MiR-210-3p enhances intermittent hypoxia-induced tumor progression via inhibition of E2F3.

PURPOSE: Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which is related to tumorigenesis and progression. Although micro-ribonucleic acid-210-3p (miR-210-3p) is correlated with hypoxia-induced tumor development, its role in the relationship between IH and tumor function remains poorly understood. The present work focused on elucidating the molecular mechanism through which miR-210-3p drives tumor progression under IH. METHODS: MiR-210-3p levels were quantified within tumor samples from patients with lung adenocarcinoma who had or did not have OSA. Correlations between miR-210-3p and polysomnographic variables were analyzed. For in vitro experiments, miR-210-3p was inhibited or overexpressed via transfection under IH conditions. Cell viability, growth, invasion and migration assays were carried out. For in vivo modeling of IH using mouse xenografts, a miR-210-3p antagomir was intratumorally injected, tumor biological behaviors were evaluated, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry and western blot were carried out for detecting miR-210-3p and E2F transcription factor 3 (E2F3) expression. RESULTS: For patients with lung adenocarcinoma and OSA, high miR-210-3p levels showed positive relation to polysomnographic variables, such as oxygen desaturation index, apnea-hypopnea index, and proportion of total sleep time with oxygen saturation in arterial blood < 90%. IH enhanced tumor viability, proliferation, migration, and invasion, downregulated E2F3 expression, and increased miR-210-3-p levels. miR-210-3p overexpression induced similar changes. These changes were reversed by miR-210-3p inhibition in vitro or miR-210-3p antagomir through intratumoral injection in vivo. CONCLUSIONS: IH-induced tumor development is driven through miR-210-3p by E2F3 suppression. MiR-210-3p represents a potential therapeutic target among patients with concomitant cancer and OSA.

A systematic review of guidelines for dual antiplatelet therapy in coronary artery bypass graft.

BACKGROUND: In most situations, many patients undergoing coronary artery bypass graft (CABG) are on dual antiplatelet therapy (DAPT), which is also required after CABG. The adjustment of antiplatelet strategy remains controversial. In this study, we systematically review current guidelines, seeking consensus and controversies to facilitate clinical practice. METHODS AND RESULTS: Guidelines are searched in PubMed, Embase, ECRI Guidelines Trust and websites of guidelines organizations and professional society. Guidelines with recommendations of DAPT for patients undergo CABG are included. Two reviewers appraised guidelines with the Appraisal of Guidelines for Research and Evaluation II (AGREE II). Relevant recommendations are extracted and summarized. A total of 14 guidelines meeting inclusion criteria are selected, with average AGREE II scores from 44% to 86%. Most guidelines score high in domains other than 'applicability'. Many guidelines are not detailed enough in reporting considerations behind recommendations. Current guidelines are consistent on the management of antiplatelet strategy before elective CABG and using DAPT after surgery for preventing graft vessel occlusion. Evidence is still lacking in urgent CABG and resumption of the previous DAPT after surgery. CONCLUSIONS: Current guidelines on DAPT in CABG are generally satisfying. Suspending P2Y12 inhibitors while aspirin continued before elective CABG is recommended, as well as 12 months of DAPT following CABG. More evidence is needed to guide antiplatelet therapy in urgent CABG and to prove the benefits of resuming previous DAPT.

