The adipose-neural axis is involved in epicardial adipose tissue-related cardiac arrhythmias.

Dysfunction of the sympathetic nervous system and increased epicardial adipose tissue (EAT) have been independently associated with the occurrence of cardiac arrhythmia. However, their exact roles in triggering arrhythmia remain elusive. Here, using an in vitro coculture system with sympathetic neurons, cardiomyocytes, and adipocytes, we show that adipocyte-derived leptin activates sympathetic neurons and increases the release of neuropeptide Y (NPY), which in turn triggers arrhythmia in cardiomyocytes by interacting with the Y1 receptor (Y1R) and subsequently enhancing the activity of the Na+/Ca2+ exchanger (NCX) and calcium/calmodulin-dependent protein kinase II (CaMKII). The arrhythmic phenotype can be partially blocked by a leptin neutralizing antibody or an inhibitor of Y1R, NCX, or CaMKII. Moreover, increased EAT thickness and leptin/NPY blood levels are detected in atrial fibrillation patients compared with the control group. Our study provides robust evidence that the adipose-neural axis contributes to arrhythmogenesis and represents a potential target for treating arrhythmia.

Association between lactate/albumin ratio and prognosis in patients with acute myocardial infarction.

BACKGROUND: The association between the lactate/albumin ratio (L/A) as a diagnostic indicator and unfavourable clinical outcomes has been established in patients with community-acquired pneumonia, sepsis and heart failure, but the connection between L/A and all-cause mortality in patients with acute myocardial infarction (AMI) has yet to be fully understood. METHODS: This was a retrospective cohort study using MIMIC-IV (v2.2) data, with 2816 patients enrolled and all-cause mortality during hospitalization as the primary outcome. Kaplan-Meier (KM) analysis was used to compare the all-cause mortality between high-level and low-level L/A groups. Receiver operating characteristic (ROC) curve, Restricted cubic splines (RCS) and Cox proportional hazards analysis were performed to investigate the relationship between L/A ratio and in-hospital all-cause mortality. RESULTS: L/A values were significantly higher in the non-survivor groups than the survival groups (1.14 [.20] vs. .60 [.36], p < .05), and area under the ROC curve [.734 (95% confidence interval, .694-.775)] was better than other indicators. Data of COX regression analysis showed that higher L/A value supposed to be an independent risk factor for in-hospital mortality. RCS analysis showed evidence of an increasing trend and a non-linear relationship between L/A and in-hospital mortality (p-value was non-linear <.05). KM survival curves were significantly lower in the high L/A group than the low L/A group (p < .001), and the former group had an increased risk of in-hospital mortality compared with the latter one (Log Rank p < .001). CONCLUSIONS: L/A demonstrates significant independent predictive power for elevated all-cause mortality during hospitalization in patients diagnosed with AMI.

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma.

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

White Matter Microstructural Alterations over the Year after Acute Ischemic Stroke in Patients with Baseline Impaired Cognitive Functions.

Background: The disruption of white matter (WM) integrity is related to poststroke cognitive impairment (PSCI). The exploration of WM integrity alterations in the chronic stage of acute ischemic stroke (AIS) may help to improve the long-term outcomes of PSCI. Methods: Sixty patients showing impaired cognitive functions within 3 days after AIS (baseline) and 25 healthy controls underwent diffusion kurtosis imaging scan and cognitive assessment at baseline and 1 year. Based on the tract-based spatial statistics (TBSS), kurtosis fractional anisotropy (KFA) and mean kurtosis (MK) were compared in WM tracts between the groups. Results: One year after AIS, 25 patients were diagnosed with PSCI and 35 patients with non-cognitive impairment (NCI). Compared with baseline, cognitive performance improved in 54 patients and remained unchanged in 6 patients at 1 year. TBSS analysis showed that there were no significant differences in WM tract integrity between the AIS and control groups at baseline (P > 0.05). Compared with the control group, the KFA and MK in multiple WM tracts in the AIS group decreased significantly at 1 year (P < 0.05). Longitudinal analysis showed that the KFA and MK of multiple WM tracts recorded at 1 year were significantly lower than those recorded at baseline in the AIS, PSCI, and NCI groups (P < 0.05), and PSCI group had a faster degeneration than NCI group (P < 0.05). Conclusion: The finding suggests that the patients with baseline impaired cognitive functions still have WM microstructural damages at 1 year poststroke, even if their cognitive function has improved or returned to normal. Cautions should be taken against the possible negative impact of these changes on long-term cognition.

