Validation of the Framingham General Cardiovascular Risk Score and Pooled Cohort Equations in a Community-Based Population: A Prospective Cohort Study Analysis 2006-2017.

Background: The 10-year atherosclerotic cardiovascular disease (ASCVD) risk - as assessed using the Framingham general cardiovascular risk score (FRS-CVD) or pooled cohort equations (PCE) - is commonly used in Western cohorts for the primary prevention of cardiovascular disease (CVD). However, the FRS-CVD and PCE have not been validated in Taiwanese cohorts. Objectives: We aimed to validate the FRS-CVD and PCE for assessing the 10-year ASCVD risk using a Taiwanese community-based population. Methods: We extracted patient data from the Landseed Integrated Outreaching Neighborhood Screening registry, a community-based prospective cohort study established in 2006. Cardiovascular events from 2006 to 2017 were determined from electronic medical records. The discriminative power and calibration of the FRS-CVD and PCE were evaluated. Results: Overall, 5,139 subjects were analyzed; the 10-year follow-up rate was 99.6%. The mean age at baseline was 52.8 ± 13.1 years, and 44.6% of the subjects were male. In total, 430 of 4,631 (9.3%) and 227 of 4,022 (5.6%) of the FRS-CVD- and PCE-like cohorts, respectively, had ASCVD events. The calibration χ2 of the FRS-CVD was 7.0267 (p = 0.6343) in males and 7.8845 (p = 0.5458) in females; the χ2 of PCE was 13.007 (p = 0.1623) in males and 38.785 (p < 0.001) in females. The area under the receiver operating characteristic curve (AUROC) of the FRS-CVD was 0.76 (0.72-0.79) in males and 0.71 (0.67-0.74) in females; the AUROC of PCE was 0.68 (0.62-0.73) in males and 0.61 (0.56-0.67) in females. Conclusions: Except for PCE in females, the FRS-CVD and PCE provided good calibration and modest discrimination in statin-naïve Taiwanese individuals without prior CVD.

Repetition of Paclitaxel-Coated Devices for the Treatment of Lower Extremity Artery Disease: Mortality Outcomes and Predictors.

Background: A recent meta-analysis reported late excess mortality in patients treated with paclitaxel-coated devices (PCDs) for symptomatic femoropopliteal disease. However, this finding is controversial. Objectives: To investigate the impact on mortality and predictors of repeat exposure to PCDs in patients with lower extremity peripheral arterial disease (LE-PAD). Methods: We analyzed registry patient-level data from two centers. A total of 214 patients were enrolled, and stratified based on terciles of cumulative dose of paclitaxel. We treated 134 patients with a single PCD exposure and 80 with multiple PCD exposures. We used the follow-up index (FUI) in Kaplan-Meier survival estimates to minimize potential selection bias. We used Cox proportional hazard and splines models to determine the predictors of mortality and assess their relationships with mortality. Results: The mean cumulative dose of paclitaxel was significantly different among groups (6.40 mg vs. 15.06 mg vs. 38.57 mg, p < 0.001). The 5-year FUI (0.93 ± 0.19 vs. 0.94 ± 0.18 vs. 0.95 ± 0.15, p = 0.836) and survival rates were not different (65.4% vs. 51.9% vs. 72.0%, p = 0.148). There was no dose-response association between paclitaxel dosage and death (p = 0.297). The predictors of death were congestive heart failure, stroke, dialysis dependence, neutrophil-lymphocyte ratio (NLR) > 3, age > 71 years, and body mass index (BMI) < 20 kg/m2. Spline model analysis validated the non-linear associations between mortality, age, BMI, and NLR. Conclusions: Repeated PCD exposure for LE-PAD did not result in excess late mortality. Predictors of mortality might change over time, and continuous variables had non-linear relationships with death.

Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates.

A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.

Erectile Dysfunction Is Not a Predictor of Atrial Fibrillation: A Population-Based Propensity-Score Matched Cohort Study.

INTRODUCTION: Erectile dysfunction (ED) has been regarded a marker of cardiovascular diseases. Nevertheless, the association between ED and incident atrial fibrillation (AF) remains unknown. AIM: To determine the association between ED and incident AF. METHODS: This population-based cohort study was conducted using the National Health Insurance Research Database in Taiwan. In total, 6,273 of patients with ED without a prior diagnosis of AF were enrolled from January 1, 2001 through December 31, 2009, and a propensity-score matching method was used to identify 3,516 patients in the ED and control groups. MAIN OUTCOME MEASURES: Newly incident AF at follow-up was recorded as the end point. RESULTS: The mean age of the study population was 40.0 ± 17.1 years, and the follow-up period was 8.0 ± 0.5 years. Compared with the control group, patients with ED were older and had more of the following comorbidities: D'Hoore Charlson Comorbidity Index, hypertension, congestive heart failure, diabetes mellitus, dyslipidemia, chronic kidney disease, coronary artery disease, stroke, chronic lung disease, major depression disorder, obstructive sleep apnea, and hyperthyroidism. After adjusting for confounders, the ED group was not associated with more incident AF compared with the control group (hazard ratio = 1.031, 95% confidence interval = 0.674-1.578, P =.888). In these patients, ED of an organic origin was associated with a trend of having AF more often compared with ED of a psychosexual type (P =.272 by log-rank test). CONCLUSION: Although ED is known as a predictor of atherosclerotic cardiovascular diseases, it is not independently associated with incident AF in men.

