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Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Background:Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations. Methods:For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression. Findings:Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51·5%) were female and 15 654 (48·5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes). A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5·09; p=0·00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk scores for schizophrenia and principal component 1 were negatively associated (β=–0·01 [SE 0·003]; p=0·017). Similar to the principal component analysis results, for individual cardiac phenotypes, we observed negative associations between polygenic risk scores for schizophrenia and indexed right ventricular end-systolic volume (β=–0·14 [0·04]; p=0·0013, pFDR=0·015), indexed right ventricular end-diastolic volume (β=–0·17 [0·08]); p=0·025; pFDR=0·082), and absolute longitudinal peak diastolic strain rates (β=–0·01 [0·003]; p=0·0024, pFDR=0·015), and a positive association between polygenic risk scores for schizophrenia and right ventricular ejection fraction (β=0·09 [0·03]; p=0·0041, pFDR=0·015). Models examining the transforming growth factor-β (TGF-β)-specific and acute inflammation-specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2·62, p=0·022;F=2·54, p=0·026). Using linkage disequilibrium score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume and right ventricular ejection fraction (p=0·0090, p=0·0077). Interpretation:High polygenic risk scores for schizophrenia are associated with decreased cardiac volumes, increased ejection fractions, and decreased absolute peak diastolic strain rates. TGF-β and inflammatory pathways might be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Reduced absolute peak diastolic strain rates indicate increased myocardial stiffness and diastolic dysfunction, which increases risk of cardiac disease. Thus, genetic risk for schizophrenia is associated with cardiac structural changes that can worsen cardiac outcomes. Further work is required to determine whether these associations are specific to schizophrenia or are also seen in other psychiatric conditions. FundingNational Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council, Academy of Medical Sciences, Edmond J Safra Foundation, British Heart Foundation.

Atherosclerosis has become a leading public health problem. Previous studies suggest that enhanced muscle strength and muscle-derived cytokines (myokines) are linked with atherosclerosis. However, no previous prospective study has examined the relationship between grip strength (GS) and carotid atherosclerosis (CAS) in middle-aged and older adults. We therefore designed a cohort study to investigate the association between GS and the incidence of CAS in a population aged 45 years and over.The cohort study (n = 1258; follow-up range: 1-6 years, median: 4.0 years, age range: 45-85 years) was performed from 2013 to 2019 in Tianjin, China. CAS was measured using a carotid artery B-mode ultrasound system and defined by increased carotid intima-media thickness and plaques. GS was measured using a handheld digital dynamometer. Adjusted Cox proportional hazards regression models were used to assess the association between quartiles of GS and CAS.The incidence of CAS was 122 cases per 1000 person-years. In the final multivariable models, the adjusted hazard ratios (HRs) [95 % confidence interval (CI)] for CAS across quartiles of weight-adjusted GS (Q1-Q4) were as follows: 1.00 (reference), 0.82 (0.63, 1.06), 0.92 (0.71, 1.19), 0.69 (0.52, 0.91) and the HRs (95 % CI) across quartiles of GS (Q1-Q4) were as follows: 1.00 (reference), 1.06 (0.83, 1.36), 0.78 (0.59, 1.02), 0.76 (0.58, 0.995). For one unit and one standard deviation (SD) increase in weight-adjusted GS, the adjusted HRs (95 % CI) of CAS were 0.16 (0.05, 0.52) and 0.82 (0.72, 0.93), respectively. For one unit and one SD increase in GS, the adjusted HRs (95 % CI) of CAS were 0.98 (0.96, 0.995), and 0.47 (0.26, 0.83), respectively.Higher GS was associated with a lower incidence of carotid atherosclerosis in middle-aged and older adults. Further studies are required to clarify the causality.

Photothermal therapy becomes a hotspot in the treatment of bone tumors. Magnesium and its alloys are regarded as potential bone implants for their favorable mechanical property and biodegradable in vivo. However, there is few research devoted to fabricating a photothermal coating on Mg alloy. In the present study, reduced graphene oxide coating with a strong photothermal effect was prepared on the surface of AZ31 via two steps. Firstly, graphene oxide coating was deposited on the surface via electrophoresis deposited (GO#), followed by a reduction process of the graphene oxide coating in ultrapure water (rGO#). GO# and rGO# coatings were characterized by SEM, Raman, XRD, FTIR, and XPS. The results revealed that, compared with GO# coating, the content of oxygen-containing (C O/C O-C, C=O, O C=O) groups on rGO# coating was significantly decreased. rGO# coating was found tightly adhered to AZ31 substrate. According to the first-principles calculations, the well-bonded heterostructure between MgO and rGO is the main reason for the strong bonding force. Moreover, the prepared rGO# coating showed a superior photothermal effect, which brings a new strategy to the treatment of bone tumors with Mg-based implants.