Serum albumin and atrial fibrillation: insights from epidemiological and mendelian randomization studies.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Low serum albumin level is linked to the emergence of many cardiovascular diseases, including AF. In this study, we aim to characterize the nature and magnitude of the prospective association between serum albumin and incident AF in the Atherosclerosis Risk in Communities (ARIC) Study and investigate any causal relevance to the association between them. ARIC Study is a population-based, prospective, cohort study of cardiovascular risk factors in four US communities, initially consisting of 15,792 participants, aged 45-64 years, recruited between 1987 and 1989 (visit 1). The final sample size was 12,833 in this study. Baseline (visit 1) characteristics were compared between groups using one-way ANOVA test, Chi square test, or Kruskal-Wallis test as appropriate. We used multivariable Cox' hazard regression models to assess the association between albumin and incident AF. Two-sample Mendelian randomization (MR) based on publicly available summary-level data from genome-wide association studies was used to estimate the causal influence of the serum albumin and incident AF. During a median follow-up of 25.1 years, 2259 (17.6%) participants developed incident AF. After multiple adjustment, serum albumin was inversely associated with incidence of AF [HR = 0.90, 95% CI 0.86-0.94, per SD (0.27 g/dL) increase; HR = 0.80, 95% CI 0.71-0.91, Q4 vs. Q1]. In MR analysis, we detected no evidence for a causal relation between serum albumin level and AF in inverse-variance weighted (IVW) method (odds ratio: 0.996, 95% CI 0.980-1.012, per 1 g/dL increase of albumin; P = 0.620) without evidence of heterogeneity between estimates from individual SNPs (Pheterogeneity = 0.981 [MR-Egger] and Pheterogeneity = 0.860 [IVW]) nor pleiotropy effect (Ppleiotropy = 0.193). The serum albumin level is independently inverse associated with incident AF in a linear pattern. However, MR analyses did not support a causal role of serum albumin in the etiology of AF.

Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials.

BACKGROUND: The cardiovascular (CV) safety in terms of heart failure among different classes of treatment remains largely unknown. We sought to assess the comparative effect of these agents on heart failure outcomes. METHODS: This study was registered in the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched. For the primary outcomes reported previously, studies between Jan 1, 1980 and June 30, 2016 were screened, and subsequently updated till Jan 24, 2019. We performed network meta-analysis to obtain estimates for the outcomes of heart failure, in particular by rankograms for ranking of heart failure risk as well as by pairwise comparisons among all classes of anti-diabetic medications. RESULTS: A total of 91 trials were included, among which were 171,253 participants and 4163 reported cases of heart failure events. As for rankograms, the surface under the cumulative ranking curves (SUCRA) of sodium-glucose co-transporters 2 and thiazolidinediones were 93.4% and 4.3%, respectively, signifying the lowest and highest risk of heart failure, respectively. As for pairwise comparisons in the network, sodium-glucose co-transporters 2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62-0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59-0.78), glucagon-like peptide-1 receptor agonists (OR: 0.65, 95% CI 0.54-0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27-0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of sodium-glucose co-transporters 2 was still significant. CONCLUSIONS: In terms of heart failure risk, sodium-glucose co-transporters 2 were the most favorable option among all classes of anti-diabetic medications.

An atmospheric water harvesting system based on the "Optimal Harvesting Window" design for worldwide water production.

Atmospheric water harvesting (AWH) is a promising solution to the water shortage problem. Current sorption-based AWH (SAWH) systems seldom obtain both wide climatic adaptability and high energy efficiency due to the lack of thermodynamic optimization. To achieve the ideal harvesting circulation in SAWH systems, the "optimal harvesting window" (OHW) design based on thermodynamic analysis was first proposed and validated by our prototype. The "OHW" theory indicates the water production rate and energy efficiency could be improved by properly reducing the adsorption temperature. As the humidity increases, the optimal adsorption temperature should be closer to the dew point of the environment. Experimental results revealed that, loaded with 3 kg widely adopted silica gel, the daily water production could reach 5.76-17.64 L/d with ultrahigh energy efficiency of 0.46-1.5 L/kWh. This prototype could also achieve optimal performance in wide climatic conditions in terms of 13-35 °C and 18%-72% RH. Lastly, the performance of photovoltaic (PV)-driven SAWH was evaluated. Results showed that a 1 m2 PV panel could generate 0.66-2 L water per day in Shanghai throughout the year, the highest in opening literature. Notably, this work introduces a promising concept that can help achieve large-scale, ultra-fast, energy-efficient AWH worldwide.

Compare clinical efficacy and safety of neoadjuvant therapy and neoadjuvant chemoradiotherapy for locally advanced rectal cancer: Meta-analysis.

BACKGROUND: To compare the efficacy and safety of total neoadjuvant therapy (TNT) and neoadjuvant chemoradiotherapy (nCRT) in the treatment of middle and low locally advanced rectal cancer. Our study will systematically collect and integrate studies to evaluate the ability of these two treatments to improve tumor shrinkage rates, surgical resection rates, tumor-free survival, and severe adverse events. AIM: To provide clinicians and patients with more reliable treatment options to optimize treatment outcomes and quality of life for patients with locally advanced rectal cancer by comparing the advantages and disadvantages of the two treatment options. METHODS: A full search of all clinical studies on the effectiveness and safety of TNT and nCRT for treating locally advanced rectal cancer identified in Chinese (CNKI, Wanfang, China Biomedical Literature Database) and English (PubMed, Embase) databases was performed. Two system assessors independently screened the studies according to the inclusion and exclusion criteria. Quality evaluation and data extraction were performed for the included literature. We used RevMan 5.3 software to perform a meta-analysis of the pathologic complete response (pCR) rate, T stage degradation rate, resection 0 (R0) rate, anal grade 3/4 acute toxicity rate, perioperative complications, overall survival (OS), and disease-free survival (DFS) in the TNT and nCRT groups. RESULTS: Finally, 14 studies were included, six of which were randomized controlled studies. A total of 3797 patients were included, including 1865 in the TNT group and 1932 in the nCRT group. The two sets of baseline data were comparable. The results of the meta-analysis showed that the pCR rate [odds ratio (OR) = 1.57, 95% confidence interval (CI): 1.30-1.90, P < 0.00001], T stage degradation rate (OR = 2.16, 95%CI: 1.63-2.57, P < 0.00001), and R0 resection rate (OR = 1.42, 95%CI: 1.09-1.85, P = 0.009) were significantly greater in the nCRT group than in the nCRT group. There was no significant difference in the incidence of grade 3/4 acute toxicity or perioperative complications between the two groups. The 5-year OS [hazard ratio (HR) = 0.84, 95%CI: 0.69-1.02, P = 0.08] and DFS (HR = 0.94, 95%CI: 0.03-1.39, P = 0.74) of the TNT group were similar to those of the nCRT group. CONCLUSION: TNT has greater clinical efficacy and safety than nCRT in the treatment of locally advanced rectal cancer.

Correlation analysis of interstitial maturity and prognosis of colorectal cancer: Meta-analysis.

BACKGROUND: To investigate the relationship between interstitial maturity and prognosis of colorectal cancer. AIM: To examine the correlation between interstitial maturity and the prognosis of colorectal cancer. METHODS: The paper database PubMed, EMBASE, Cochranelibrary, Springerlink, CNKI, and Wanfang database were searched until December 2023. "tumor stroma maturity" "desmoplastic stroma reaction" "desmoplastic reaction" "stroma reaction" "degree of stroma reaction "" stroma classification" "stroma density" "colorectal cancer" "colon cancer" "rectal cancer" "prognosis" were searched for the search terms. Two system assessors independently screened the literature quality according to the inclusion exclusion criteria, Quality evaluation and data extraction were performed for the included literatures, and meta-analysis was performed for randomized control trials included at using Review Manager 5.2 software. RESULTS: Finally, data of 9849 patients with colorectal cancer from 19 cosets in 15 literatures were included, including 4339 patients with mature type (control group), 3048 patients with intermediate type (intermediate group) and 2456 patients with immature type (immature group). The results of meta-analysis showed: Relapse-free survival [hazard ratio (HR) = 2.66, 95% confidence interval (CI): 2.30-3.08; P < 0.00001], disease-free survival (HR = 3.68, 95%CI: 2.33-5.81; P < 0.00001) and overall survival (HR = 1.70, 95%CI: 1.53-1.87; P < 0.00001) were significantly lower than those in mature group (control group); relapse-free survival (HR = 1.36, 95%CI: 1.17-1.59; P < 0.0001) and disease-free survival rate (HR = 1.85, 95%CI: 1.53-2.24; P < 0.0001) was significantly lower than the mature group (control group). CONCLUSION: There is the correlation between tumor interstitial maturity and survival prognosis of colorectal cancer, and different degrees of tumor interstitial maturity have a certain impact on the quality of life of colorectal cancer patients.