Alirocumab effect on preventing periprocedural ischaemic events in coronary heart disease patients undergoing coronary stenting (APPEASE trial): study protocol of a multicentre, open-label, randomised controlled trial.

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.

"Stapling" scFv for multispecific biotherapeutics of superior properties.

Single-chain fragment variable (scFv) domains play an important role in antibody-based therapeutic modalities, such as bispecifics, multispecifics and chimeric antigen receptor T cells or natural killer cells. However, scFv domains exhibit lower stability and increased risk of aggregation due to transient dissociation ("breathing") and inter-molecular reassociation of the two domains (VL and VH). We designed a novel strategy, referred to as stapling, that introduces two disulfide bonds between the scFv linker and the two variable domains to minimize scFv breathing. We named the resulting molecules stapled scFv (spFv). Stapling increased thermal stability (Tm) by an average of 10°C. In multiple scFv/spFv multispecifics, the spFv molecules display significantly improved stability, minimal aggregation and superior product quality. These spFv multispecifics retain binding affinity and functionality. Our stapling design was compatible with all antibody variable regions we evaluated and may be widely applicable to stabilize scFv molecules for designing biotherapeutics with superior biophysical properties.

Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections.

Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of virulence determinants, making it difficult to identify single targets for the development of vaccines or monoclonal therapies. We described a human-derived anti-S. aureus monoclonal antibody (mAb)-centyrin fusion protein ("mAbtyrin") that simultaneously targets multiple bacterial adhesins, resists proteolysis by bacterial protease GluV8, avoids Fc engagement by S. aureus IgG-binding proteins SpA and Sbi, and neutralizes pore-forming leukocidins via fusion with anti-toxin centyrins, while maintaining Fc- and complement-mediated functions. Compared with the parental mAb, mAbtyrin protected human phagocytes and boosted phagocyte-mediated killing. The mAbtyrin also reduced pathology, reduced bacterial burden, and protected from different types of infections in preclinical animal models. Finally, mAbtyrin synergized with vancomycin, enhancing pathogen clearance in an animal model of bacteremia. Altogether, these data establish the potential of multivalent mAbs for treating and preventing S. aureus diseases.

Association between lactate/albumin ratio and mortality in patients with heart failure after myocardial infarction.

AIMS: Lactate/albumin ratio (L/A) is a recognized prognostic index of patients with heart failure (HF) after myocardial infarction (MI). We aim to evaluate the prognostic value of L/A ratio in predicting in-hospital mortality for those patients. METHODS AND RESULTS: We enrolled qualified patients from Medical Information Mart for Intensive Care IV database for retrospective study. A receiver operating characteristic (ROC) curve of the subjects was applied to determine the predicted value and the best cut-off value of L/A on admission. Univariate/multivariate Cox regression analysis and restricted cubic splines (RCS) were performed to identify the association between hospital admission and hospital mortality. The Kaplan-Meier (KM) method was used to draw the survival curve of the two groups with different L/A levels at admission. L/A values at admission were significantly higher in the death groups than the survival groups [1.36 (1.20) vs. 0.62 (0.36), P < 0.05], and area under the ROC curve [0.780 (95% confidence interval, 0.772-0.827)] was better than other indicators, and the best the cut-off value was 0.671. Data of Cox regression analysis showed that higher L/A value supposed to be an independent risk factor for in-hospital mortality. RCS analysis showed evidence of an increasing trend and a non-linear relationship between L/A and in-hospital mortality (P value was non-linear <0.05). KM survival curves were significantly lower in the high L/A group than the low L/A group (P < 0.001), and the former group had an increased risk of in-hospital mortality compared with the latter one (log rank P < 0.001). CONCLUSIONS: Elevated L/A ratio on admission is an independent predictor of high in-hospital mortality in post-MI heart failure patients, which proved to be better than lactate, Sequential Organ Failure Assessment score and other related indicators.

