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Abstract Background We aimed to characterize the associations between physical activity levels and the risk of developing age-related diseases in the Coronary Artery Risk Development in Young Adults (CARDIA) study and used Mendelian randomization (MR) to assess whether there are causal relationships between physical activity levels and the risk of developing 8 age-related diseases (coronary atherosclerosis, ischemic heart disease, angina, Alzheimer’s disease, hypertension, type 2 diabetes, hyperlipidemia, and venous thromboembolism). Methods Based on the data available in the CARDIA, we obtained data related to five disease states: coronary heart disease, hypertension, diabetes, hyperlipidemia, and venous thromboembolism. Binary logistic regression analysis estimated the multivariable-adjusted associations between different physical activity statuses and diseases. For the MR study, we used summary-level data from a recently published genome-wide association study on physical activity (including vigorous physical activity and accelerometer-based physical activity) conducted with participants from the UK Biobank study. We selected the above 8 age-related diseases as our outcomes. Results In the CARDIA-based analysis, the risk of developing coronary heart disease [OR (95% CI): 0.562 (0.397–0.795)], hypertension [OR (95% CI): 0.703 (0.601–0.821)], diabetes [OR (95% CI): 0.783 (0.620–0.988)], and hyperlipidemia [OR (95% CI): 0.792 (0.662–0.949)] was negatively related to physical activity status when participants achieved the physical activity target. Our MR results support a negative causal association between genetically determined vigorous physical activity levels and the risk of developing 3 age-related diseases, namely, angina, hypertension and type 2 diabetes. Moreover, our results also support a negative causal association between genetically determined accelerometer-based physical activity levels and the risk of developing angina. Conclusions Promotion of physical activity is likely to prevent specific age-related diseases.

The development of the Internet of Things (IoT) has brought great convenience to people. However, some information security problems such as privacy leakage are caused by communicating with risky users. It is a challenge to choose reliable users with which to interact in the IoT. Therefore, trust plays a crucial role in the IoT because trust may avoid some risks. Agents usually choose reliable users with high trust to maximize their own interests based on reinforcement learning. However, trust propagation is time-consuming, and trust changes with the interaction process in social networks. To track the dynamic changes in trust values, a dynamic trust inference algorithm named Dynamic Double DQN Trust (Dy-DDQNTrust) is proposed to predict the indirect trust values of two users without direct contact with each other. The proposed algorithm simulates the interactions among users by double DQN. Firstly, CurrentNet and TargetNet networks are used to select users for interaction. The users with high trust are chosen to interact in future iterations. Secondly, the trust value is updated dynamically until a reliable trust path is found according to the result of the interaction. Finally, the trust value between indirect users is inferred by aggregating the opinions from multiple users through a Modified Collaborative Filtering Average-based Similarity (SMCFAvg) aggregation strategy. Experiments are carried out on the FilmTrust and the Epinions datasets. Compared with TidalTrust, MoleTrust, DDQNTrust, DyTrust and Dynamic Weighted Heuristic trust path Search algorithm (DWHS), our dynamic trust inference algorithm has higher prediction accuracy and better scalability.

Abstract Chronic liver disease and cancer are global health challenges. The role of the circadian clock as a regulator of liver physiology and disease is well established in rodents, however, the identity and epigenetic regulation of rhythmically expressed genes in human disease is less well studied. Here we unravel the rhythmic transcriptome and epigenome of human hepatocytes using male human liver chimeric mice. We identify a large number of rhythmically expressed protein coding genes in human hepatocytes of male chimeric mice, which includes key transcription factors, chromatin modifiers, and critical enzymes. We show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer, perturbs the transcriptome by altering the rhythmicity of the expression of more than 1000 genes, and affects the epigenome, leading to an activation of critical pathways mediating metabolic alterations, fibrosis, and cancer. HCV-perturbed rhythmic pathways remain dysregulated in patients with advanced liver disease. Collectively, these data support a role for virus-induced perturbation of the hepatic rhythmic transcriptome and pathways in cancer development and may provide opportunities for cancer prevention and biomarkers to predict HCC risk.

Abstract Background Insulin resistance and diabetes are associated with an increased risk of frailty, and frailty is associated with cardiovascular disease and premature mortality. We aim to investigate the impact of long‐term insulin resistance trajectories on future frailty and cardiovascular risk among young adults. Methods In total, 3168 participants with a 30‐year follow‐up period. The baseline period covered the first 15 years as the exposure period. Insulin resistance was determined using the homeostasis model assessment for insulin resistance (HOMA‐IR), and three trajectories (low, moderate, and high) were constructed. The subsequent 15 years constituted the event accrual period. Frailty was assessed using a deficit accumulation mode, and cardiovascular outcomes were obtained from the 15‐year event accrual period. Results The mean age of all 3168 participants was 41.0 (37.0–43.0) years, with 1750 (55.2%) being women. Participants in the high level of insulin resistance trajectory had an increased prevalence of frailty (OR: 1.55, 95% CI: 1.05–2.30, P = 0.028). Although no statistically significant associations were observed after full adjustment, single‐factor analysis indicated association between the moderate and high trajectories and frailty progression. Additionally, participants with high level of insulin resistance trajectory were associated with an increased risk of cardiovascular disease, coronary heart disease, and stroke. A notable correlation between HOMA‐IR trajectory and cardiovascular diseases was still discernible within the subgroup where the frailty index ≥0.12 (HR: 2.12, 95% CI: 1.17–3.83, P = 0.013) (P for interaction >0.05). Conclusions Long‐term high level of insulin resistance is associated with high prevalence of frailty, and an increased risk of cardiovascular events. Emphasizing the importance of early prevention and intervention for abnormal glucose metabolism in young adults to prevent frailty and cardiovascular disease.

Background In the past decade, the biological functions of various RNA modifications in mammals have been uncovered. N4‐acetylcytidine (ac4C), a highly conserved RNA modification, has been implicated in human diseases. Despite this, the involvement of RNA ac4C modification in cardiac physiology and pathology remains incompletely understood. NAT10 (N‐acetyltransferase 10) stands as the sole acetyltransferase known to catalyze RNA ac4C modification. This study aims to explore the role of NAT10 and ac4C modification in cardiac physiology and pathology. Methods and Results Cardiac‐specific knockout of NAT10, leading to reduced RNA ac4C modification, during both neonatal and adult stages resulted in severe heart failure. NAT10 deficiency induced cardiomyocyte apoptosis, a crucial step in heart failure pathogenesis, supported by in vitro data. Activation of the p53 signaling pathway was closely associated with enhanced apoptosis in NAT10‐deficient cardiomyocytes. As ac4C modification on mRNA influences translational efficiency, we employed ribosome footprints coupled with RNA sequencing to explore genome‐wide translational efficiency changes caused by NAT10 deficiency. We identified and validated that the translational efficiency of Kmt5a was suppressed in NAT10 knockout hearts due to reduced ac4C modification on its mRNA. This finding was consistent with the observation that Kmt5a protein levels were reduced in heart failure despite unchanged mRNA expression. Knockdown of Kmt5a in cardiomyocytes recapitulated the phenotype of NAT10 deficiency, including increased cardiomyocyte apoptosis and activated p53 signaling. Finally, overexpression of Kmt5a rescued cardiomyocyte apoptosis and p53 activation induced by NAT10 inhibition. Conclusions Our study highlights the significance of NAT10 in cardiomyocyte physiology, demonstrating that NAT10 loss is sufficient to induce cardiomyocyte apoptosis and heart failure. NAT10 regulates the translational efficiency of Kmt5a, a key mediator, through mRNA ac4C modification during heart failure.

Abstract Background Patients with overweight/obesity and type 2 diabetes are encouraged to lose weight, but not all losing weight gain better cardiovascular health, especially old adults. The change in skeletal muscle mass (SMM) could be the key that explains the heterogenous cardiovascular effects of weight loss. This study aims to assess whether the cardiovascular effects of weight loss vary for those gaining skeletal muscle along with weight loss. Methods The old adults with overweight/obesity and type 2 diabetes in the Look AHEAD study having muscle measurement from dual‐energy X‐ray absorptiometry were included. Based on the weight change (WC) and SMM change (SMMC) between baseline and the 4‐year follow‐up, participants were allocated into three groups—weight gain (WG) group, weight loss with muscle loss (WL‐ML) group and weight loss with muscle gain (WL‐MG) group. Cox proportional hazards regression was performed to evaluate the cardiovascular risk of those gaining or losing SMM with weight loss compared with those gaining weight. Among the participants with weight loss, the ratio of SMMC/WC was calculated, and the association of SMMC/WC with primary cardiovascular outcome was assessed. Results A total of 491 participants were included in the study with an average age of 64.56 ± 3.81 years old. A total of 47.0% were male and 49.9% were from the intensive lifestyle intervention arm. Based on their WC and SMMC, 43 were assigned to the WG group, 373 to the WL‐ML group and 75 to the WL‐MG group. Over a follow‐up of almost 10 years, 97 participants encountered the primary endpoint. The WG group had the highest incidence of 25.59%, the WL‐MG group had the lowest incidence of 9.33% and the WL‐ML group had 21.18% (P = 0.040). In the fourth adjusted Cox model, the WL‐MG group achieved significantly decreased odds of the primary endpoint compared with the WG group (hazard ratio [HR] 0.33, 95% confidence interval [CI] [0.12, 0.87], P = 0.026), whilst the WL‐ML group did not (HR 0.91, 95% CI [0.47, 1.78], P = 0.670). Among the participants with weight loss, when SMMC/WC reached around 50%, this HR soared to approximately two‐fold. Conclusions The participants gaining SMM along with weight loss achieved the lowest odds of adverse cardiovascular events, whilst those who lost SMM along with weight loss had comparable cardiovascular risk with those gaining weight. The more muscle lost during weight loss, the greater the harm. The cardiovascular effects of weight loss were modulated by whether the participants gained SMM meanwhile losing weight.

Abstract Aims This study aimed to assess the effect of blood pressure (BP) index, in terms of level and variability, on the progression of cardiovascular and renal diseases in patients with both heart failure (HF) and chronic kidney disease (CKD). Methods and results The study involved patients with HF and CKD from the database of the Chronic Renal Insufficiency Cohort (CRIC) study. The study endpoint includes the following: (i) primary endpoint, including cardiovascular disease (CVD) events, renal events, and all‐cause death; (ii) CVD events; (iii) renal events; and (iv) all‐cause death. Among 3939 participants in the CRIC study, a total of 382 patients were included. The duration of the follow‐up was 6.3 ± 2.7 years, the age was 60.2 ± 8.9 years, and 57.6% were male. BP index included 20 indicators in relation to BP level and variability, 4 of which were analysed including baseline systolic BP (SBP), standard deviation of SBP, coefficient of variation of diastolic BP (DBP CV), and average real variability of pulse pressure. In the Cox regression analysis after adjustment, baseline SBP was significant for the risk of primary endpoint [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.03–1.44, P = 0.02] and renal events (HR 1.54, 95% CI 1.22–1.95, P

Abstract Background The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance (IR). However, whether the TyG index has prognostic value in patients with moderate to severe aortic stenosis (AS) remains unclear. Methods This study enrolled 317 patients with moderate to severe AS at the First Affiliated Hospital of Sun Yat-Sen University. The patients were grouped according to the cut-off value of the TyG index. Cox regression with Firth’s penalized maximum likelihood method and restricted cubic splines regression were conducted to assess the association between the TyG index and all-cause mortality. The added value of the TyG index included in the traditional risk factors model for outcome prediction was also analyzed. Results Among 317 patients (mean age 67.70 years, 62.8% male), there was 84 all-cause mortality during a median 38.07 months follow-up. After fully adjusting for confounders, a per-unit increase in the TyG index was associated with a 62% higher all-cause mortality risk (HR 1.622, 95% CI 1.086–2.416, p = 0.018). The restricted cubic splines regression model revealed a linear association between the TyG index and the risk of all-cause mortality (p for nonlinearity = 0.632). The addition of the TyG index in the basic risk model has an incremental effect on the prediction of mortality [C-statistic change from 0.755 to 0.768; continuous net reclassification improvement (95% CI): 0.299 (0.051–0.546), p = 0.017; integrated discrimination improvement: 0.017 (0.001–0.033), p = 0.044]. Conclusions Higher IR assessed by the TyG index was associated with a higher risk of all-cause mortality in patients with moderate and severe AS.

Background: Low-density lipoprotein cholesterol (LDL-C) and type 2 diabetes (T2DM) are both independent risk factors for aortic stenosis (AS). In AS patients, whether LDL-C or T2DM is associated with fast AS progression (FASP) and their interaction is unknown. This study aims to test the hypothesis that there is a heightened risk of FASP when elevated LDL-C coexists with T2DM. Methods: The Real-world Data of Cardiometabolic Protections (RED-CARPET) study enrolled participants with mild (peak aortic velocity = 2–3 m/s), moderate (3–4 m/s) and severe (≥4 m/s) AS between January 2015 and December 2020 at a single center. Participants were further stratified by baseline LDL-C joint T2DM, follow-up echocardiography was performed after 6 months, and the primary outcome was FASP, defined as the annual change in aortic peak velocity (≥0.3 m/s/year). Results: Among the 170 participants included, 45.3% had mild AS, 41.2% had moderate AS, and 13.5% had severe AS. The mean age was 66.84 ± 12.64 years, and 64.1% were women. During the follow-up period of 2.60 ± 1.43 years, 35 (20.6%) cases of FASP were identified. Using non-T2DM with LDL-C

Background An association between variability of cardiovascular risk factors and cardiovascular events has been reported. We examined whether intensive lifestyle intervention (ILI) for weight loss decreased variability of cardiovascular risk factors with a view to additional cardiometabolic benefits. Methods and Results This study was a post hoc secondary analysis of the Look AHEAD (Action for Health in Diabetes) study. Cardiovascular risk factors were measured at 1‐year intervals for 4 years in 4249 adults with overweight or obesity and type 2 diabetes who were randomly assigned to ILI or diabetes support and education. Long‐term variability was defined as the SD of cardiovascular risk factors during 4‐year follow‐up. At multiple linear regression analysis, compared with the diabetes support and education group, the ILI group was associated with reduced variability of fasting blood glucose (β=−1.49 [95% CI, −2.39 to −0.59]), total cholesterol (β=−1.12 [95% CI, −1.75 to −0.48]), and low‐density lipoprotein cholesterol (β=−1.04 [95% CI, −1.59 to −0.49]), as well as increased variability of systolic blood pressure (β=0.27 [95% CI, 0.00–0.54]). No significant effect of ILI was found on the variability of diastolic blood pressure (β=−0.08 [95% CI, −0.22 to 0.05]). Conclusions Among adults with overweight or obesity and type 2 diabetes, ILI may reduce long‐term variability of fasting blood glucose, total cholesterol, and low‐density lipoprotein cholesterol. Our results support that ILI should be recommended to individuals with diabetes as part of management of long‐term glycemic and blood lipid control.

Abstract Objective We aimed to investigate the association between visit‐to‐visit heart rate variability (VVHRV) and all‐cause mortality in patients diagnosed with atrial fibrillation (AF). Previous studies have shown a positive correlation between VVHRV and several adverse outcomes. However, the relationship between VVHRV and the prognosis of AF remains uncertain. Methods In our study, we aimed to examine the relationship between VVHRV and mortality rates among 3983 participants with AF, who were part of the AFFIRM study (Atrial Fibrillation Follow‐Up Investigation of Rhythm Management). We used the standard deviation of heart rate (HRSD) to measure VVHRV and divided the patients into four groups based on quartiles of HRSD (1st,

Summary: Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. Hypoxia inducible factors (HIFs) define metabolic responses to low oxygen and regulate inflammatory responses in the lower respiratory tract. We demonstrate a role for HIFs to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors reduce the expression of the RSV entry receptor nucleolin and inhibit viral cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for this respiratory pathogen.

Abstract Aims/introduction Weight variability is associated with cardiovascular outcomes in diabetic patients. However, whether the guideline‐recommended intensive lifestyle intervention (ILI) will affect this association in overweight or obese adults with diabetes is not well established. Materials and Methods In 3,859 participants from the Action for Health in Diabetes (Look AHEAD) trial, the associations of 4 year weight variability measured by variability independent of the mean (VIM) with major adverse cardiovascular event (MACE) and secondary outcomes in ILI and diabetes support & education (DSE) arm were evaluated. Results During a median follow‐up of 9.6 years, 255 (12.9%) participants in the ILI arm and 247 (13.2%) participants in the DSE arm developed MACE. Participants with the highest quartile of weight variability (VIM Q4) experienced a 2.23‐fold higher risk of MACE compared with the lowest quartile (VIM Q1) in the DSE arm (hazard ratio [HR] 2.23; 95% CI 1.51–3.30). Compared with the lowest weight variability (VIM Q1), participants with the highest weight variability (VIM Q4) were associated with higher risks of secondary cardiovascular composite outcome (HR 1.88; 95% CI 1.20–2.95), all‐cause mortality (HR 3.19; 95% CI 1.75–5.82), and myocardial infarction (HR 1.95; 95% CI 1.12–3.37) in the DSE arm. Conclusions Among the overweight or obese individuals with type 2 diabetes mellitus, rising weight variability was independently associated with increased MACE risks in the DSE arm. Therefore, a guideline‐recommended ILI strategy for weight loss should be adopted to improve cardiovascular outcomes without worrying about the effect of weight fluctuations.

Supercritical anti-solvent fluidized bed (SAS-FB) coating technology has the advantages of reducing particle size, preventing high surface energy particle aggregation, improving the dissolution performance and bioavailability of insoluble drugs. The poor solubility of Biopharmaceutics Classification System (BCS) class IV drugs poses challenges in achieving optimal bioavailability. Numerous anti-cancer drugs including paclitaxel (PTX) belong to the BCS class IV, hindering their therapeutic efficacy. To address this concern, our study explored SAS-FB technology to coat PTX with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) onto lactose. Under our optimized conditions, we achieved a PTX coating efficiency of 96.8%. Further characterization confirmed the crystalline state of PTX in the lactose surface coating by scanning electron microscopy and X-ray powder diffraction. Dissolution studies indicated that SAS-FB processed samples release over 95% of the drug within 1 min. Moreover, cell transmembrane transport assays demonstrated that SAS-FB processed PTX samples co-coated with TPGS had an enhanced PTX internalization into cells and a higher permeability coefficient compared to those without TPGS. Finally, compared to unprocessed PTX, SAS-FB (TPGS) and SAS-FB processed samples showed a 2.66- and 1.49-fold increase in oral bioavailability in vivo, respectively. Our study highlights the efficacy of SAS-FB co-coating for PTX and TPGS as a promising strategy to overcome bioavailability challenges inherent in BCS class IV drugs. Our approach holds broader implications for enhancing the performance of similarly classified medications.

Electrochemical CO2 reduction is a typical surface-mediated reaction, with its reaction kinetics and product distributions largely dependent on the dynamic evolution of reactive species at the cathode–catholyte interface and on the resultant mass transport within the hydrodynamic boundary layer in the vicinity of the cathode. To resolve the complex local reaction environment of branching CO2 reduction pathways, we here present a differential electrochemical mass spectroscopic (DEMS) approach for Cu electrodes to investigate CO2 mass transport, the local concentration gradients of buffering anions, and the Cu surface topology effects on CO2 electrolysis selectivity at a temporal resolution of ∼400 ​ms. As a proof of concept, these tuning knobs were validated on an anion exchange membrane electrolyzer, which delivered a Faradaic efficiency of up to 40.4% and a partial current density of 121 ​mA ​cm−2 for CO2-to-C2H4 valorization. This methodology, which bridges the study of fundamental surface electrochemistry and the upgrading of practical electrolyzer performance, could be of general interest in helping to achieve a sustainable circular carbon economy.

Abstract Sulfide solid electrolyte (SSE)‐based all‐solid‐state Li batteries (ASSLBs) can overcome the problems of low energy density and safety concern of current Li‐ion batteries. However, the practical application of SSE‐based ASSLBs is suffered from several problems, especially interfacial issues between Li metal anode (LMA) and SSEs. Therefore, in this study, the problems of the LMA–SSE interface and their corresponding solutions are reviewed. First, the interfacial problems are summarized, namely the side reactions of SSEs, the Li dendrite growth, and poor contact between the electrode and electrolyte. Second, the available strategies to improve the robustness of the interface are discussed, including the protection of the LMA, substitution of the LMA, and modification of SSEs. Third, the characterization methods used to analyze the morphological and compositional evolution of the interface during cycling are introduced. Finally, the limitations and future research directions are proposed.

Introduction Percutaneous coronary intervention (PCI)-related myocardial infarction (type 4a MI) and major periprocedural myocardial injury have been demonstrated leading to poor prognosis of patients with coronary heart disease (CHD) undergoing elective PCI and still remain high occurrence even after the therapy of dual antiplatelet agents and statins. Proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to be effectively in reducing the risk of acute MI (AMI). However, the effect of alirocumab on preventing PCI-related MI or major periprocedural myocardial injury in patients with CHD undergoing elective PCI remains uncertain.Methods and analysis Alirocumab effect on Preventing Periprocedural ischaemic Events in coronary heart diseAse patients undergoing coronary StEnting trial is a multicentre, open-label, randomised controlled trial aiming to determine whether alirocumab could reduce the incidence of type 4a MI or major periprocedural myocardial injury in patients with CHD undergoing elective PCI. In total, 422 non-AMI CHD patients planned to undergo elective PCI will be randomly assigned to receive standard pharmacotherapy of CHD (control group) or additional use of subcutaneous alirocumab 75 mg 1 day before procedure (alirocumab group). The primary outcome is type 4a MI or major periprocedural myocardial injury defined as high-sensitivity cardiac troponin elevating above 5×99 th percentile upper reference limit in 48 hours after PCI. Patients will continue receiving standard pharmacotherapy or additional biweekly subcutaneous alirocumab 75 mg for 3 months according to the initial randomisation group. We will follow up for 3 months and record all the major adverse cardiovascular events (MACEs). Incidence of PCI-related MI or major periprocedural myocardial injury, and MACE in 3 months after PCI will be compared between control group and alirocumab group.Ethics and dissemination Ethics approval has been obtained from the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University with approval number: (2022)02-140-01. The results of this study will be reported through peer-reviewed journals and conference presentations.Trial registration number ChiCTR2200063191.

Summary: Human immunodeficiency virus 1 (HIV-1) causes major health burdens worldwide and still lacks curative therapies and vaccines. Circadian rhythms are endogenous daily oscillations that coordinate an organism’s response to its environment and invading pathogens. Peripheral viral loads of HIV-1 infected patients show diurnal variation; however, the underlying mechanisms remain unknown. Here, we demonstrate a role for the cell-intrinsic clock to regulate rhythmic HIV-1 replication in circadian-synchronized systems. Silencing the circadian activator Bmal1 abolishes this phenotype, and we observe BMAL1 binding to the HIV-1 promoter. Importantly, we show differential binding of the nuclear receptors REV-ERB and ROR to the HIV-long terminal repeat at different circadian times, demonstrating a dynamic interplay in time-of-day regulation of HIV-1 transcription. Bioinformatic analysis shows circadian regulation of host factors that control HIV-1 replication, providing an additional mechanism for rhythmic viral replication. This study increases our understanding of the circadian regulation of HIV-1, which can ultimately inform new therapies.

Background Coronary artery calcification (CAC) is a crucial indicator of subclinical atherosclerotic cardiovascular disease. The relationship between long‐term insulin resistance (IR) trajectory and CAC has been explored in few studies. Therefore, this study aimed to investigate whether the long‐term IR time series of young adults are associated with the incidence of CAC in midlife. Methods and Results In a cohort study comprising 2777 participants from the CARDIA (Coronary Artery Risk Development in Young Adults) study, the homeostasis model assessment for IR was used to measure IR levels, and group‐based trajectory modeling was used to fit three 25‐year homeostasis model assessments for IR trajectories. Logistic regression was used to estimate the association between the 3 homeostasis model assessments for IR trajectories and CAC events at year 25. The results showed that among 2777 participants (mean age, 50.10±3.58 years; 56.2% women; 46.4% Black), there were 780 incident CAC events after a 25‐year follow‐up. After full adjustment, the prevalence of CAC was higher in the moderate‐ (odds ratio [OR], 1.40 [1.10–1.76]) and the high‐level homeostasis model assessments for IR trajectories (OR, 1.84 [1.21–2.78]) than in the low‐level trajectory. This association was observed in obese individuals despite the negative interaction between IR and different types of obesity (all P interactions >0.05). Conclusions Our study revealed that young adults with a higher level of IR were more likely to develop CAC in middle age. Furthermore, this association persisted in obese individuals. These findings highlight the importance of identifying subclinical cardiovascular risk factors and implementing primary prevention measures.

Background: Few studies have examined the relationship between the fluctuation of heart rate control over time and cardiovascular outcomes in patients with atrial fibrillation. Our study sought to evaluate the independent association between time in target range (TIR) of resting heart rate and cardiovascular outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) study. Methods: Target range of resting heart was defined as less than 80 beats per minute (bpm) for both rate and rhythm control groups. Time in target range was estimated over the first 8 months of follow-up using Rosendaal interpolation method. The association between TIR of resting heart rate and cardiovascular outcomes was estimated using adjusted Cox proportional hazards regression models. Results: Time in target range of resting heart rate (months 0 through 8) was 71 ± 34% in the rate control group and 83 ± 27% in the rhythm control group. Each 1-SD increase in TIR of resting heart rate was significantly associated with lower risk of major adverse cardiovascular events after full adjustment for demographics, medical history and history of prior heart surgery, as well as all-cause mortality. Conclusions: Time in target range of resting heart rate independently predicts the risk of cardiovascular outcomes in patients with atrial fibrillation. Long-term maintenance of heart rate on target is of great importance for patients with atrial fibrillation.

Soft materials bearing rigid, lightweight, and vibration-dampening properties offer distinct advantages over traditional wooden and metal-based fillings for spent fuel transport casks, due to their low density, tunable structure, excellent mechanical properties, and ease of processing. In this study, a novel type of rigid polyurethane foam is prepared using a conventional polycondensation reaction between isocyanate and hydroxy groups. Moreover, the density and size of the pores in these foams are precisely controlled through simultaneous gas generation. The as-prepared polyurethane exhibits high thermal stability exceeding 185 °C. Lifetime predictions based on thermal testing indicate that these polyurethane foams could last up to over 60 years, which is double the lifetime of conventional materials of about 30 years. Due to their occlusive structure, the mechanical properties of these polymeric materials meet the design standards for spent fuel transport casks, with maximum compression and tensile stresses of 6.89 and 1.37 MPa, respectively, at a testing temperature of −40 °C. In addition, these polymers exhibit effective flame retardancy; combustion ceased within 2 s after removal of the ignition source. All in all, this study provides a simple strategy for preparing rigid polymeric foams, presenting them as promising prospects for application in spent fuel transport casks.

Abstract Background This study aimed to investigate the associations between the triglyceride-glucose (TyG) index in young adulthood with incident cardiovascular disease (CVD) and mortality. Methods We included 4,754 participants from the Coronary Artery Risk Development in Young Adults study at baseline. The TyG index was calculated as ln (fasting TG [mg/dl] × fasting glucose [mg/dl]/2), and the TyG index trajectories were identified by using the latent class growth mixture model. We evaluated the association between the baseline and trajectories of the TyG index with incident CVD events and all-cause mortality using Cox proportional hazards regression analysis. The added value of the TyG index included in pooled cohort equations for CVD prediction was also analyzed. Results Among 4754 participants (mean age 24.72 years, 45.8% male, 51.2% black), there were 158 incident CVD events and 246 all-cause mortality during a median 25 years follow-up. After adjusting for multiple confounding variables, each one-unit increase in the TyG index was associated with a 96% higher CVD risk (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.44–2.66) and a 85% higher all-cause mortality risk (HR 1.85, 95% CI 1.45–2.36). Three distinct trajectories of the TyG index along the follow-up duration were identified: low (44.0%), moderate (45.5%), and high (10.5%). Compared with those participants in the low TyG index trajectory group, those in the high TyG index trajectory group had a greater risk of CVD events (HR 2.35, 95% CI 1.34–4.12) and all-cause mortality (HR 3.04, 95% CI 1.83–5.07). The addition of baseline TyG index to pooled cohort equations for CVD improved the C-statistics (P