Worse Prognosis in Heart Failure Patients with 30-Day Readmission.

BACKGROUND: Heart failure (HF) readmission results in substantial expenditure on HF management. This study aimed to evaluate the readmission rate, outcome, and predictors of HF readmission. METHODS: Patients with reduced left ventricular ejection fraction (LVEF < 40%) who were admitted for acute decompensation of de novo HF were enrolled to analyze readmission rate, mortality and predictors of readmission. RESULTS: A total of 433 de novo HF patients with LVEF < 40% were enrolled during the period August 2013 to December 2014. The in-hospital and 6-month mortality rates were 3.9% and 15.2%, respectively. In those patients surviving the index HF hospitalization, the 30-day and 6-month readmission rates were 10.9% and 27%, respectively. At the end of the 6-month follow-up, the readmission group had higher mortality than the non-readmission group (27.66% vs. 10.36%; p = 0.001). The survivors of the 30-day readmission had similar mortality rates at 6 months, regardless of the cause of readmission (cardiovascular vs. non-cardiovascular: 25% vs. 30.43%, p = 0.677). Among all the parameters, prescription of beta blockers independently reduced the risk of 30-day readmission (odds ratio 0.15; 95% confidence interval 0.02-0.99; p = 0.049). CONCLUSIONS: Those HF patients who suffered from 30-day readmission had worse prognosis at the 6-month follow-up. Regardless of the readmission causes, the patients surviving the 30-day readmission had similar mortality rates at 6-month follow-up. These results underscored the importance of reducing readmission as a means to improve HF outcome.

From genus to phylum: large-subunit and internal transcribed spacer rRNA operon regions show similar classification accuracies influenced by database composition.

We compared the classification accuracy of two sections of the fungal internal transcribed spacer (ITS) region, individually and combined, and the 5' section (about 600 bp) of the large-subunit rRNA (LSU), using a naive Bayesian classifier and BLASTN. A hand-curated ITS-LSU training set of 1,091 sequences and a larger training set of 8,967 ITS region sequences were used. Of the factors evaluated, database composition and quality had the largest effect on classification accuracy, followed by fragment size and use of a bootstrap cutoff to improve classification confidence. The naive Bayesian classifier and BLASTN gave similar results at higher taxonomic levels, but the classifier was faster and more accurate at the genus level when a bootstrap cutoff was used. All of the ITS and LSU sections performed well (>97.7% accuracy) at higher taxonomic ranks from kingdom to family, and differences between them were small at the genus level (within 0.66 to 1.23%). When full-length sequence sections were used, the LSU outperformed the ITS1 and ITS2 fragments at the genus level, but the ITS1 and ITS2 showed higher accuracy when smaller fragment sizes of the same length and a 50% bootstrap cutoff were used. In a comparison using the larger ITS training set, ITS1 and ITS2 had very similar accuracy classification for fragments between 100 and 200 bp. Collectively, the results show that any of the ITS or LSU sections we tested provided comparable classification accuracy to the genus level and underscore the need for larger and more diverse classification training sets.

Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction.

INTRODUCTION: Acute kidney injury (AKI) following acute myocardial infarction (AMI) is associated with unfavorable prognosis. Endothelial activation and injury were found to play a critical role in the development of both AKI and AMI. This pilot study aimed to determine whether the plasma markers of endothelial injury and activation could serve as independent predictors for AKI in patients with AMI. METHODS: This prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with AMI receiving percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. AKI was defined as elevation of serum creatinine of more than 0.3 mg/dL within 48 hours. RESULTS: In total, 13 out of 132 (9.8%) patients with AMI developed AKI within 48 hours. Compared with patients without AKI, patients with AKI had increased plasma levels of Ang-2 (6338.28 ± 5862.77 versus 2412.03 ± 1256.58 pg/mL, P = 0.033) and sTM (7.6 ± 2.26 versus 5.34 ± 2.0 ng/mL, P < 0.001), and lower estimated glomerular filtration rate (eGFR) (46.5 ± 20.2 versus 92.5 ± 25.5 mL/min/1.73 m2, P < 0.001). Furthermore, the areas under the receiver operating curves demonstrated that plasma thrombomodulin (TM) and Ang-2 levels on day 1 of AMI had modest discriminative powers for predicting AKI development following AMI (0.796, P <0.001; 0.833, P <0.001; respectively). CONCLUSIONS: Endothelial activation, quantified by plasma levels of TM and Ang-2 may play an important role in development of AKI in patients with AMI.