Redistribution of adipose tissue is associated with left atrial remodeling and dysfunction in patients with atrial fibrillation.

Objective: Adipose tissue is recognized as a crucial regulator of atrial fibrillation (AF). However, the effect of epicardial adipose tissue (EAT) on the pathophysiology of AF might be different from that of other adipose tissues. The purpose of this study was to explore the distribution features of different adipose tissues in AF patients and their relationships with left atrial (LA) remodeling and function. Methods: A total of 205 participants (including 112 AF and 93 non-AF patients) were recruited. Color doppler ultrasound was used to measure the thickness of subcutaneous, extraperitoneal, and intra-abdominal adipose tissue. Cardiac CT scan was performed to measure the mean thickness of EAT surrounding the whole heart (total-EAT) and specific regions, including left atrium (LA-EAT), left ventricle, right ventricle, interventricular groove, and atrioventricular groove. LA anatomical remodeling and function were measured by echocardiography, while electrical remodeling was evaluated by P-wave duration and dispersion using Electrocardiography (obtained after cardioversion or ablation in AF patients). Relationship between the thickness of different adipose tissues and LA remodeling and function was analyzed. Results: The thickness of subcutaneous, extraperitoneal, and intra-abdominal adipose tissue was similar between AF and non-AF patients, and had no or only weak association with LA remodeling and dysfunction. However, compared to non-AF participants, total-EAT thickness significantly increased in both paroxysmal and persistent AF patients (non-AF vs. paroxysmal AF vs. persistent AF: 6.31 ± 0.63 mm vs. 6.76 ± 0.79 mm vs. 7.01 ± 1.18 mm, P < 0.001), which was positively correlated with the LA size and P-wave duration and dispersion, and negatively correlated with LA ejection fraction and peak strain rate. More interestingly, EAT thickness in AF patients did not increase uniformly in different regions of the heart. Compared to EAT surrounding the other regions, LA-EAT was found to accumulate more greatly, and had a closer relationship to LA remodeling and dysfunction. Multivariate logistic regression analysis also showed that LA-EAT was significantly correlated with the presence of AF (OR = 4.781; 95% CI 2.589-8.831, P < 0.001). Conclusion: Rather than other adipose tissues, accumulation and redistribution of EAT, especially surrounding the LA, is associated with LA remodeling and dysfunction in AF patients.

Impact of albumin infusion on prognosis of intensive care unit patients with congestive heart failure-hypoalbuminemia overlap: a retrospective cohort study.

Background: Hypoalbuminemia is common in congestive heart failure (CHF) patients. Serum albumin is associated with the prognosis of CHF patients. Impact of albumin infusion on prognosis of patients with CHF-hypoalbuminemia overlap remains unclear. We retrospectively investigated the impact of albumin infusion on prognosis of intensive care unit (ICU) patients with CHF-hypoalbuminemia overlap. Methods: We enrolled all patients whose diagnosis included CHF [ICD-9 (international classification of diseases 9) code =428.0] at first ICU admission from the MIMIC III (Medical Information Mart for Intensive Care III) database, and excluded those with missing serum albumin values, with serum albumin >3.4 g/dL or <18 years old. According to the exposure of albumin infusion during hospitalization, patients were stratified into non-albumin and albumin groups. Propensity-score matching (PSM) was performed (1:1 ratio) to control for baseline confounding. Outcome measures were in-hospital mortality as well as length of stay in the ICU (ICU LOS) and the hospital (hospital LOS). Results: There were 3,190 eligible patients in the initial search. Patients with albumin infusion had markedly higher in-hospital mortality (36.42% vs. 21.81%, P<0.001), longer ICU LOS [median 6.93 (3.39-14.82) vs. 3.84 (1.96-8.00) days, P<0.001], and longer hospital LOS [median 17.46 (11.45-28.33) vs. 10.92 (6.81-18.00) days, P<0.001] than those without albumin infusion. The multivariate logistic regression analysis revealed that albumin infusion [odds ratio (OR), 1.509; 95% confidence interval (CI), 1.164-1.957; P=0.002] was significantly associated with increased risk of in-hospital mortality. After PSM, a cohort of 429 pairs of patients was included in the final analysis. Patients with albumin infusion had markedly higher in-hospital mortality (34.97% vs. 27.27%, P=0.015), longer ICU LOS [median 8.43 (4.33-16.28) vs. 6.43 (3.07-13.66) days, P<0.001], and longer hospital LOS [median 16.92 (11.27-28.06) vs. 13.33 (8.00-21.10) days, P<0.001] than those without albumin infusion. The multivariate logistic regression analysis revealed that albumin infusion (OR, 1.594; 95% CI, 1.143-2.223; P=0.006) was significantly associated with increased risk of in-hospital mortality. Conclusions: Albumin infusion increased in-hospital mortality, ICU LOS, and hospital LOS in ICU patients with CHF-hypoalbuminemia overlap.

