collected and analyzed. Results: A total of 17 patients were proved normal coronaries angiographically. The incidence of the conditions mimicking as STEMI is 7.9%. Alternative diagnosis was coronary spasm (n = 7), peri-myocarditis (n = 6), apical ballooning syndrome (n = 3), anaphylactic shock (n = 1). Compared with STEMI group, patients in normal coronaries group were younger, with a less premature family history of coronary artery disease (CAD), and reported angina. The 30-day mortality rate in the normal coronaries group was 5.9%. Conclusions: Cautiously evaluating CAD risk factors and symptoms of angina and awareness of alternative diagnosis are important to make a prompt diagnosis without compromising accuracy in the patients presenting as suspected STEMI.

BackgroundRecent studies demonstrated that oral anticoagulants (OACs) should be considered for patients with atrial fibrillation and 1 risk factor in addition to sex. Because age is an important determinant of ischemic stroke, the strategy for stroke prevention may be different for these patients in different age strata. The aim of this study was to investigate whether OACs should be considered for patients aged 20 to 49 years with atrial fibrillation and a CHA2DS2‐VASc score of 1 (men) or 2 (women). Methods and ResultsUsing the Taiwan National Health Insurance Research Database, 7374 male patients with atrial fibrillation and a CHA2DS2‐VASc score of 1 and 4461 female patients with atrial fibrillation and a CHA2DS2‐VASc score of 2 and all without antithrombotic therapies were identified and stratified into 3 groups by age. The threshold for the initiation of OACs for stroke prevention was set at a stroke rate of 1.7% per year for warfarin and 0.9% per year for non–vitamin K antagonist OACs. Among male patients aged 20 to 49 years with a CHA2DS2‐VASc score of 1, the risk of ischemic stroke was 1.30% per year and ranged from 0.94% per year for those with hypertension to 1.71% for those with congestive heart failure. Among female patients aged 20 to 49 years with a CHA2DS2‐VASc score of 2, the risk of ischemic stroke was 1.40% per year and ranged from 1.11% per year for those with hypertension to 1.67% for those with congestive heart failure. ConclusionsFor atrial fibrillation patients aged 20 to 49 years with 1 risk factor in addition to sex, non–vitamin K antagonist OACs should be considered for stroke prevention to minimize the risk of a potentially fatal or disabling event.

Mesenchymal stem cells (MSCs) are promising tools for the treatment of diseases such as infarcted myocardia and strokes because of their ability to promote endogenous angiogenesis and neurogenesis via a variety of secreted factors. MSCs found in the Wharton's jelly of the human umbilical cord are easily obtained and are capable of transplantation without rejection. We isolated MSCs from Wharton's jelly and bone marrow (WJ-MSCs and BM-MSCs, respectively) and compared their secretomes. It was found that WJ-MSCs expressed more genes, especially secreted factors, involved in angiogenesis and neurogenesis. Functional validation showed that WJ-MSCs induced better neural differentiation and neural cell migration via a paracrine mechanism. Moreover, WJ-MSCs afforded better neuroprotection efficacy because they preferentially enhanced neuronal growth and reduced cell apoptotic death of primary cortical cells in an oxygen-glucose deprivation (OGD) culture model that mimics the acute ischemic stroke situation in humans. In terms of angiogenesis, WJ-MSCs induced better microvasculature formation and cell migration on co-cultured endothelial cells. Our results suggest that WJ-MSC, because of a unique secretome, is a better MSC source to promote in vivo neurorestoration and endothelium repair. This study provides a basis for the development of cell-based therapy and carrying out of follow-up mechanistic studies related to MSC biology.