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The prognostic value of chronic obstructive pulmonary disease (COPD) as a comorbidity in heart failure has been well documented. However, the role of pulmonary function indices in patients with heart failure and preserved ejection fraction (HFpEF) remains to be elucidated. Subjects with HFpEF received pulmonary function tests and echocardiogram. Total lung capacity (TLC), residual volume (RV), forced expiratory flow rate between 25% and 75% of vital capacity (FEF25-75), forced expiratory volume in the 1.sup.st second (FEV1), forced vital capacity (FVC), and vital capacity (VC) were measured. Echocardiographic indices, including pulmonary artery systolic pressure (PASP), the ratio of early ventricular filling flow velocity to the septal mitral annulus tissue velocity (E/e'), and left ventricular mass (LVM), were recorded. National Death Registry was linked for the identification of mortality. A total of 1194 patients (72.4±13.2 years, 59% men) were enrolled. PASP, E/e' and LVM were associated with either obstructive (RV/TLC, FEV1 and FEF25-75) or restrictive (VC and TLC) ventilatory indices. During a mean follow-up of 23.0±12.8 months, 182 patients died. Subjects with COPD had a lower survival rate than those without COPD. While VC, FVC, RV/TLC, and FEV1 were all independently associated with all-cause mortality in patients without COPD, only FEF25-75 was predictive of outcomes in those with COPD. The abnormalities of pulmonary function were related to the cardiac hemodynamics in patients with HFpEF. In addition, these ventilatory indices were independently associated with long-term mortality, especially in those without COPD.

A dominating set of a graph G = ( V , E ) is a subset U of its vertices V , such that any vertex of G is either in U , or has a neighbor in U . The dominating-set problem is to find a minimum dominating set in G . Dominating sets are of critical importance for various types of networks/graphs, and find therefore potential applications in many fields. Particularly, in the area of communication, dominating sets are prominently used in the efficient organization of large-scale wireless ad hoc and sensor networks. However, the dominating set problem is also a hard optimization problem and thus currently is not efficiently solvable on classical computers. Here, we propose a biomolecular and a quantum algorithm for this problem, where the quantum algorithm provides a quadratic speedup over any classical algorithm. We show that the dominating set problem can be solved in O ( 2 n / 2 ) queries by our proposed quantum algorithm, where n is the number of vertices in G . We also demonstrate that our quantum algorithm is the best known procedure to date for this problem. We confirm the correctness of our algorithm by executing it on IBM Quantum’s qasm simulator and the Brooklyn superconducting quantum device. And lastly, we show that molecular solutions obtained from solving the dominating set problem are represented in terms of a unit vector in a finite-dimensional Hilbert space.

Methods for profiling DNA methylation differ in the physical principles used to detect modified cytosines. Harris et al . compare the performances of four sequencing-based technologies for genome-wide analysis of DNA methylation and combine two methods to enable detection of allelic differences in epigenetic marks. Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression.

Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a debilitating and life‐threatening condition with a heterogeneous clinical presentation. Recent guidelines from the United States and Europe have been published to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies for patients with ATTR‐CM. These guidelines highlight the importance of an early diagnosis to optimize therapeutic outcomes, specifying the use of tests and imaging techniques to allow accurate, noninvasive diagnosis of ATTR‐CM. However, as regional practice variations across Asia may limit access to healthcare, availability of specific tests, and expertise in assessing diagnostic images, there is an ongoing need to provide an Asian perspective on these clinical guidelines. This review article provides practical recommendations for the diagnosis and monitoring of patients with ATTR‐CM in Asia, highlighting the need for additional guidelines to support a broad and diverse population, consider differing healthcare systems and diagnostic testing availability, and provide a flexible yet robust algorithm.