The feasibility and safety of a simple method for coronary sinus blood sampling during catheter ablation of arrhythmias.

Background: Coronary sinus (CS) blood sampling gives an insight into the localized pathophysiology of heart diseases. However, additional specifically-designed or modified catheters were needed in most previous studies, making the convenience of clinical application unsatisfactory. This study aimed to introduce a simple method for CS blood sampling without using additional catheters during catheter ablation (CA) of arrhythmias, and to investigate its feasibility and safety. Methods: A total of 119 patients undergoing CA were prospectively enrolled, including 25 with paroxysmal supraventricular tachycardia (PSVT), 30 with premature ventricular complexes (PVC), and 64 with atrial fibrillation (AF). Cannulation and sampling of CS was performed via the femoral vein using a conventional 8F SR0TM or 8.5F SL1TM introducer sheath (St. Jude Medical) guided by a 6F steerable diagnostic catheter (St. Jude Medical). The success rate and any suspicious complications were recorded. Untargeted liquid chromatograph-mass spectrometer (LC-MS)-based metabonomics of CS samples versus peripheral venous samples were also performed. Results: CS blood samples were successfully collected from 114 patients, with an overall success rate of 95.8%. Among patients with different arrhythmias, the success rates were similar, with 96.0% in PSVT, 96.7% in PVC, and 95.3% in AF (P=0.223). Adverse events occurred in four (3.4%) patients, including two patients with occasional atrial ectopic beats without causing any discomfort, and two patients with new-onset paroxysmal AF lasting for about 2 min. No serious complications were noted. Metabonomics analysis showed that CS samples provided a number of different metabolites (93 in PVST, 217 in PVC, and 109 in AF) versus peripheral samples. Conclusions: Our method for CS blood sampling during CA is feasible and safe, and can provide useful cardiometabolic information that is significantly different from a peripheral sample.

Folic Acid Attenuates Contrast-Induced Nephropathy in Patients With Hyperhomocysteinemia Undergoing Coronary Catheterization: A Randomized Controlled Trial.