Capillary osmosis in a charged nanopore connecting two large reservoirs.

Experimental evidence revealed that the performance of nanopore-based biosensing devices can be improved by applying a salt concentration gradient. To provide a theoretical explanation for this observation and explore the mechanisms involved, we model the capillary osmosis (or diffusioosmosis) in a charged solid-state nanopore connecting two large reservoirs. The effects of nanopore geometry and the reservoir salt concentrations are examined. We show that the capillary osmotic flow is from the high salt concentration reservoir to the low salt concentration one, and its magnitude has a maximum as the reservoir salt concentrations vary. In general, the shorter the nanopore and/or the smaller its radius, the faster the osmotic flow. This flow enhances the current recognition, and the ion concentration polarization across nanopore openings raises the entity capture rate, thereby being capable of improving the performance of electrophoresis-based biosensors. The results gathered provide necessary information for designing nanopore-based biosensor devices.

Cardiovascular Toxicity of Molecular Targeted Therapy in Cancer Patients: A Double-Edged Sword.

UNLABELLED: The annual incidence of cancer has increased over the past 20 years, yet the 5-year relative survival rate for cancer has improved with the increasing availability of advanced therapies, including molecular targeted therapy. Cardiovascular toxicity can develop with this type of targeted therapy, which can cause serious side effects including left ventricular dysfunction, hypertension, hypotension, QT prolongation, thromboembolism, and myocardial ischemia. In many ways, the quality of life primarily depends on the health status of patient cardiopulmonary function. However, risk factor assessment, routine monitoring, and prompt intervention remain the best strategy to deal with these patients with malignancies, to ensure that their cardiopulmonary function is maintained at the highest possible level. Most previous studies on cardiovascular toxicity have focused on conventional chemotherapy. Molecular targeted therapy is a novel anticancer treatment; however, due to potentially adverse cardiovascular events from this therapy, oncologists and cardiologists need to work together to maximize the benefits. In this review, we focused on target therapy-induced cardiovascular toxicities, in particular cardiac structural, electrophysiological, and vascular effects. KEY WORDS: Cardiovascular toxicity; Molecular target therapy.

Association between corrected QT interval and long-term cardiovascular outcomes in elderly patients who had undergone endovascular therapy for lower extremity arterial disease.

Background: Population-based studies have reported the association between prolonged corrected QT (QTc) intervals and an increased risk of adverse cardiovascular events. Data regarding the association between longer QTc intervals and incident cardiovascular outcomes in patients with lower extremity arterial disease (LEAD) are scarce. Objective: To examine the impact of QTc interval on long-term cardiovascular outcomes in elderly patients with symptomatic LEAD. Methods: This cohort study extracted data from the Tzu-chi Registry of ENDovascular Intervention for Peripheral Artery Disease (TRENDPAD) and enrolled 504 patients aged ≥ 70 treated with endovascular therapy for atherosclerotic LEAD from July 1, 2005, to December 31, 2019. The main outcomes of interest were all-cause mortality and major adverse cardiovascular events (MACE). Multivariate analysis was conducted using the Cox proportional hazard model to determine independent variables. We performed interaction analysis between corrected QT and other covariates and Kaplan-Meier analysis to compare the outcome of interest among the groups stratified by the tercile of QTc intervals. Results: A total of 504 patients [235 men (46.6%); mean age, 79.9 ± 6.2 years; mean QTc interval, 459 ± 33 msec] entered the final data analysis. We categorized the baseline patient characteristics according to terciles of QTc intervals. During the median follow-up time of 3.15 (interquartile ranges, 1.65-5.42) years, we noted 264 deaths and 145 MACEs. The 5-year rates of freedom from all-cause mortality (71% vs. 57% vs. 31%, P < 0.001) and MACEs (83% vs. 67% vs. 46%, P < 0.001) were significantly different among the tercile groups. Multivariate analysis showed that a 1-SD increase in the QTc interval increased the risk of all-cause mortality [hazard ratio (HR) 1.49, P < 0.001] and MACEs (HR 1.59, P < 0.001) after adjusting for other covariates. The interaction analysis showed that QTc interval and C-reactive protein levels were most strongly associated with death (HR = 4.88, 95% CI 3.09-7.73, interaction P < 0.001) and MACEs (HR = 7.83, 95% CI 4.14-14.79, interaction P < 0.001). Conclusions: In elderly patients with symptomatic atherosclerotic LEAD, a prolonged QTc interval is associated with advanced limb ischemia, multiple medical comorbidities, increased risk of MACEs, and all-cause mortality.