The preferred configuration for bridging patients with respiratory failure while awaiting lung transplantation is venovenous extracorporeal membrane oxygenation (VV ECMO). However, the protective effect of VV ECMO on the lung, as well as the underlying mechanisms, are still unknown.We investigated the role of VV ECMO in preventing lung injury in vivo using a rat model. Additionally, the effects of Hippo/YAP signaling on alveolar epithelial type II cells (AT2)-mediated alveolar epithelial recovery in VV ECMO rats were also investigated. In the bronchoalveolar lavage fluid (BALF) and lung tissue, RNA sequencing, lung injury, edema, and cytokine expression were evaluated.VV ECMO significantly improved severe hypoxemia, reduced lung edema, and inflammatory response, and altered alveolar epithelial function, as indicated by reduced protein concentrations in BALF. This was associated with Hippo/YAP signaling activation, according to RNA sequencing analysis. Furthermore, we discovered that after VV ECMO, AT2 cells proliferated and differentiated, and this increase in AT2 cell activity was correlated to the increased nuclear expression of YAP, which is critical for alveolar epithelial recovery from lung injury. During VV ECMO, verteporfin-induced YAP inhibition and the loss of the oxygenator delayed lung alveolar epithelial recovery and led to a prolonged inflammatory response.These findings suggest that VV ECMO protects against lung injury by activating the Hippo/YAP signaling pathway. Strategies aimed at increasing YAP activity in AT2 cells could thus aid alveolar epithelial recovery, making VV ECMO easier for lung transplantation.

Abnormal placental trophoblast function is the main cause of missed abortion (MA). Src kinase-associated phosphoprotein 2 (SKAP2) indirectly affects actin reunion, which is significantly associated with cell migration.Twenty women with MA and 20 healthy women who underwent voluntarily induced abortion were included in this study. Immunohistochemistry, qRT-PCR, and western blotting were used to determine SKAP2, WAVE2, and ARP2 expression in the villous tissues. We investigated the effects of SKAP2 and the W336K mutant (blocked SKAP2 Src homology 3 function) on growth and migration in HTR8/SVneo cells using the CCK8 assay, flow cytometry, and transwell assay. The effects of SKAP2 on the WAVE2-ARP2/3 signaling pathway in HTR8/SVneo cells were evaluated by western blotting and immunofluorescence.Compared to the women in the voluntary abortion group, SKAP2 and WAVE2 expression levels were downregulated in the villous of patients with MA. In HTR8/SVneo cells, SKAP2 siRNA silencing regulated the growth and migration, while SKAP2 overexpression promoted growth and migration, and inhibited apoptosis. Additionally, SKAP2 regulated the expression of WAVE2 and ARP2, as well as the colocalization of actin with WAVE2. The SKAP2 W336K mutant could not alter WAVE2 and ARP2 expression, nor HTR8/SVneo cell growth and migration, with or without SKAP2 siRNA transfection.SKAP2 could activate the WAVE2-ARP2/3 pathway resulting in an increase of growth and migration in trophoblasts. SKAP2 probably played an important role in MA by affecting the growth and migration of trophoblasts.

The main parameters for achieving the optimum microwave dissipation performance in bi-layer absorbers are micromorphological characteristics, filler content composition, and layer configurations. In this research, two different doped strontium hexaferrite powders with SrFe10Al2O19 (PSrAl) and SrFe10CoTiO19 (CSrCoTi) chemical formulas were prepared through a solvothermal method. This study aims to identify optimal absorption conditions for bilayer samples by combining different magnetic compositions with varying ferromagnetic resonance and diverse morphologies with different layer arrangements. Single layer absorber samples comprising PSrAl powder with a polygonal pyramidal particle shape displayed dominating dielectric loss behavior and ferromagnetic resonance at about 11.6 GHz, according to the findings. On the other hand, absorber samples containing CSrCoTi powder with crochet ball like particle morphology, exhibit dominant magnetic loss behavior in the studied frequency range, with ferromagnetic resonance around 8.8 GHz. According to the results of bi-layer absorber samples, superior microwave dissipation performance could be achieved by inserting PSrAl powder in the top layer as a matching layer with 0.5 mm thickness and CSrCoTi powder as an absorbing layer 2 mm-thick. For a bi-layer absorber with a 2.5 mm total thickness The EAB (effective absorption bandwidth) is equal to 3.1 GHz at X-band and the minimum reflection loss is equal to −22 dB. The tuning morphology, which improved impedance matching and absorption properties by increasing the wave propagation path in the sample, synergistic effect between two distinct layers, and overlapping of resonance peaks of two components, is credited with this remarkable microwave absorption feature.