Background: Hyperhomocysteinemia is a risk factor for contrast-induced nephropathy. Folic acid can attenuate such nephropathies in rats. The protective effect of folic acid against contrast-induced nephropathy has not been studied in humans. We aimed to investigate the effect of folic acid on the incidence of contrast-induced nephropathy (CIN) after coronary catheterization in patients with hyperhomocysteinemia. Methods: This was a single-center, prospective, double-blind, randomized controlled trial (ClinicalTrials.gov, NCT02444013). In total, 412 patients (mean age: 65 ± 12 years, 268 male) with plasma homocysteine ≥15 µM, who underwent coronary arteriography (CAG) or percutaneous coronary intervention (PCI) from May 2015 to August 2018, were enrolled. Patients were randomly assigned to two groups: a treatment group (n = 203), taking 5 mg of folic acid (orally, three times/day) immediately after enrollment and for 72 h after operation, and a control group (n = 209), taking placebo. Contrast-induced nephropathy was defined as an increase in serum creatinine of >25% or 44 µM within 48 or 72 h after contrast medium administration. Results: In total, 50 (12%) patients developed CIN after 48 h after catheterization, including 16 (8%) in the treatment group and 34 (16%) in the control group (P = 0.009). Meanwhile, 53 (13%) patients developed CIN after 72 h of CAG/PCI, including 18 (9%) in the treatment group and 35 (17%) in the control group (P = 0.017). The incidence of contrast-induced nephropathy in the treatment group was lower than that in the control group (P = 0.017). Logistic regression analysis confirmed that administration of folic acid was a protective factor against contrast-induced nephropathy (RD = 0.0788, 95%CI: 0.0105-0.1469, P = 0.019). We found no serious adverse events associated with folic acid. No death or hemodialysis occurred in either group. Conclusions: Perioperative administration of folic acid attenuates the incidence of contrast-induced nephropathy after coronary catheterization in patients with hyperhomocysteinemia. Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT02444013].

Atrial fibrillation increases inpatient and 4-year all-cause mortality in critically ill patients with liver cirrhosis.

BACKGROUND: The association between atrial fibrillation (AF) and cirrhosis is unclear. Therefore, the aim of the present study was to determine the association between AF and short-term and 4-year mortality in critically ill patients with cirrhosis using a large database. METHODS: The Medical Information Mart for Intensive Care III (MIMIC III) database was used to identify patients with cirrhosis hospitalized in an intensive care unit from 2001 to 2012. Demographic and clinical data were extracted from the database. Clinical data and demographic information were collected for each patient in our study. Kaplan-Meier analysis and multivariate Cox regression models were performed to examine the relation between atrial fibrillation and in-hospital and 4-year all-cause mortality. RESULTS: A total of 1,481 patients (mean age: 58 years, 68% male) with liver cirrhosis were included in the analysis, and the prevalence of AF was 14.18%. The inpatient all-cause mortality rate was 26.6%, and patients who died in hospital had a significantly higher rate of AF (21.57% vs. 11.50%, P<0.001). Multivariate Cox regression analysis indicated that AF was significantly associated with inpatient all-cause mortality [hazard ratio (HR): 1.52, 95% confidence interval (CI): 1.19-1.95, P<0.001], and 4-year all-cause mortality (HR: 1.55, 95% CI: 1.12-2.13, P=0.008). Kaplan-Meier survival analysis showed that patients with AF had a significantly higher inpatient and 4-year all-cause mortality. CONCLUSIONS: Critically ill patients with liver cirrhosis have a high rate of AF, and the presence of AF is an independent risk factor for inpatient and 4-year all-cause mortality.

Inhaled Beta2-Agonists Increase In-Hospital Mortality in ICU Patients with Heart Failure.

The impact of beta2-agonists (B2As) on heart failure (HF) remains controversial. This study aimed to investigate whether inhaled B2As increased in-hospital mortality in ICU patients with HF.The Multiparameter Intelligent Monitoring in Intensive Care III database was initially searched to identify adult patients (≥ 18 years old) with HF in ICU. Then, patients using or not using inhaled B2As were matched using propensity score matching on a 1:1 basis to control for baseline confounders. In-hospital mortality was compared between the two groups, and logistic regression analysis was performed to assess the association between B2As and in-hospital mortality.The initial search retrieved 2345 eligible patients with HF from the database. After propensity score matching, 705 pairs of patients were included in the final analysis. Patients using B2As had markedly higher in-hospital mortality than those not using B2As (4.68% versus 2.27%; P = 0.013). In the multivariate logistic regression analysis, B2A use (odd ratios (OR), 2.471; 95% confidence interval (CI), 1.289-4.734; P = 0.006), stroke (OR, 4.581; 95% CI, 1.621-12.948; P = 0.004), and simplified acute physiology score II (SAPS-II) scores (OR, 1.090; 95% CI, 1.064-1.116; P < 0.001) were significantly associated with increased risk of in-hospital mortality, whereas renin angiotensin system inhibitor use (OR, 0.396; 95% CI, 0.202-0.778; P = 0.007) was significantly associated with decreased risk of in-hospital mortality. Subgroup analysis further indicated that the association between B2A use and mortality was significant only in patients with HF without chronic pulmonary disease (OR, 2.427; 95% CI, 1.351-4.362; P = 0.003), but not in those with chronic pulmonary disease (OR, 2.094; 95% CI, 0.582-7.537; P = 0.258).In ICU patients with HF but without chronic pulmonary disease, the use of inhaled B2As is associated with increased in-hospital mortality.

Cardiac Derived CD51-Positive Mesenchymal Stem Cells Enhance the Cardiac Repair Through SCF-Mediated Angiogenesis in Mice With Myocardial Infarction.

Objective: Many tissues contained resident mesenchymal stromal/stem cells (MSCs) that facilitated tissue hemostasis and repair. However, there is no typical marker to identify the resident cardiac MSCs. We aimed to determine if CD51 could be an optimal marker of cardiac MSCs and assess their therapeutic potential for mice with acute myocardial infarction (AMI). Methods: Cardiac-derived CD51+CD31-CD45-Ter119- cells (named CD51+cMSCs) were isolated from C57BL/6 mice(7-day-old) by flow cytometry. The CD51+cMSCs were characterized by proliferation capacity, multi-differentiation potential, and expression of typical MSC-related markers. Adult C57BL/6 mice (12-week-old) were utilized for an AMI model via permanently ligating the left anterior descending coronary artery. The therapeutic efficacy of CD51+cMSCs was estimated by echocardiography and pathological staining. To determine the underlying mechanism, lentiviruses were utilized to knock down gene (stem cell factor [SCF]) expression of CD51+cMSCs. Results: In this study, CD51 was expressed in the entire layers of the cardiac wall in mice, including endocardium, epicardium, and myocardium, and its expression was decreased with age. Importantly, the CD51+cMSCs possessed potent self-renewal potential and multi-lineage differentiation capacity in vitro and also expressed typical MSC-related surface proteins. Furthermore, CD51+cMSC transplantation significantly improved cardiac function and attenuated cardiac fibrosis through pro-angiogenesis activity after myocardial infarction in mice. Moreover, SCF secreted by CD51+cMSCs played an important role in angiogenesis both in vivo and in vitro. Conclusions: Collectively, CD51 is a novel marker of cardiac resident MSCs, and CD51+cMSC therapy enhances cardiac repair at least partly through SCF-mediated angiogenesis.

Adding Adjuvants to Fluoropyrimidine-based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: An Option Worthy of Serious Consideration.

The application of fluoropyrimidine-based neoadjuvant chemoradiotherapy (Fu-nCRT) of locally advanced rectal cancer (LARC) has become a common therapeutic regimen. In order to improve the efficacy and enable more patients to benefit from this treatment, an accumulation of studies have been carried out on the auxiliary use of other drugs with Fu-nCRT. However, due to specific challenges and the potential opportunities that coexist in this field, a more reasonable approach to the mode of treatment remains to be explored. In this review, we have summarized the results of the studies on the combination of Fu-nCRT with cytotoxic drugs, anti-tumor angiogenesis, and anti-EGFR agents, as well as the status of the application of immune checkpoint inhibitors in the neoadjuvant therapy of LARC patients.

Prognostic value of the albumin-bilirubin score in critically ill patients with heart failure.