Stilbenes with potent cytotoxicity from the seedcases of Paeonia suffruticosa Andrews.

Stilbenes (based on the 1,2-diphenylethylene skeleton) are a class of plant polyphenols with rich structural and bioactive diversity. Twenty-six stilbenes, including five undescribed compounds (7,8-dioxy-4,3',5'-trihydroxystilbene, trans-13'-methoxygnetin H, suffruticosol E, paestibenetrimerols A and B), were isolated from the seedcases of Paeonia suffruticosa Andrews. Their structures were elucidated by spectroscopic analyses and comparison with previously reported data. The absolute configurations of trans-13'-methoxygnetin H, suffruticosol E, paestibenetrimerols A and B were assigned from their respective electronic circular dichroism (ECD) spectra. Additionally, the structures of known compounds suffruticosols A, B and rockiol B were revised and the absolute configurations of them, and along with (+)-davidiol A, were also further determined by ECD. The isolated compounds, trans-gnetin H, cis-gnetin H and suffruticosol E, were found to have potent cytotoxicity against the DU-145 and MDA-MB-231 cell lines with IC50 values of 4.89-8.61 µM. The preliminary antitumor structure-activity relationship of these stilbenes is discussed as well.

Case series: Montgomery T-tube placement for subglottic tracheal stenosis: a report of 3 cases.

RATIONALE: Subglottic tracheal stenosis is stenosis of the trachea between the vocal cords and the lower margin of the cricoid cartilage. The Montgomery T-tube is used as a tracheostomy tube and a combined tracheal stent to avoid postoperative tracheal stenosis. PATIENT CONCERNS: Because the stenosis is close to the glottis, surgical treatment is complex, and many complications may arise. DIAGNOSES: Subglottic tracheal stenosis. INTERVENTIONS: The patients underwent endotracheal intubation or tracheotomy because of acute pancreatitis, laryngeal malignancy, or cerebral hemorrhage after endotracheal intubation or tracheotomy and presented with varying degrees of tracheal stenosis and dyspnea. We relieved airway stenosis and improved dyspnea in these 3 patients by placing a Montgomery T-tube. OUTCOMES: None of the 3 patients had intraoperative complications. In 2 of the cases, airway secretions were stored after surgery. LESSONS: Montgomery T-tube placement is safe and effective for patients with complex subglottic tracheal stenosis.

Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study.

AIMS: We aimed to explore the heterogeneous treatment effects (HTEs) for spironolactone treatment in patients with Heart failure with preserved ejection fraction (HFpEF) and examine the efficacy and safety of spironolactone medication, ensuring a better individualized therapy. METHODS AND RESULTS: We used the causal forest algorithm to discover the heterogeneous treatment effects (HTEs) from patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Cox regressions were performed to assess the hazard ratios (HRs) of spironolactone medication for cardiovascular death and drug discontinuation in each group. The causal forest model revealed three representative covariates and participants were partitioned into four subgroups which were Group 1 (baseline BMI ≤ 31.71 kg/m2 and baseline ALP ≤ 80 U/L, n = 759); Group 2 (BMI ≤ 31.71 kg/m2 and ALP > 80 U/L, n = 1088); Group 3 (BMI > 31.71 kg/m2 , and WBC ≤ 6.6 cells/µL, n = 633); Group 4 (BMI > 31.71 kg/m2 and WBC > 6.6 cells/µL, n = 832), respectively. In the four subgroups, spironolactone therapy reduced the risk of cardiovascular death in high-risk group (Group 4) with both high BMI and WBC count (HR: 0.76; 95% CI 0.58 to 0.99; P = 0.045) but increased the risk in low-risk group (Group 1) with both low BMI and ALP (HR: 1.45; 95% CI 1.02 to 2.07; P = 0.041; P for interaction = 0.020) but showed similar risk of drug discontinuation (P for interaction = 0.498). CONCLUSION: Our study manifested the HTEs of spironolactone in patients with HFpEF. Spironolactone treatment in HFpEF patients is feasible and effective in patients with high BMI and WBC while harmful in patients with low BMI and ALP. Machine learning model could be meaningful for improved categorization of patients with HFpEF, ensuring a better individualized therapy in the clinical setting.

GP73 enhances the ox-LDL-induced inflammatory response in THP-1 derived macrophages via affecting NLRP3 inflammasome signaling.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease with its molecular basis incompletely understood. Here, we determined whether the Golgi phosphoprotein 73 (GP73), a novel protein highly related to inflammation and disrupted lipid metabolism, was involved in the development of atherosclerosis. METHODS: Public microarray databases of human vascular samples were analyzed for expression patterns. Apolipoprotein-E-gene-deficient (ApoE-/-) mice (8-week-old) were randomly assigned to either a chow diet group or a high-fat diet group. The levels of serum GP73, lipid profiles and key inflammatory cytokines were determined by ELISA. The aortic root plaque was isolated and used for by Oil Red O staining. PMA-differentiated THP-1 macrophages were transfected with GP73 small interfering RNA (siRNA) or infected with adenovirus expressing GP73, and then stimulated with oxidized low density lipoprotein (ox-LDL). The expressions of pro-inflammatory cytokines and signal pathway key targets were determined by ELISA kit and Western blot respectively. In addition, ichloro-dihydro-fluorescein diacetate (DCFH-DA) was used to measure the intracellular ROS levels. RESULTS: The expressions of GP73 and NLRP3 were substantially upregulated in human atherosclerotic lesions. There were significant linear correlations between GP73 and inflammatory cytokines expressions. High-fat diet-induced atherosclerosis and increased levels of plasma inflammatory mediators (IL-1ß, IL-18, and TNF-α) were observed in ApoE-/- mice. Besides, the expressions of GP73 in the aorta and serum were significantly upregulated and positively correlated with the NLRP3 expression. In the THP-1 derived macrophages, ox-LDL treatment upregulated the expressions of GP73 and NLRP3 proteins and activated the inflammatory responses in a concentration-dependent and time-dependent manner. Silencing of GP73 attenuated the inflammatory response and rescued the decreased migration induced by ox-LDL, inhibiting the NLRP3 inflammasome signaling and the ROS and p-NF-κB activation. CONCLUSIONS: We demonstrated that GP73 promoted the ox-LDL-induced inflammation in macrophages by affecting the NF-κB/NLRP3 inflammasome signaling, and may play a role in atherosclerosis.

Finite Element Analysis of Elastoplastic Elements in the Iwan Model of Bolted Joints.

The Iwan model is composed of elastoplastic elements and is widely used to represent the stiffness degradation of bolted joints under mixed-mode loading (normal and tangential loading). The latest static methods of parameter identification established the relationship between the elastoplastic elements and the contact pressure under normal loading. Under mixed-mode loading, the parameters of the Iwan model are dynamic for the evolution of contact conditions. Therefore, static parameter identification methods are not suitable for the dynamic Iwan model. A new technique was proposed to identify the parameters of the elastoplastic elements in this paper. Firstly, several different finite element models were established. The influence of the contact method and the thread structure were analyzed, and a reliable and efficient bolted-joint modeling method was proposed. Secondly, the evolution of contact conditions was studied. The dynamic elliptical contact model and the ellipticity discrete method were proposed. Finally, the residual stiffness of the Iwan model was analyzed to establish the mapping between the residual stiffness and the bending of the screw. The results can provide a technique for identifying the parameters of the dynamic Iwan model.