Left ventricular dysfunction is a known risk factor for morbidity and mortality in hemodialysis patients. The prognostic value of left ventricular global longitudinal strain (LV GLS) among those with preserved left ventricular ejection fraction (LVEF) remains uncertain. Subjects with end-stage renal disease initiated hemodialysis at Taipei Veteran General Hospital between 2015 and 2018 were registered. All participants received annually echocardiographic studies thereafter. Left ventricular end-systolic volume (LVESV), end-diastolic volume (LVEDV) and internal diameter in systole (LVIDs), LVEF, and LV GLS were measured. A LV GLS of > – 15.9% was defined as reduced LV GLS. Clinical outcomes of mortality and hospitalization for heart failure (HHF) were followed. A total of 319 patients with preserved LVEF (66.3 ± 15.1 years, 48.6% men) were recruited in the study. Subjects with reduced LV GLS had more coronary artery disease (CAD), higher LVESV and LVIDs, but were similar in age, gender, co-morbidities, biochemistries and other echocardiographic parameters as the counterpart. Both CAD [(odds ratio (OR) and 95% confidence intervals (CIs): 1.669, 1.023–2.724], and LVESV (OR per-1 mL and 95% CIs: 1.073, 1.004–1.146) were independent determinants of reduced LV GLS. Kaplan-Meier analysis indicated that patients with reduced LV GLS had a significantly lower event-free survival rate compared to those with preserved GLS. The multivariate Cox regression analysis further demonstrated LV GLS as a significant predictor of adverse clinical events (hazard ratio per-1% and 95% CIs: 1.055, 1.002–1.110) after accounting for age, gender, and diabetes. Among the hemodialysis patients with preserved LVEF, LV GLS but not the conventional left ventricular functional indices were associated with long-term mortality and HHF. CAD could be a modifiable risk factor among the subjects with reduced LV GLS.

Epicardial fat was closely related to atrial fibrillation (AF). Transthoracic echocardiography (TTE) has been proposed to be a convenient imaging tool in assessing epicardial adipose tissue (EAT). The goal of the present study was to investigate whether the EAT thickness measured on TTE was a useful parameter in predicting procedural outcomes of AF ablations. A total of 227 paroxysmal AF (PAF) and 56 non-paroxysmal AF (non-PAF) patients receiving catheter ablations from 2008-2010 were enrolled. Echocardiography-derived regional EAT thickness from parasternal long-axis view was quantified for each patient. Free of recurrence was defined as the absence of atrial arrhythmias without using antiarrhythmic agents after ablations. The mean EAT thickness of the study population was 6.1 ± 0.8 mm. Non-PAF patients had a thicker EAT than that of PAF patients (7.0 ± 0.7 mm versus 5.9 ± 0.7 mm, p value <0.001). During the follow-up of 16 ± 9 months, there were 95 patients (33.6%) suffering from recurrences of atrial arrhythmias. Non-PAF, chads2 score, left atrial diameter and EAT thickness were independent predictors of recurrence after catheter ablations. At a cutoff value of 6 mm for PAF and 6.9 mm for non-PAF, the measurement of EAT thickness could help us to identify patients at risk of recurrences. EAT thickness may serve as a useful parameter in predicting recurrences after AF ablations. Compared to other imaging modalities, TTE can be an alternative choice with less cost and time in assessing the effects of EAT on ablation outcomes.

Tumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA), a key regulator of inflammation, may be involved in the pathogenesis of pulmonary arterial hypertension (PAH). A total of 48 PAH patients (age 50.1 ± 13.1 years, 22.9% men), 25 hypertensive subjects, and 26 healthy controls were enrolled. TIFA protein expression in peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured. Pulmonary arterial hemodynamics were derived from right heart catheterization. PAH patients had the highest expression of TIFA, TNF-α, and IL-1β. TIFA protein expression was significantly associated with IL-1β (r = 0.94; P  < 0.001), TNF-α (r = 0.93; P  < 0.001), mean pulmonary artery pressure (r = 0.41; P  = 0.006), and pulmonary vascular resistance (r = 0.41; P  = 0.007). TIFA protein expression could independently predict the presence of PAH (odds ratio [95% confidence interval per-0.1 standard deviation]: 1.72 [1.37–2.16]; P  < 0.001) and outperformed echocardiographic estimation. Ex vivo silencing of TIFA protein expression in PBMCs led to the suppression of the cellular expression of IL-1β and TNF-α. IL-1β and TNF-α mediated 80.4% and 56.6% of the causal relationship between TIFA and PAH, respectively, supporting the idea that TIFA protein is involved in the pathogenesis of PAH.

BackgroundAdult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity.MethodsEnvironmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables.FindingsIn the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202–0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186–0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures.InterpretationThese results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by α-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan–Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression‐free survival, cancer‐specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K‐AKT‐mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT‐mTOR pathway. Furthermore, the overexpression of NTRK3 in UM‐UC‐14 cells promoted AKT‐mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT‐mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.