Accurate, rapid taxonomic classification of fungal large-subunit rRNA genes.

Taxonomic and phylogenetic fingerprinting based on sequence analysis of gene fragments from the large-subunit rRNA (LSU) gene or the internal transcribed spacer (ITS) region is becoming an integral part of fungal classification. The lack of an accurate and robust classification tool trained by a validated sequence database for taxonomic placement of fungal LSU genes is a severe limitation in taxonomic analysis of fungal isolates or large data sets obtained from environmental surveys. Using a hand-curated set of 8,506 fungal LSU gene fragments, we determined the performance characteristics of a naïve Bayesian classifier across multiple taxonomic levels and compared the classifier performance to that of a sequence similarity-based (BLASTN) approach. The naïve Bayesian classifier was computationally more rapid (>460-fold with our system) than the BLASTN approach, and it provided equal or superior classification accuracy. Classifier accuracies were compared using sequence fragments of 100 bp and 400 bp and two different PCR primer anchor points to mimic sequence read lengths commonly obtained using current high-throughput sequencing technologies. Accuracy was higher with 400-bp sequence reads than with 100-bp reads. It was also significantly affected by sequence location across the 1,400-bp test region. The highest accuracy was obtained across either the D1 or D2 variable region. The naïve Bayesian classifier provides an effective and rapid means to classify fungal LSU sequences from large environmental surveys. The training set and tool are publicly available through the Ribosomal Database Project.

Diffusiophoresis of a polyelectrolyte in a salt concentration gradient.

The diffusiophoresis of a polyelectrolyte subject to an applied salt concentration gradient is modeled theoretically. The entirely porous type of particle is capable of simulating entities such as DNA, protein, and synthetic polymeric particles. The dependence of the diffusiophoretic behavior of the polyelectrolyte on its physical properties, and the types of ionic species and their bulk concentrations are discussed in detail. We show that in addition to the effects coming from the polarization of double layer and the difference in the ionic diffusivities, the polarization of the condensed counterions inside the polyelectrolyte might also be significant. The last effect, which has not been reported previously, reduces both the electric force and the hydrodynamic force acting on the polyelectrolyte. Both the direction and the magnitude of the diffusiophoretic velocity of the polyelectrolyte are found to highly depend upon its physical properties. These results provide valuable references for applications such as DNA sequencing and catalytic nano- or micromotors.

Dynamic spreading of nanofluids on solids part II: modeling.

Recent studies on the spreading phenomena of liquid dispersions of nanoparticles (nanofluids) have revealed that the self-layering and two-dimensional structuring of nanoparticles in the three-phase contact region exert structural disjoining pressure, which drives the spreading of nanofluids by forming a continuous wedge film between the liquid (e.g., oil) and solid surface. Motivated by the practical applications of the phenomenon and experimental results reported in Part I of this two-part series, we thoroughly investigated the spreading dynamics of nanofluids against an oil drop on a solid surface. With the Laplace equation as a starting point, the spreading process is modeled by Navier-Stokes equations through the lubrication approach, which considers the structural disjoining pressure, gravity, and van der Waals force. The temporal interface profile and advancing inner contact line velocity of nanofluidic films are analyzed through varying the effective nanoparticle concentration, the outer contact angle, the effective nanoparticle size, and capillary pressure. It is found that a fast and spontaneous advance of the inner contact line movement can be obtained by increasing the nanoparticle concentration, decreasing the nanoparticle size, and/or decreasing the interfacial tension. Once the nanofluidic film is formed, the advancing inner contact line movement reaches a constant velocity, which is independent of the outer contact angle if the interfacial tension is held constant.

Dynamic spreading of nanofluids on solids. Part I: experimental.

Nanofluids have enhanced thermophysical properties compared to fluids without nanoparticles. Recent experiments have clearly shown that the presence of nanoparticles enhances the spreading of nanofluids. We report here the results of our experiments on the spreading of nanofluids comprising 5, 10, and 20 vol % silica suspensions of 19 nm particles displacing a sessile drop placed on a glass surface. The contact line position is observed from both the top and side views simultaneously using an advanced optical technique. It is found that the nanofluid spreads, forming a thin nanofluid film between the oil drop and the solid surface, which is seen as a bright inner contact line distinct from the conventional three-phase outer contact line. For the first time, the rate of the nanofluidic film spreading is experimentally observed as a function of the nanoparticle concentration and the oil drop volume. The speed of the inner contact line is seen to increase with an increase in the nanoparticle concentration and decrease with a decrease in the drop volume, that is, with an increase in the capillary pressure. Interestingly, the formation of the inner contact line is not seen in fluids without nanoparticles.

Rejuvenating hepatic tumor microenvironment immunity with a phosphatidylserine-targeting small molecule drug conjugate.

We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8+ T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment.