Understanding the Underlying Mechanism of an Abnormal P Wave.

This case report describes a patient in their 70s presenting to the hospital with dyspnea and fatigue.

Mortality in patients admitted to hospital with heart failure in China: a nationwide Cardiovascular Association Database-Heart Failure Centre Registry cohort study.

BACKGROUND: China has the largest burden of heart failure worldwide. However, large-scale studies on heart failure mortality are scarce. We aimed to investigate mortality and identify risk factors for mortality among patients with heart failure in China. METHODS: This prospective cohort study used data from the China Cardiovascular Association (CCA) Database-Heart Failure Centre Registry, which were linked to the National Mortality Registration Information Management System by the Chinese Centre for Disease Control and Prevention. We included patients enrolled from Jan 1, 2017, to Dec 31, 2021, across 572 CCA Database-Heart Failure Centre certified hospitals in 31 provinces of mainland China. Eligible patients were aged 18 years or older (younger than 100 years) with a principal discharge diagnosis of heart failure based on Chinese heart failure guidelines. All-cause mortality at 30 days, 1 year, and 3 years for patients with heart failure were calculated and the causes of death were recorded. Multivariable analysis was used to analyse factors associated with all-cause mortality and cardiovascular mortality. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2200066305. FINDINGS: Of the 327 477 patients in the registry, 230 637 eligible adults with heart failure were included in our analyses. Participant mean age was 69·3 years (SD 13·2), 94 693 (41·1%) participants were female, and 135 944 (58·9%) were male. The median follow-up time was 531 days (IQR 251-883). Post-discharge all-cause mortality of patients with heart failure at 30 days was 2·4% (95% CI 2·3-2·5), at 1 year was 13·7% (13·5-13·9), and at 3 years was 28·2% (27·7-28·6). Cardiovascular death accounted for 32 906 (71·5%) of 46 006 all-cause deaths. Patients with heart failure with reduced ejection fraction had the highest all-cause mortality. A lower guideline adherence score was independently associated with the increase of all-cause and cardiovascular mortality. INTERPRETATION: In China, mortality for patients with heart failure is still high, especially in patients with reduced ejection fraction. Our findings suggest that guideline-directed medical therapy needs to be improved. FUNDING: National High Level Hospital Clinical Research Funding, the Capital's Funds for Health Improvement and Research, and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Topological magnetoelectric response in ferromagnetic axion insulators.

The topological magnetoelectric effect (TME) is a hallmark response of the topological field theory, which provides a paradigm shift in the study of emergent topological phenomena. However, its direct observation is yet to be realized due to the demanding magnetic configuration required to gap all surface states. Here, we theoretically propose that axion insulators with a simple ferromagnetic configuration, such as the MnBi2Te4/(Bi2Te3)n family, provide an ideal playground to realize the TME. In the designed triangular prism geometry, all the surface states are magnetically gapped. Under a vertical electric field, the surface Hall currents give rise to a nearly half-quantized orbital moment, accompanied by a gapless chiral hinge mode circulating in parallel. Thus, the orbital magnetization from the two topological origins can be easily distinguished by reversing the electric field. Our work paves the way for direct observation of the TME in realistic axion-insulator materials.

Lung Fibroblasts Take up Breast Cancer Cell-derived Extracellular Vesicles Partially Through MEK2-dependent Macropinocytosis.

Extracellular vesicles (EV) have emerged as critical effectors in the cross-talk between cancer and normal cells by transferring intracellular materials between adjacent or distant cells. Previous studies have begun to elucidate how cancer cells, by secreting EVs, adapt normal cells at a metastatic site to facilitate cancer cell metastasis. In this study, we utilized a high-content microscopic screening platform to investigate the mechanisms of EV uptake by primary lung fibroblasts. A selected library containing 90 FDA-approved anticancer drugs was screened for the effect on fibroblast uptake of EVs from MDA-MB-231 breast cancer cells. Among the drugs identified to inhibit EV uptake without exerting significant cytotoxicity, we validated the dose-dependent effect of Trametinib (a MEK1/2 inhibitor) and Copanlisib (a PI3K inhibitor). Trametinib suppressed macropinocytosis in lung fibroblasts and inhibited EV uptake with a higher potency comparing with Copanlisib. Gene knockdown and overexpression studies demonstrated that uptake of MDA-MB-231 EVs by lung fibroblasts required MEK2. These findings provide important insights into the mechanisms underlying lung fibroblast uptake of breast cancer cell-derived EVs, which could play a role in breast cancer metastasis to the lungs and suggest potential therapeutic targets for preventing or treating this deadly disease. SIGNIFICANCE: Through a phenotypic screen, we found that MEK inhibitor Trametinib suppressed EV uptake and macropinocytosis in lung fibroblasts, and that EV uptake is mediated by MEK2 in these cells. Our results suggest that MEK2 inhibition could serve as a strategy to block cancer EV uptake by lung fibroblasts.

Multidimensional Widefield Infrared-Encoded Spontaneous Emission Microscopy: Distinguishing Chromophores by Ultrashort Infrared Pulses.

Photoluminescence (PL) imaging has broad applications in visualizing biological activities, detecting chemical species, and characterizing materials. However, the chemical information encoded in the PL images is often limited by the overlapping emission spectra of chromophores. Here, we report a PL microscopy based on the nonlinear interactions between mid-infrared and visible excitations on matters, which we termed MultiDimensional Widefield Infrared-encoded Spontaneous Emission (MD-WISE) microscopy. MD-WISE microscopy can distinguish chromophores that possess nearly identical emission spectra via conditions in a multidimensional space formed by three independent variables: the temporal delay between the infrared and the visible pulses (t), the wavelength of visible pulses (λvis), and the frequencies of the infrared pulses (ωIR). This method is enabled by two mechanisms: (1) modulating the optical absorption cross sections of molecular dyes by exciting specific vibrational functional groups and (2) reducing the PL quantum yield of semiconductor nanocrystals, which was achieved through strong field ionization of excitons. Importantly, MD-WISE microscopy operates under widefield imaging conditions with a field of view of tens of microns, other than the confocal configuration adopted by most nonlinear optical microscopies, which require focusing the optical beams tightly. By demonstrating the capacity of registering multidimensional information into PL images, MD-WISE microscopy has the potential of expanding the number of species and processes that can be simultaneously tracked in high-speed widefield imaging applications.

Ultrasensitive visual detection of the food-borne pathogen via MOF encapsulated enzyme.

Various methods have been made to achieve sensitive detection (10 CFU/mL) of Escherichia coli O157:H7 (E. coli) in real samples, however, they are complex, time-consuming, or instrument-dependent. Enzyme-catalyzed reactions are one of the most efficient methods to amplify signals for sensitive detection. ZIF-8 owning stability, porosity, and high specific area are suitable for embedding enzymes which can effectively protect enzyme activity and thus improve detection sensitivity. Herein, a simple visual assay of E. coli with the limits of detection of 1 CFU/mL was developed based on this stable enzyme-catalyzed amplified system. A microbial safety test of milk, orange juice, seawater, cosmetic, and hydrolyzed yeast protein, was successfully performed with the limits of detection of 10 CFU/mL by the naked eye. And this bioassay possessed high selectivity and stability making the developed detection method practically promising.

Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth.

Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in ß-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in ß-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.

Cancer-cell-secreted miR-122 suppresses O-GlcNAcylation to promote skeletal muscle proteolysis.

A decline in skeletal muscle mass and low muscular strength are prognostic factors in advanced human cancers. Here we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc transferase (OGT). Mechanistically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation; the miR-122-mediated decrease in OGT resulted in increased RYR1 abundance. We further found that muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation and was elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, through increasing RYR1, led to higher cytosolic Ca2+ and calpain protease activation, which triggered cleavage of desmin filaments and myofibrillar destruction. This was associated with reduced skeletal muscle mass and contractility in tumour-bearing mice. Our findings link O-GlcNAcylation to muscular protein homoeostasis and contractility and reveal a mechanism of cancer-associated muscle dysregulation.

Performance of Prognostic Risk Scores in Elderly Chinese Patients with Heart Failure.

PURPOSE: Elderly heart failure (HF) patients have different clinical characteristics and poorer prognosis compared with younger patients. Prognostic risk scores for HF have not been validated well in elderly patients. We aimed to validate the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in an elderly Chinese HF cohort. PATIENTS AND METHODS: This retrospective study enrolled 675 elderly HF patients (age≥70 years) discharged from our hospital between 2012 and 2017. The performance of the two risk scores was evaluated in terms of discrimination, using receiver-operating characteristic analysis, and calibration using a calibration plot and Hosmer-Lemeshow (H-L) test. Absolute risk reclassification was used to compare the two scores. RESULTS: During the mean follow-up time of 32.6 months, 193 patients (28.6%) died, and 1-year mortality was 10.5%. The predicted median 1-year mortality was 8% for the SHFM and 18% for the MAGGIC score. A Kaplan-Meier survival curve demonstrated that event rates of all-cause mortality significantly increased with increasing SHFM and MAGGIC scores. The discriminatory capacity of the SHFM was greater than that of the MAGGIC score (c-statistics were 0.72 and 0.67, respectively; P = 0.05). The calibration plot for the SHFM was better than that for MAGGIC score for 1-year mortality (SHFM: H-L χ2 =8.2, P = 0.41; MAGGIC: H-L χ2 =18.8, P =0.02). Compared with the MAGGIC score, the net reclassification index (NRI) of the SHFM was 2.96% (Z=5.88, P< 0.0001). CONCLUSION: The SHFM performs better than MAGGIC score, having good discrimination, calibration and risk classification for the prediction of 1-year mortality in elderly Chinese HF patients.

Frailty related all-cause mortality or hospital readmission among adults aged 65 and older with stage-B heart failure inpatients.

BACKGROUND: Frailty increases the adverse outcomes of clinical heart failure; however, the relationship between frailty and stage-B heart failure (SBHF) remains unknown. We aimed to explore the epidemiology and predictive value of frailty in older adults with SBHF. METHODS: A prospective cohort of SBHF inpatients aged 65 years or older who were hospitalized between September 2018 and February 2019 and were followed up for 6 months were included. SBHF was defined as systolic abnormality, structural abnormality (left ventricular enlargement, left ventricular hypertrophy, wall motion abnormalities, valvular heart disease), or prior myocardial infarction. Frailty was assessed by the Fried frailty phenotype. Multivariable Cox proportional hazards regression was used to explore the independent risk and prognostic factors. RESULTS: Data of 443 participants (age: 76.1 ± 6.79 years, LVEF: 62.8 ± 4.92%, men: 225 [50.8%], frailty: 109 [24.6%]) were analyzed. During the 6-month follow-up, 83 (18.7%) older SBHF inpatients experienced all-cause mortality or readmission, and 29 (6.5%) of them developed clinical HF. Frail individuals had a 1.78-fold (95%CI: 1.02-3.10, P = 0.041) higher risk of 6-month mortality or readmission and a 2.83-fold (95%CI 1.24-6.47, P = 0.014) higher risk of developing clinical HF, independent of age, sex, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide level. CONCLUSIONS: Frailty is common in older SBHF inpatients and should be considered to help identify individuals with an increased risk of mortality or readmission, and developing clinical HF. TRIAL REGISTRATION: ChiCTR1800017204 .

Adding high-sensitivity C-reactive protein to frailty assessment to predict mortality and cardiovascular events in elderly inpatients with cardiovascular disease.

OBJECTIVE: Chronic inflammation is associated with major adverse cardiovascular events (MACEs), mortality, and frailty. Our aim was to add high-sensitivity C-reactive protein (hsCRP) to the frailty assessment to predict its association with prognosis of older adults with cardiovascular disease (CVD). METHODS: A comprehensive geriatric assessment was conducted at baseline in 720 in-patients aged ≥65 years with CVD. We divided the population into frailty and non-frailty groups according to the Fried phenotype, and hsCRP was further combined with frailty to stratify all patients into c-frailty and non-c-frailty groups. Predictive validity was tested using Cox proportional hazards regression model analysis and the discriminative ability was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Of all the subjects enrolled, 51.0% were male and the mean age was 75.32 ± 6.52 years. The all-cause death and MACE rate was 6.4% at the 1-year follow-up. Frailty and c-frailty were independent predictors of all-cause death and MACE (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.35-4.83, p = 0.004; HR: 3.67, 95% CI: 1.83-7.39, p < 0.001). Adding hsCRP to the frailty model resulted in a significant increase in the area under the ROC curve from 0.74 (95% CI: 0.70-0.77) to 0.77 (95% CI: 0.71-0.84) (p = 0.0132) and a net reclassification index of 7.9% (95% CI: 1.96%-12.56%, p = 0.012). CONCLUSION: Adding hsCRP to the frailty assessment is helpful to identify a subgroup of older CVD patients with a higher risk of death and MACE over a period of 1 year. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018. URL: http://www.chictr.org.cn/showproj.aspx?proj=28931.

Prevalence and Prognostic Significance of Frailty in Gerontal Inpatients With Pre-clinical Heart Failure: A Subgroup Analysis of a Prospective Observational Cohort Study in China.

Objective: To evaluate the prognostic value of frailty in gerontal pre-clinical heart failure (stage B heart failure, SBHF) inpatients. Background: The association between frailty and SBHF remains unknown. Methods: We conducted a subgroup analysis of a prospective observational cohort study on frailty. The previous study recruited 1,000 elderly inpatients who were consecutively admitted to a tertiary referral hospital in Beijing, China, from September 2018 to February 2019. The outcomes were all-cause death or readmission at 1-year follow-up. SBHF was diagnosed for asymptomatic cardiac structural or functional abnormalities. Frailty was assessed using the Comprehensive Geriatric Assessment-Frailty Index (CGA-FI). Results: Overall, 531 inpatients aged ≥65 years were deemed to have SBHF and followed up for 1 year. Of them, 34.5% exhibited frailty. During the follow-up period, all-cause death or readmission occurred in 157 (29.5%) participants. Of these participants, 36.6% (67/183) and 25.9% (90/348) belonged to the frail and non-frail groups, respectively (χ2 = 6.655, P = 0.010). Frailty, defined by the CGA-FI, rather than Fried frailty phenotype, could independently predict 1-year all-cause death or readmission (hazard ratio, 1.56; 95% confidence interval, 1.03-2.35; P = 0.034) and was more suitable for predicting all-cause death or readmission than N-terminal pro-B-type natriuretic peptide in female SBHF inpatients aged 80 years or over(AUCCGA-FI vs. AUCNT-proBNP 0.654 vs. 0.575, P = 0.017). Conclusions: Frailty is highly prevalent even among SBHF inpatients aged ≥65 years. The CGA-FI can independently predict 1-year all-cause death or readmission, rather than Fried frailty phenotype. Frailty in gerontal SBHF inpatients deserves more attention. Clinical Trial registration: ChiCTR1800017204; date of registration: 07/18/2018.

The effect of comprehensive assessment and multi-disciplinary management for the geriatric and frail patient: A multi-center, randomized, parallel controlled trial.

BACKGROUND: A comprehensive geriatric assessment (CGA) of elderly patients is useful for detecting the patients vulnerabilities. Exercise and early rehabilitation, nutritional intervention, traditional Chinese medicine (TCM), standardized medication guidance, and patient education can, separately, improve and even reverse the physical frailty status. However, the effect of combining a CGA and multi-disciplinary management on frailty in elderly patients remains unclear. The present study assessed the effects of a CGA and multi-disciplinary management on elderly patients with frailty in China. METHODS: In this study, 320 in patients with frailty ≥70 years old will be randomly divided into an intervention group and a control group. The intervention group will be given routine management, a CGA and multi-disciplinary management involving rehabilitation exercise, diet adjustment, multi-drug evaluation, acupoint massage in TCM and patient education for 12 months, and the control group will be followed up with routine management for basic diseases. The primary outcomes are the Fried phenotype and short physical performance battery (SPPB). The secondary outcomes are the clinical frailty scale (CFS), non-elective hospital readmission, basic activities of daily living (BADL), 5-level European quality of life 5 dimensions index (EQ-5D), nutrition risk screening-2002 (NRS-2002), medical insurance expenses, fall events, and all-cause mortality. In addition, a cost-effectiveness study will be carried out. DISCUSSION: This paper outlines the protocol for a randomized, single-blind, parallel multi-center clinical study. This protocol, if beneficial, will demonstrate the interaction of various intervention strategies, will help improve elderly frailty patients, and will be useful for clinicians, nurses, policymakers, public health authorities, and the general population. TRIAL REGISTRATION: Chinese Clinical Trials Register, ChiCTR1900022623. Registered on April 19, 2019, http://www.chictr.org.cn/showproj.aspx?proj=38141.

Predicting non-elective hospital readmission or death using a composite assessment of cognitive and physical frailty in elderly inpatients with cardiovascular disease.

BACKGROUND: We aimed to assess the utility of the combination of the mini-mental state examination (MMSE) + clock drawing test (CDT) and the Fried phenotype for predicting non-elective hospital readmission or death within 6 months in elderly inpatients with cardiovascular disease (CVD). METHODS: A single-center prospective cohort was conducted from September 2018 to February 2019. Inpatients ≥65 years old were recruited. Predictive validity was tested using a Cox proportional hazards regression model analysis, and the discriminative ability was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: A total of 542 patients were included. Overall, 12% (64/542) screened positive for cognitive impairment, 16% (86/542) were physically frail and 8% (44/542) had cognitive impairment combined with physical frailty, showing an older age (P < 0.001) and a lower education level (P < 0.001) than physically frail patients. A total of 113 patients (20.9%) died or were readmitted at 6 months. Frail participants with a normal (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.06-2.82, P = 0.028) or impaired cognition (HR: 2.50, 95% CI: 1.27-4.91, P = 0.008) had a higher risk of non-elective hospital readmission or death than robust patients after adjusting for the age, sex, education level, marital status, the presence of diabetes mellitus, heart failure, and history of stroke. The area under the ROC curve (AUC) showed that the discriminative ability in relation to 6 months readmission and death for the MMSE + CDT + Fried phenotype was 0.65 (95% CI: 0.60-0.71), and the AUC for men was 0.71 (95% CI: 0.63-0.78), while that for women was 0.60 (95% CI: 0.51-0.69). CONCLUSIONS: Accounting for cognitive impairment in the frailty phenotype may allow for the better prediction of non-elective hospital readmission or death in elderly inpatients with CVD in the short term. TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018.

Urinary 8-oxo-7,8-dihydroguanosine as a potential biomarker of frailty for elderly patients with cardiovascular disease.

The diagnosis of frailty is usually subjective, which calls for objective biomarkers in clinical medicine. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGsn) and 8-oxo-7, 8-dihydroguanosine (8-oxoGsn) in urine are two aging biomarkers that have not been explored deeply in cases of frailty. A total of 508 elderly patients with cardiovascular disease (mean age 75.0 ± 6.5 years, 50.8% males) were enrolled consecutively. Frailty was assessed by the Fried phenotype (robust: 0 score; pre-frail: 1-2 scores; frail: 3-5 scores). The concentrations of 8-oxoGsn and 8-oxodGsn in urine were measured by improved ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Urinary creatinine (Cre) was tested to correct the 8-oxoGsn and 8-oxodGsn levels. According to the Fried phenotype score, the proportions of robust, pre-frail, and frail subjects were 20.5% (104/508), 53.9% (274/508), and 25.6% (130/508), respectively. The urinary 8-oxoGsn/Cre (P < 0.001) differed significantly among these 3 groups, but the urinary 8-oxodGsn/Cre (P = 0.600) showed no marked difference. Univariate and multivariate logistic regression showed that the age (odds ratio [OR] = 1.090, P < 0.001), systolic blood pressure (OR = 0.981, P = 0.008), 8-oxoGsn/Cre (OR = 1.203, P = 0.007), hemoglobin (OR = 0.980, P = 0.007), and sodium (OR = 0.915, P = 0.044) were independently associated with frailty. The sensitivity and specificity to identify frailty were 53.08% and 71.96%, respectively, for 8-oxoGsn/Cre at the optimal cut-off value of 3.879 µmol/mol according to the maximal Youden index. Urinary 8-oxoGsn, as a recognized biomarker of RNA oxidation, is independently associated with frailty in elderly patients with cardiovascular disease. However, the urinary 8-oxodGsn shows no obvious correlation with frailty. To obtain a better diagnostic performance for frailty, more biomarkers from different pathophysiological pathways should be explored in the future.