Association of Residential Proximity to the Coast With Incident Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: Little is known about how the residential distance to the coast is associated with incident myocardial infarction (MI) and which mechanisms may explain the association. We aim to explore this association using data from a prospective, population-based cohort with unprecedented sample size, and broad geographical coverage. METHODS: In this study, 377,340 participants from the UK Biobank were included. RESULTS: It was shown that 4,059 MI occurred during a median 8.0 years follow-up. Using group (<1 km) as reference, group (20-50 km) was associated with a lower risk of MI (hazard ratio, HR 0.79, 95% CI 0.64-0.98) and a U-shaped relation between distance to the coast and MI was shown with the low-risk interval between 32 and 64 km (p non-linear = 0.0012). Using participants of the intermediate region (32-64 km) as a reference, participants of the offshore region (<32 km) and inland region (>64 km) were both associated with a higher risk of incident MI (HR 1.12, 95% CI 1.04-1.21 and HR 1.09, 95% CI 1.01-1.18, respectively). HR for offshore region (<32 km) was larger in subgroup with low total physical activity (<24 h/week) (HR 1.24, 95% CI 1.09-1.42, p interaction = 0.043). HR for inland region (>64 km) was larger in subgroup in urban area (HR 1.12, 95% CI 1.03-1.22, p interaction = 0.065) and in subgroup of high nitrogen dioxide (NO2) air pollution (HR 1.29, 95% CI 1.11-1.50, p interaction = 0.021). CONCLUSION: We found a U-shaped association between residential distance to the coast and incident MI, and the association was modified by physical activity, population density, and air pollution.

Deep Phenotyping and Prediction of Long-term Cardiovascular Disease: Optimized by Machine Learning.

BACKGROUND: Prediction of cardiovascular disease (CVD) is important in clinical practice. Machine learning (ML) may offer an improved alternative to current CVD risk stratification in individual patients. We aim to identify important predictors and compare ML models with traditional models according to their prediction performance in a large long-term follow-up cohort. METHODS: The Atherosclerosis Risk in Communities (ARIC) study was designed to study the progression of subclinical disease to cardiovascular events over a 25-year follow-up period. All phenotypic variables at visit 1 were obtained. All-cause death, CVD, and coronary heart disease were the outcomes for analysis. The ML framework involved variable selection using the random survival forest (RSF) method, model building, and 5-fold cross-validation. Model performance was evaluated by discrimination using the Harrell concordance index (C-index), accuracy using the Brier score (BS), and interpretability using the number of variables in the model. RESULTS: Of the 14,842 participants in ARIC, the average age was 54.2 years, with 45.2% male and 26.2% Black participants. Thirty-eight unique variables were selected in the RSF top 20 importance ranking of all 6 outcomes. Aging, hypertension, glucose metabolism, renal function, coagulation, adiposity, and sodium retention dominated the predictions of all outcomes. The ML models outperformed the regression models and established risk scores with a higher C-index, lower BS, and varied interpretability. CONCLUSIONS: The ML framework is useful for identifying important predictors of CVD and for developing models with robust performance compared with existing risk models.

Wnt/ß­catenin signaling: Causes and treatment targets of drug resistance in colorectal cancer (Review).

Colorectal cancer (CRC) is the third most common malignant tumor in humans. Chemotherapy is used for the treatment of CRC. However, the effect of chemotherapy remains unsatisfactory due to drug resistance. Growing evidence has shown that the presence of highly metastatic tumor stem cells, regulation of non­coding RNAs and the tumor microenvironment contributes to drug resistance mechanisms in CRC. Wnt/ß­catenin signaling mediates the chemoresistance of CRC in these three aspects. Therefore, the present study analyzed the abundant evidence of the contribution of Wnt/ß­catenin signaling to the development of drug resistance in CRC and discussed its possible role in improving the chemosensitivity of CRC, which may provide guidelines for its clinical treatment.

Hypertension and Atrial Fibrillation: A Study on Epidemiology and Mendelian Randomization Causality.