Background and aims: The benefits of reaching ideal cardiovascular health (CVH) are well known, but it is unclear whether positive CVH changes from young adulthood to middle age reduce subclinical atherosclerosis risk. This study examined associations of changes in CVH from young adulthood to middle age and CVH in young adulthood with subclinical atherosclerosis. Methods: Data was analyzed from the Coronary Artery Risk Development in Young Adults (CARDIA) study. CVH was examined at years 0 and 20 using Life Simple 7 metrics from AHA guideline. Coronary artery calcium (CAC) was identified at years 20 and 25. Carotid intima-media thickness (IMT) was identified at year 20. Results: Among 2,935 participants (56.2% women, 46.7% black), the change of CVH score was –1.26 (2.13). For per 1-unit increase in CVH at baseline, the adjusted odds ratios (ORs) of presence of CAC and IMT were 0.81 (95% CI 0.78, 0.86) and 0.85 (95% CI 0.76, 0.94), respectively. For per 1-unit increase in CVH changes, the adjusted ORs of CAC and IMT were 0.86 (95% CI 0.82, 0.90) and 0.81 (95% CI 0.73, 0.90). Compared with stable moderate CVH, improvement from moderate to high was associated with a lower risk of CAC (0.64 [95% CI 0.43, 0.96]), while retrogression from moderate to low was associated with a higher risk of CAC (1.45 [95% CI 1.19, 1.76]). Conclusions: Positive changes of CVH during young adulthood are associated with negative subclinical atherosclerosis risk in middle age, indicating the importance of reaching an ideal cardiovascular health status through young adulthood.

A self-organized geometric model is proposed for data dimension reduction to improve the robustness of manifold learning. In the model, a novel mechanism for dimension reduction is presented by the autonomous deforming of data manifolds. The autonomous deforming vector field is proposed to guide the deformation of the data manifold. The flattening of the data manifold is achieved as an emergent behavior under the virtual elastic and repulsive interaction between the data points. The manifold’s topological structure is preserved when it evolves to the shape of lower dimension. The soft neighborhood is proposed to overcome the uneven sampling and neighbor point misjudging problems. The simulation experiment results of data sets prove its effectiveness and also indicate that implicit features of data sets can be revealed. In the comparison experiments, the proposed method shows its advantage in robustness.

Here, the authors report the functionalization of monolayer transition metal dichalcogenides with hydrogen-bonded 2D supramolecular networks of cyanuric acid and melamine, leading to a pronounced n-doping effect and enhancement of MoS2 catalytic activity for hydrogen evolution reactions.

ObjectiveIn order to prevent flue gas from polluting the ship deck and air intake, a numerical analysis of flue gas diffusion characteristics is carried out. MethodsFirst, a flue gas diffusion model is established using the computational fluid dynamics (CFD) method, and statistical performance indicators are introduced to evaluate and verify the accuracy of the model. On this basis, the effect of exhaust temperature on the flue gas diffusion process in a static wind environment is studied in order to understand the mechanisms of the flue gas deposition and diffusion processes, and the influence of flue gas on the ship's air intake is further analyzed. ResultsThe results show that the exhaust temperature determines the transition process of flue gas from a heavy gas cloud to a neutral gas cloud, thereby determining the diffusion/sedimentation effect. As flue gas diffuses vertically in static windy environment, the pollution is concentrated in the middle of the ship; when the exhaust temperature reaches 417 K, the flue gas will not settle significantly but directly diffuse into the normal temperature environment. ConclusionThe results of this study can provide a theoretical basis for the design of ship exhaust parameters and air intake layout.

BackgroundChronically high blood pressure (HBP) is a known risk factor for cardiovascular diseases. We measured the intensity of hypertensive exposure in young adults and calculated its prognostic significance for subclinical atherosclerosis in middle age.MethodsThe Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled 5,115 healthy black and white Americans who were 18–30 years old at baseline (1985–1986). The intensity of hypertensive exposure was calculated as the area under the curve (mm Hg × years) from baseline to year 15. Coronary artery calcium (CAC) was identified at years 15, 20, and 25, and intima-media thickness (IMT) was identified at year 20.ResultsAt baseline, the mean age was 40.1 years; 55.1% of participants were women, and 46.5% were black. After adjustment, cumulative systolic BP (SBP) was positively associated with CAC [hazard ratio (HR) = 1.23 (1.14, 1.32)] and IMT [β = 0.022 (0.017, 0.028)]. For CAC, the C-statistic for cumulative SBP was 0.643 (0.619, 0.667); compared to baseline SBP, the net reclassification index (NRI) of cumulative SBP was 0.180 (0.115, 0.256) and the integrated discrimination improvement (IDI) was 0.023 (0.012, 0.036). For IMT, the C-statistic for cumulative SBP was 0.674 (0.643, 0.705), the NRI was 0.220 (0.138, 0.305), and the IDI was 0.008 (0.004, 0.0012).ConclusionGreater intensity of hypertensive exposure in early adulthood is associated with subclinical atherosclerosis in middle age and provides better prognostic value than baseline BP for early cardiovascular risk.

The preparation of nanocages with unprecedented architectures may lead to new functions. Here the authors report the self-assembly of organic cages featuring twin cavities; the geometry and pocket size determine the molecular packing and the proton conductivity performance.

The bottom-up synthesis and preliminary characterizations of a new biphenylene-based 2D framework are presented. This new low-dimensional carbon allotrope potentially completes the many hypothesized carbon networks based on biphenylene.

Background Currently available guidelines contain conflicting recommendations on the management of blood pressure (BP) in patients with diabetes mellitus (DM). Therefore, it is necessary to appraise the guidelines and summarize the agreements and differences among recommendations. Methods Four databases and the websites of guideline organizations were searched for guidelines regarding BP targets and thresholds for pharmacologic therapy in DM patients, and the included guidelines were appraised with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Results In 6,498 records identified, 20 guidelines met our inclusion criteria with 64.0% AGREE II scores (interquartile range, 48.5% to 72.0%). The scores of the European and American guidelines were superior to those of the Asian guidelines (both adjusted P140 mm Hg (10 guidelines, 50%) and diastolic BP thresholds >90 mm Hg (nine guidelines, 45%). The tiny minority of the guidelines provided the relevant recommendations regarding the lower limit of official BP targets and the ambulatory BP monitoring (ABPM)/home BP monitoring (HBPM) targets and thresholds in DM patients. Conclusion The lower official BP targets (

Summary: Background: Whether the association between post-therapeutic left ventricular volume change and long-term outcomes in ischaemic cardiomyopathy is influenced by the performance of coronary artery bypass grafting (CABG) remains unclear. We sought to perform a post-hoc analysis of the Surgical Treatment of Ischaemic Heart Failure (STICH) trial to investigate this association in patients treated with medical therapy (MED) with or without CABG. Methods: From July 24, 2002, to May 5, 2007, 1212 patients with ischaemic cardiomyopathy were enrolled in the STICH trial (NCT00023595) from 99 sites in 22 countries, and were randomly assigned to undergo CABG plus MED or MED alone. We completed a post-hoc analysis of this trial. Patients with paired left ventricular end-systolic volume index (ESVI) measured at baseline and 4-months were included in our analysis. The association between change in ESVI from baseline to 4-months and cardiovascular mortality or all-cause mortality was assessed in MED arm and CABG plus MED arm. Findings: 523 patients were included, with 291 (55.6%) assigned to MED arm and 232 (44.4%) to CABG plus MED arm. At a 4-month follow-up, ESVI reduction was more likely to occur among patients undergoing CABG plus MED. After a median follow-up of 10.3 years, for each 26% (1- standard deviation) decrement in ESVI, it was associated with a 22% lower risk of cardiovascular mortality (HR 0.78; 95% CI, 0.65-0.94) and 19% lower risk of all-cause mortality (HR 0.81; 95% CI, 0.69-0.95) in MED arm, whereas this association was not shown in CABG plus MED arm (cardiovascular mortality: HR 0.90; 95%CI, 0.74-1.10; all-cause mortality: HR 0.93; 95%CI, 0.79-1.09). A 16% reduction in ESVI was determined to be the most appropriate threshold of change in ESVI in the MED arm. Interpretation: In patients with ischaemic cardiomyopathy, left ventricular volume change was associated with long-term prognosis after medical therapy alone, whereas was likely not an optimal benchmark for evaluating the survival benefits associated with CABG. A more than 16% reduction in ESVI might assist in therapeutic efficacy assessment and prognostic evaluation in medically treated patients. Funding: National Natural Science Foundation of China; Natural Science Funds of Guangdong Province.

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.

Background The associations of time‐averaged cumulative blood pressure (BP) from midlife to late life with microvasculature expressed as retinal vessel diameters is not well studied. The aim of this study was to evaluate the association of cumulative systolic BP and diastolic BP (DBP) with retinal vessel calibers, focusing on race differences. Methods and Results The analysis included 1818 adults from the ARIC (Atherosclerosis Risk in Communities) study attending the fifth visit (2011–2013; age 77±5 years, 17.1% Black participants). Time‐averaged cumulative BPs were calculated as the sum of averaged BPs from adjacent consecutive visits (visits 1–5) indexed to total observation time (24±1 years). Summarized estimates for central retinal arteriolar equivalent and central retinal venular equivalent at the fifth visit represent average retinal vessel diameters. The arteriole:venule ratio was calculated. We tested for effect modification by race. Results from multiple linear regression models suggested that higher time‐averaged cumulative DBP (β [95% CI] per 1‐SD increase: −1.78 [−2.53, −1.02], P

Summary: Background: We aimed to assess whether the cardiovascular effects of intensive lifestyle intervention (ILI) vary for those who can maintain the lower body weight after weight loss through ILI. Methods: In the secondary analysis of the Look AHEAD trial, we identified the status of weight loss for the participants in the ILI arm based on body weight time in range (TIR). These participants were allocated to three groups according to body weight TIR: 0% (n = 727), >0% to 50% (n = 656), and >50% to 100% (n = 811). For each group, cardiovascular outcomes were compared with matched participants receiving diabetes support & education (DSE) using 1:1 propensity score matching and Cox regression. Findings: During a median of 9·5 years of follow-up, participants with TIR of >50% to 100% can effectively maintain their body weight after weight loss through ILI; participants with TIR of 0% or >0% to 50% do not achieve or maintain weight loss. Compared with the corresponding matched participants in the DSE arm, participants with TIR of >50% to 100% in the ILI arm had a 45% lower risk of the primary outcome (HR 0·55, 95% CI 0·40–0·76), and no significant effects were found on the risk of the primary outcome in participants with TIR of 0% (HR 1·12, 95% CI 0·86–1·46) or >0% to 50% (HR 1·14, 95% CI 0·85–1·52). Interpretation: In adults with overweight/obesity and type 2 diabetes, ILI might help in lowering the risk of cardiovascular events when the lower body weight is maintained after weight loss. Funding: None.

The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the human liver transcriptome but their role in hepatitis B virus infection is largely unknown. Here, Zhuang et al. show that REV-ERB regulates hepatitis B virus entry and BMAL1 directly binds HBV DNA and activates viral genome transcription.

Abstract Background Echocardiography (echo) is the primary imaging modality for infective endocarditis (IE). However, the recommendations on timing and mode selection for transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) vary across guidelines, which can be confusing for clinical decision makers. In this case, we aim to appraise the quality of recommendations by appraising the quality of various guidelines. Methods A search of guidelines containing recommendations for the appropriate use of echo in adult IE patients published in English between 2007 and 2019 was conducted. The APPRAISAL OF GUIDELINES FOR RESEARCH & EVALUATION II (AGREE II) instrument was applied independently by two reviewers to assess the integrated quality of the identified guidelines. The recommendations of concern are extracted from related chapters. Results A total of 9 guidelines met the criteria, with AGREE II scores ranging from 36 to 79%, and the domain of “stakeholder involvement” received the lowest score. The most contentious issue is whether a follow-up TEE is mandatory in uncomplicated native valve IE with an initial positive TTE. Conflicting recommendations are presented with a low evidence level based on little evidence. Conclusions In general, the recommendations proposed in the 9 identified guidelines on the appropriate use of echo are satisfying. The guideline quality score can be taken into account by the clinicians when evaluating the recommendations for clinical decisions. Additional studies with high evidence level should be conducted on the most controversial issues of whether a subsequent TEE is mandatory in uncomplicated native valve IE with an initial positive TTE.

Background There is a paucity of evidence regarding the association between visit‐to‐visit blood pressure variability and residual cardiovascular risk. We aimed to provide relevant evidence by determining whether high systolic blood pressure (SBP) variability in the optimal SBP levels still influences the risk of cardiovascular disease. Methods and Results We studied 7065 participants (aged 59.3±5.6 years; 44.3% men; and 82.9% White) in the ARIC (Atherosclerosis Risk in Communities) study with optimal SBP levels from visit 1 to visit 3. Visit‐to‐visit SBP variability was measured by variability independent of the mean in the primary analysis. The primary outcome was the major adverse cardiovascular event (MACE), defined as the first occurrence of all‐cause mortality, coronary heart disease, stroke, and heart failure. During a median follow‐up of 19.6 years, 2691 participants developed MACEs. After multivariable adjustment, the MACE risk was higher by 21% in participants with the highest SBP variability (variability independent of the mean quartile 4) compared with the lowest SBP variability participants (variability independent of the mean quartile 1) (hazard ratio, 1.21; 95% CI, 1.09–1.35). The restricted cubic spline showed that the hazard ratio for MACE was relatively linear, with a higher variability independent of the mean being associated with higher risk. These association were also found in the stratified analyses of participants with or without hypertension. Conclusions In adults with optimal SBP levels, higher visit‐to‐visit SBP variability was significantly associated with a higher risk of MACE regardless of whether they had hypertension. Therefore, it may be necessary to further focus on the visit‐to‐visit SBP variability even at the guideline‐recommended optimal blood pressure levels.