Due to the time-varying operation conditions, chemical processes are characterized by non-stationary characteristics, which makes it a great challenge for conventional process monitoring methods to capture the non-stationary variations In the non-stationary processes, the abnormality would cause the stationary variables to be non-stationary. In this article, a non-stationarity sensitive cointegration analysis monitoring method is proposed to explore potential non-stationary variations. First, the essential non-stationary variables are distinguished using Augmented Dickey-Fuller test to eliminate the influence of essential non-stationary under normal conditions. Then by further analyzing the faulty data, the variables which are sensitive to the non-stationary variations are selected. On this basis, cointegration analysis models are established for both the essential non-stationary variables and non-stationarity sensitive variables to explore long-term dynamic equilibrium relationship, respectively. With the selection of non-stationarity sensitive variables, the potential faulty information is emphasized in the process monitoring model, which makes the model capable to handle the non-stationary variations. Finally, the monitoring results are combined through Bayesian inference criterion. The proposed method is applied on the Tennessee Eastman process and a vinyl acetate monomer plant model, and the feasibility and performance are demonstrated.

Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer.CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478.Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; plt;0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (lt;1%) occurred in the bicalutamide group.In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile.Jiangsu Hengrui Pharmaceuticals.

We propose a robust post-selection inference method based on the Huber loss for the regression coefficients, when the error distribution is heavy-tailed and asymmetric in a high-dimensional linear model with an intercept term. The asymptotic properties of the resulting estimators are established under mild conditions. We also extend the proposed method to accommodate heteroscedasticity assuming the error terms are symmetric and other suitable conditions. Statistical tests for low-dimensional parameters or individual coefficient in the high-dimensional linear model are also studied. Simulation studies demonstrate desirable properties of the proposed method. An application to a genomic dataset about riboflavin production rate is provided.

Death in high- and intermediate-risk patients after self-expanding transcatheter (TAVR) and surgical aortic valve replacement (surgery) differed in mechanisms and timing. In both risk groups, 1-year all-cause mortality was lower in TAVR than in surgery patients. The differences in mechanism and timing of death in low-risk patients has not been studied. This report explores the mechanisms of death during 3 time periods; 0 to 30 days (early), 31 to 120 days (recovery), and 121 to 365 days (late).We retrospectively examined the mechanisms and timing of death following TAVR or surgery in the randomized Evolut Low Risk Trial. Patients were enrolled between March 2016 and November 2018 from 86 designated TAVR centers. Mechanisms of death were categorized as due to technical reasons, failure to repair, complications linked to death, failure to recover or other.All-cause mortality at 1 year was 2.2% for TAVR and 2.8% for surgery, p = 0.44. Early deaths included 3 TAVR patients, all due to technical reasons, and 8 surgery patients (1 technical, 5 complications and 2 failed to recover). Recovery period deaths included 6 TAVR patients (4 complications, 1 failed to recover and 1 other), and 1 surgery patient from complications of valve endocarditis. Late period deaths included 6 TAVR patients and 9 surgery patients, primarily due to complications.In this low-risk study cohort, no patient died from failure to repair the valve; reduction in procedural complications in the TAVR and surgery groups remain opportunities for further improvement in outcomes. Clinical Trial Registrations (clinicaltrials.gov): NCT02701283 (Evolut Low Risk).

Transmembrane protein 16F (TMEM16F) is a ubiquitously expressed Ca

Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disease caused by mutations in the X-linked dystrophin (

The human-centered robotic systems demand safe and robust controllers in many applications. This paper proposes an adaptive proxy-based sliding mode control approach for a class of typical second-order nonlinear systems. A new PID-type virtual coupling is designed between a virtual proxy and the physical object. Considering the unknown bound of lumped disturbances, an adaptation law is applied to online adjust the gain of a sign function which ensures the proxy to track the reference accurately. By using the Lyapunov theorem, the closed-loop system stability is proved. Both simulations and experiments are conducted to verify the proposed method based on a real-world pneumatic muscle actuator control platform. The results show that the proposed adaptive proxy-based sliding mode control approach presents better tracking accuracy, safety, and robustness than the conventional PID control and sliding mode control.