Introduction: Hypertension (HT) and atrial fibrillation (AF) often coexist. However, the causality between these two conditions remains to be determined. Methods: We used individual participant data from the Atherosclerosis Risk in Communities (ARIC) prospective cohort with 9,474 participants. HT was ascertained at visit 1 (1987-1989), and incident AF was identified by ECGs conducted during study examinations at each visit, hospital discharge codes, and death certificates. We used the Kaplan-Meier estimate to compute the cumulative incidence of AF by the HT subgroup. Then we used Cox hazard regression model to assess the association between HT and incident AF. The causality between genetically determined HT and AF was analyzed by the two-sample Mendelian randomization (MR) based on publicly summarized genome-wide association studies (GWASs) data. Results: A total of 1,414 cases (14.9%) of AF were identified during the follow-up period (median 24.1 years). After adjusting for all covariates, the hazard ratio between the participants with HT and incident AF was 1.50 [95% confidence interval (CI) 1.29-1.73]. In the HT → AF MR analysis, we detected a causal correlation between HT and AF (OR: 1.90, 95% CI 1.18-3.04, P = 0.01) with no evidence of heterogeneity from single-nucleotide polymorphisms. Besides, the genetically determined SBP and DBP (10 mmHg) were consistently associated with a higher risk of AF. Conclusions: In the ARIC study, the incident AF increased by 50% in patients with HT. In the MR analysis, our results supported causal inference between HT and AF.

Education and heart failure: New insights from the atherosclerosis risk in communities study and mendelian randomization study.

INTRODUCTION: We aim to characterize the nature and magnitude of the prospective association between education and incident heart failure (HF) in the Atherosclerosis Risk in Communities (ARIC) Study and investigate any causal relevance to the association between them. METHODS: The final sample size was 12,315 in this study. Baseline characteristics between education levels were compared using 1-way ANOVA test, the Kruskal-Wallis test, or the χ2 test. We used the Kaplan-Meier estimate to compute the cumulative incident of HF by education levels and the difference in estimate was compared using the log-rank test. Cox hazard regression models were used to explore the association between education levels and incident HF. Two-sample Mendelian randomization (MR) based on publicly available summary-level data from genome-wide association studies (GWASs) was used to estimate the causal influence of the education and incident HF. RESULTS: During a median follow-up of 25.1years, 2453 cases (19.9%) of incident HF occurred. After multiple adjustments in the final model, participants in the intermediate and advanced education levels were still associated with 18% and 21% decreased rate of incident HF separately. In MR analysis, we detected a protective causal association between education and HF (P=0.005). CONCLUSIONS: Participants with higher education levels were associated with a decreased rate of incident HF. There was a causal association between education and HF.

Association between serum cystatin C level and hemodynamically significant aortic stenosis: a prospective cohort study.

BACKGROUND: Cystatin C (CysC) is a cysteine protease inhibitor involved in proteins catabolism and plays an essential role in human vascular pathophysiology. CysC may also increase the risk of aortic stenosis (AS), but limited studies have reported on this association. This study aimed to investigate if elevated serum CysC levels are associated with hemodynamically significant AS. METHODS: Serum CysC levels were estimated in 4,791 participants, samples were collected in 1990-1992. The study population was divided into quintile groups. Follow-up continued in 2011-2013 when participants returned for echocardiography examination. Incidence of aortic valve disease (AVD) was ascertained by Doppler echocardiography through the end of 2013. AVD defined in hemodynamic progression was assessed and classified as aortic sclerosis, mild stenosis, and moderate-to-severe stenosis. RESULTS: Overall, a total of 4,791 participants (mean age: 54.8 ± 5.0 years, females: 57.6%, blacks: 8.2%) were included in this study. During a follow-up of 21 years, we identified 736 cases (15.4%) of aortic sclerosis, 194 cases (4.0%) of mild stenosis, and 42 cases (0.7%) of moderate-to-severe stenosis. Compared with serum CysC levels within individual quintile groups, the odds ratio (OR) was per standard deviation associated with an increased incidence of AVD (OR = 1.15, 95% CI: 1.05-1.26,P = 0.002). CONCLUSIONS: In this large population-based study, an increased serum CysC levels is independently associated with the incidence of hemodynamically significant AS. However, this association appears not to extend to patients with extremely high serum CysC levels and necessitate further investigation.

Unsuspected intraspecific variability in the toxin production, growth and morphology of the dinoflagellate Alexandrium pacificum R.W. Litaker (Group IV) blooming in a South Western Mediterranean marine ecosystem, Annaba Bay (Algeria).

Physiological plasticity gives HABs species the ability to respond to variations in the surrounding environment. The aim of this study was to examine morphological and physiological variability in Alexandrium pacificum R.W. Litaker (Group IV) (former Alexandrium catenella) blooming in Annaba bay, Algeria. Monoclonal cultures of up to 30 strains of this neurotoxic dinoflagellate were established by the germination of single resting cysts from the surface sediment of this southern Mediterranean marine ecosystem. Ribotyping confirmed formally for the first time that A. pacificum is developing in Eastern Algerian waters. Toxin analyses of A. pacificum strains revealed substantial intraspecific variability in both the profile and toxin amount. However, the toxin profile of most strains is characterized by the dominance of GTX6 (up to 96 mol %) which is the less toxic paralytic molecule. The toxin concentrations in the isolated strains varied widely between 3.8 and 30.82 fmol cell-1. We observed an important variation in the growth rate of the studied A. pacificum strains with values ranging from 0.05 to 0.33 d-1. The lag time of the studied strains varied widely and ranged from 4 to 20 days. The intraspecific diversity could be a response to the selection pressure which may be exerted by different environmental conditions over time and which can be genetically and in turn physiologically expressed. This study highlights, for the first time, that the sediment of a limited area holds an important diversity of A. pacificum cysts which give when germinate populations with noticeable physiological plasticity. Consequently, this diversified natural populations allow an exceptional adaptation to specific environmental conditions to outcompete local microalgae and to establish HABs which could explain why this dinoflagellate is successful and expanding worldwide.

Long-term tracking of fasting blood glucose variability and peripheral artery disease in people without diabetes.

INTRODUCTION: Long-term changes of fasting blood glucose (FBG) in relation to lower-extremity peripheral artery disease (lower-extremity PAD) in people without diabetes has barely been reported. Our study aimed to investigate the association between FBG variability and the incidence of lower-extremity PAD in people without diabetes. RESEARCH DESIGN AND METHODS: We included 7699 participants without prior lower-extremity PAD and diabetes from the Atherosclerosis Risk in Communities study in the final analysis. At least two measurements of FBG were required during follow-up. Variability of FBG was identified using SD, coefficient of variation (CV), variability independent of the mean (VIM) and average real variability. Lower-extremity PAD was defined as an ankle brachial index <0.9, or hospitalization with a lower-extremity PAD diagnosis. Cox regression model was used to calculate HR for incidence of lower-extremity PAD and FBG variability. RESULTS: During a median follow-up of 19.5 years, 504 (6.5 %) lower-extremity PAD events were observed, 54.4% (n=274) were male, and 17.5% (n=88) were African-American. FBG variability was positively associated with incident lower-extremity PAD, with a linear relationship. HRs for CV and VIM were 1.015 (95% CI: 1.001 to 1.03; p=0.023), and 1.032 (95% CI: 1.004 to 1.06; p=0.022) for lower-extremity PAD, respectively. Participants in the lowest quartile of CV were at lower lower-extremity PAD risk compared with the highest ones (HR: 1.499, 95% CI: 1.16 to 1.938; p=0.002). CONCLUSIONS: Higher FBG variability was independently associated with increased prevalence of lower-extremity PAD in people without diabetes. TRIAL REGISTRATION NUMBER: NCT00005131.