Background The association between blood pressure control and clinical outcomes is unclear among patients with heart failure with preserved ejection fraction. Both too high and too low of systolic blood pressure (SBP) have been reported to be related to poor clinical prognosis. This study aimed to assess the association between time in SBP target range and adverse clinical events among patients with heart failure with preserved ejection fraction. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, a randomized clinical trial that compared the efficacy and safety of spironolactone in patients with heart failure with preserved ejection fraction. Time in target range (TTR) was calculated using linear interpolation, with the target range of SBP defined as 110 to 130 mm Hg. The association between TTR with adverse outcomes was estimated using multivariable Cox regression to adjust for multiple confounders. Participants with greater TTR were younger, more likely to be White, had less comorbidities, and lower body mass index. After adjusting for multiple covariates including mean SBP, 1‐SD increment (38.3%) of TTR was significantly associated with a decreased risk of primary composite end point (hazard ratio [HR], 0.81 [0.73–0.90]), as well as a lower risk of all‐cause mortality (HR, 0.81 [0.73–0.90]), cardiovascular death (HR, 0.78 [0.68–0.90]), and heart failure hospitalization (HR, 0.85 [0.74–0.97]). Results were similar when participants were categorized by TTR groups. Subgroup analyses showed that the associations were more significant in young people than in the old (Pinteraction=0.028). Conclusions In patients with heart failure with preserved ejection fraction, greater time in SBP target range was statistically associated with a decreased risk of cardiovascular outcomes and mortality events beyond blood pressure level, especially among younger patients.

Abstract The robust fully conjugated covalent organic frameworks (COFs) are emerging as a novel type of semi‐conductive COFs for optoelectronic and energy devices due to their controllable architectures and easily tunable the highest occupied molecular orbital (HOMO) and the lowest occupied molecular orbital (LUMO) levels. However, the carrier mobility of such materials is still beyond requirements due to limited π‐conjugation. In this study, a series of new polyarylether‐based COFs are rationally synthesized via a direct reaction between hexadecafluorophthalocyanine (electron acceptor) and octahydroxyphthalocyanine (electron donor). These COFs have typical crystalline layered structures, narrow band gaps as low as ≈0.65 eV and ultra‐low resistance (1.31 × 10−6 S cm−1). Such COFs can be composed of two different metal‐sites and contribute improved carrier mobility via layer‐altered staking mode according to density functional theory calculation. Due to the narrow pore size of 1.4 nm and promising conductivity, such COFs and electrochemically exfoliated graphene based free‐standing films are fabricated for in‐plane micro‐supercapacitors, which demonstrate excellent volumetric capacitances (28.1 F cm−3) and excellent stability of 10 000 charge–discharge cycling in acidic electrolyte. This study provides a new approach toward dioxin‐linked COFs with donor‐acceptor structure and easily tunable energy levels for versatile energy storage and optoelectronic devices.

Enhancement of protein synthesis from mRNA translation is one of the key steps supporting cardiomyocyte hypertrophy during cardiac remodeling. The methyltransferase-like5 (METTL5), which catalyzes m6A modification of 18S rRNA at position A1832, has been shown to regulate the efficiency of mRNA translation during the differentiation of ES cells and the growth of cancer cells. It remains unknown whether and how METTL5 regulates cardiac hypertrophy. In this study, we have generated a mouse model, METTL5-cKO, with cardiac-specific depletion of METTL5 in vivo. Loss function of METTL5 promotes pressure overload-induced cardiomyocyte hypertrophy and adverse remodeling. The regulatory function of METTL5 in hypertrophic growth of cardiomyocytes was further confirmed with both gain- and loss-of-function approaches in primary cardiomyocytes. Mechanically, METTL5 can modulate the mRNA translation of SUZ12, a core component of PRC2 complex, and further regulate the transcriptomic shift during cardiac hypertrophy. Altogether, our study may uncover an important translational regulator of cardiac hypertrophy through m6A modification.

Objective: In our present study, our objective was to appraise guidelines on antithrombotic therapy in atrial fibrillation post-percutaneous coronary intervention and to explore the differences in treatment practices for better informed decision-making. Methods: We searched for English language guidelines published between January 2000 and December 2020 at MEDLINE, Embase and websites of guideline organizations. Guidelines with recommendations on antithrombotic regimens for patients with AF undergoing PCI were included. Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was applied to assess guidelines. The reporting of conflicts of interest (COI) was evaluated separately by the RIGHT (Reporting Item for Practice Guidelines in Healthcare) checklist as supplementary items. Results: Sixteen guidelines were included, among which 13 (81.25%) were considered as ‘recommended’ and 1 (6.25%) as ‘unrecommended.’ The average scores of guidelines ranged from 55% to 88% (70% as good quality). Among the 6 domains of AGREE II, scope and purpose (84%) and editorial independence(87%) were considered to be the fields in which CPGs performed best, evidenced by the highest mean AGREE II scores. The domains in which the reviewed CPGs received the lowest mean scores were stakeholder involvement (63%) and applicability (58%). The intraclass correlation coefficient scores were excellent in each domain. The overall quality of the selected CPGs was optimal, with the highest score in domain ‘scope and purpose’, and the lowest score in the domain ‘applicability.’ The reporting of COI was satisfactory. Conclusions: For the recommendations on antithrombotic strategies, guidelines with high AGREE II scores still exist discrepancy on the timing and selection. Current guidance documents on the treatment vary in methodological rigor and recommendations are not always consistent.

Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, subgenomic RNAs, and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.

The most widely used material as a hole-transport layer (HTL) for effective normal perovskite solar cells (PSCs) is still 2,2′,7,7′-Tetrakis[N, N-di(4-methoxyphenyl)amino]-9,9′-spirobifluorene (Spiro-OMeTAD), which requires heavy doping with the hydroscopic Lithium bis(trifluoromethanesulfonyl)imide (Li-ΤFSI). However, the long-term stability and performance of PCSs are frequently hampered by the residual insoluble dopants in the HTL, Li+ diffusion throughout the device, dopant by-products, and the hygroscopic nature of Li-TFSI. Due to the high cost of Spiro-OMeTAD, alternative efficient low-cost HTLs, such as octakis(4-methoxyphenyl)spiro[fluorene-9,9′-xanthene]-2,2′,7,7′-tetraamine) (X60), have attracted attention. However, they require doping with Li-TFSI, and the devices develop the same Li-TFSI-derived problems. Here, we propose Li-free 1-Ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (EMIM-TFSI) as an efficient p-type dopant of X60, resulting in a high-quality HTL with enhanced conductivity and deeper energy levels The optimized X60:EMIM-TFSI-enabled devices exhibit a higher efficiency of 21.85% and improved stability, compared to the Li-TFSI-doped X60 devices. The stability of the optimized EMIM-TFSI-doped PSCs is greatly improved, and after 1200 hr of storage under ambient conditions, the resulting PSCs maintain 85% of the initial PCE. These findings offer a fresh method for doping the cost effective X60 as the HTL with a Li-free alternative dopant for efficient, cheaper, and reliable planar PSCs.

Objectives: Gliomas remain one of serious public health problems worldwide which demand further and deeper investigation. The aim of this study was to explore the association between synapse defective protein 1 homolog 1 (SYDE1) and gliomas via public database analysis and in vitro validation to determine the potential diagnostic and prognostic values.Methods and Results: Compared with healthy brain tissues, there was a significant increase in SYDE1 expression in glioma tissues. Additionally, SYDE1 exhibited higher expression levels in glioma patients with unfavorable clinicopathological factors. In vitro knockdown of SYDE1 in glioma cell lines A172 inhibited their migrative and invasive ability but not the proliferative ability. GO and KEGG pathway analysis of the top 100 genes coexpressed with SYDE1 showed enrichments of tumor-associated terms. Further bioinformatic analysis revealed that the SNHG16/hsa-miR-520e/SYDE1 axis might be involved in glioma development.Conclusions:SYDE1 is expressed at higher levels in gliomas than in healthy brains, and can promote metastasis and invasion but not proliferation of gliomas. Furthermore, SYDE1 has values in the diagnosis and prognosis prediction of gliomas.

Summary: The coronavirus disease 2019 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract via spike glycoprotein binding to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism's response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced interferon-stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2.

Glycemic variability was found associated with left ventricular structure and function in type 2 diabetes. But it is still unclear that whether the greater visit-to-visit fasting glucose (FG) variability in young adulthood among the community population is associated with cardiac function alteration and cardiac remodeling at midlife. The community-based prospective cohort study of Coronary Artery Risk in Young Adult (CARDIA) recruited young participants at the baseline age of 18–30 years during the period of 1985–1986 (Year 0). FG was measured at Year 0, 2, 10, 15, 20, and 25. The echocardiographic evaluation of cardiac structure and function was conducted at year 25. A total of 2,600 young adults mean (SD) aged at 24.9 years (3.6) of which 57.3% were women and 46.7% were African Americans had been included in the study. After multivariable adjusted, higher SD of mean FG (SDFG) is associated with lower early peak diastolic septal mitral annular velocity (e') (β [SE], −0.214 [0.080], P < 0.01) and higher E/e' (β [SE], 0.307 [0.094], P < 0.01), and higher coefficient of variation of the mean FG (CVFG) is also associated with lower e' (β [SE], −0.141[0.066], P < 0.05) and higher E/e' (β [SE], 0.204 [0.078], P < 0.01). The higher average real variation of mean FG (ARVFG) is associated with higher E/e' (β [SE], 0.178 [0.085], P < 0.05) and higher left ventricular mass index (LVMI) (β [SE], 1.240 [0.618], P < 0.05). The higher FG variability in young adulthood is associated with the subclinical change of left ventricular (LV) diastolic function at midlife.

Background: Blood pressure variability (BPV) has long been considered a risk factor for cardiovascular events. We aimed to investigate whether post-operative systolic BPV was associated with early and late all-cause mortality in patients undergoing coronary artery bypass grafting (CABG).Methods: Clinical variables and blood pressure records within the first 24 h in the post-operative intensive care unit stay from 4,509 patients operated on between 2001 and 2012 were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. BPV was measured as the coefficient of the variability of systolic blood pressure, and we compared patients in the highest quartile with patients in the other three quartiles.Results: After full adjustment, patients in the highest quartile of BPV were at a higher risk of intensive care unit mortality (OR = 2.02, 95% CI: 1.11–3.69), 30-day mortality (OR = 1.92, 95% CI: 1.22–3.02), and 90-day mortality (HR = 1.64, 95% CI: 1.19–2.27). For 2,892 patients with a 4-year follow-up, the association between a higher post-operative BPV and the risk of 4-year mortality was not significant (HR = 1.17, 95% CI: 0.96–1.42). The results were supported by the comparison of survival curves and remained generally consistent in the subgroup analyses and sensitivity analyses.Conclusions: Our findings demonstrated that in patients undergoing CABG, a higher post-operative BPV was associated with a higher risk of early mortality while the association was not significant for late mortality. Post-operative BPV can support doctors in identifying patients with potential hemodynamic instability and making timely clinical decisions.

Background: Systolic or diastolic blood pressure (BP) variability is associated with an increased risk of cardiovascular events. We assessed whether BP variability measured by mean arterial pressure (MAP) was associated with increased risk of heart failure (HF) and death in individuals with or without hypertension.Methods: We evaluated 9,305 Atherosclerosis Risk in Communities (ARIC) study participants with or without hypertension and calculated BP variability based on MAP values from visit 1 to 4 [expressed as standard deviation (SD), average real variability (ARV), coefficient of variation (CV), and variability independent of the mean (VIM)]. Multivariate-adjusted Cox regression model and restricted cubic spline curve were used to evaluate the associations of MAP variability with all-cause mortality and HF.Results: During a median follow-up of 16.8 years, 1,511 had an HF event and 2,903 died. Individuals in the highest quartile of VIM were both associated with a 21% higher risk of all-cause mortality [hazard ratio (HR), 1.21; 95% CI, 1.09–1.35] and HF (HR, 1.21; 95% CI, 1.04–1.39) compared with the lowest quartile of VIM. Cubic spline curves reveal that the risk of deaths and HF increased with MAP variability when it reached a higher level. Results were similar in individuals with normotension (all-cause mortality: HR, 1.30; 95% CI, 1.09–1.55; HF, HR, 1.49; 95% CI, 1.12–1.98).Conclusions: In individuals with or without hypertension, greater visit-to-visit MAP variability was associated with a higher risk of all-cause mortality and HF, indicating that the BP variability assessed by MAP might be a potential risk factor for HF and death.

AimTo determine whether long-term intensity of glycemic exposure (IGE) during young adulthood is associated with multiple target organs function at midlife independent of single fasting glucose (FG) measurement.MethodsWe included 2,859 participants, aged 18–30 years at Y0, in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. IGE was calculated as the sum of (average FG of two consecutive examinations × years between the examinations) over 25 years. Target organs function was indicated by cardiac structure, left ventricular (LV) systolic function, LV diastolic function, coronary artery calcium (CAC), and urine albumin-to-creatinine ratio (UACR) at Y25. We evaluated the associations between IGE with target organs function using linear regression models and estimated the associations between IGE with numbers of organs involved (0, 1, or ≥ 2 organs) using multinomial logistic regression models.ResultsA 1-SD increment of IGE was significantly associated with worse target organs function after multivariable adjustment: left ventricular mass (β [SE], 5.468 [1.175]); global longitudinal strain (β [SE], 0.161 [0.071]); E/e’ ratio (β[SE], 0.192 [0.071]); CAC score (β [SE], 27.948 [6.116]); and log UACR (β [SE], 0.076 [0.010]). Besides, IGE was independently associated with having ≥ 2 organs involved in both overall population (OR [95% CI], 1.48 [1.23, 1.41], P < 0.001) and subgroups stratified by diabetes at Y25.ConclusionHigher intensity of glycemic exposure during young adulthood was independently associated with subclinical alterations of target organs function at midlife. Our findings highlight the importance of early screening and management of IGE in youth.

Water oxidation is considered the bottleneck reaction for light-driven water splitting due to the sluggish kinetics and poor stability. Here, authors show metal- and heteroatom-doped carbons as effective catalysts for both electrochemical and photoelectrochemical water splitting.