BACKGROUND: This study sought to examine the association between the albumin-bilirubin (ALBI) score and short-term and 4-year all-cause mortality in critically ill patients with heart failure (HF), and to build a simple and effective new predictive model. METHODS: The Monitoring in Intensive Care Database III was used to identify patients with HF who had been admitted to the intensive care unit (ICU) from 2001 to 2012. Correlations between ALBI scores and other commonly used risk-scoring methods and short-term and 4-year all-cause mortality were examined using the Kaplan-Meier method and Cox proportional hazards-regression models. RESULTS: The data of 3,381 ICU patients were included in the study, of whom 53.7% were male. The patients had a mean age of 70.02±12.55 years, and a short-term mortality rate of 27.7%. The ALBI score of survivors [-1.80 (-2.09 to -1.44)] was significantly lower than that of non-survivors [-1.43 (-1.80 to -0.99)] (P<0.001), and independently predicted short-term all-cause mortality and higher 4-year mortality. The area under the receiver operating characteristic curve (AUC) of the ALBI score for short-term mortality was 0.676, and that of the Get With the Guidelines-Heart Failure (GWTG-HF) score was 0.643. The new model, which combined the ALBI and GWTG-HF (the GWTG-HF-ALBI), had an AUC of 0.713. The AUC of the ALBI score for predicting 4-year all-cause mortality was 0.596, that of the GWTG-HF score was 0.638, and that of the GWTG-HF-ALBI risk score was 0.650. CONCLUSIONS: The ALBI score is useful at predicting the mortality of patients with HF requiring ICU admission. The GWTG-HF-ALBI model is simpler to use than other models that contain subjective items, such as the Glasgow Coma Score, and can be used to predict the short-term and 4-year all-cause mortality of these patients.

Protective effect of bone marrow mesenchymal stem cell-derived exosomes on cardiomyoblast hypoxia-reperfusion injury through the miR-149/let-7c/Faslg axis.

Ischaemia-reperfusion injury (IRI) is closely related to cardiovascular disease (CVD), which is the leading cause of death and disability. Exosomes appear to be involved in several diseases, including CVD. However, the role of mesenchymal stem cell (MSC)-derived exosomes in IRI remains unclear. miRNA expression levels in exosomes from rat normal MSCs or hypoxia-reoxygenation (H/R) MSCs were determined by qPCR and the two significantly upregulated miRNAs were selected for further investigation. Rat cardiomyoblasts (H9c2) were transfected with either miRNA mimics or scramble controls, followed by H/R induction. The effects of miRNA overexpression and exosome administration on H/R damage were then investigated. H/R increased Faslg, suppressed ß-catenin, inhibited cell proliferation and migration, and stimulated apoptosis and reactive oxygen species (ROS) production. miR-149 or Let-7c mimics or exosomes reversed H/R-induced damage. The luciferase reporter assay proved the targeted regulation of Faslg by both miR149 and Let-7c. Inhibition of ß-catenin suppressed cell migration, proliferation, and ΔΨm but increased apoptosis and ROS. Overall, bone marrow MSC-derived exosomes protected rat cardiomyoblasts from H/R injury via the miR-149/Let-7c/Faslg axis.

Impact of long-term glucose variability on coronary atherosclerosis progression in patients with type 2 diabetes: a 2.3 year follow-up study.

BACKGROUND: Glycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations [median 2.3 (1.8-3.1) years] were included. Fasting plasma glucose (FPG) was measured every 1-3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression. RESULTS: In the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm3, and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV [CV-HbA1c: ß = 0.241 (0.019-0.462), P = 0.034; CV-FPG: ß = 0.265 (0.060-0.465), P = 0.012], annual TPV progression [CV-HbA1c: ß = 0.214 (0.023-0.405), P = 0.029; CV-FPG: ß = 0.218 (0.037-0.399), P = 0.019], and significant atherosclerosis progression [CV-HbA1c: odds ratio [OR] = 1.367 (1.149-1.650), P = 0.010; CV-FPG: OR = 1.321 (1.127-1.634), P = 0.013]. CONCLUSIONS: Long-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM. Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered.

Predictive value of P wave terminal force in lead V1 for atrial fibrillation: A meta-analysis.

BACKGROUND: Several studies have explored the association between P wave terminal force in lead V1 (PTFV1) and risk of atrial fibrillation (AF) occurrence, but the results were controversial. This meta-analysis aimed to examine whether abnormal PTFV1 could predict AF occurrence. METHODS: We searched PubMed, Embase, and Cochrane Library databases for articles published before August 25, 2018. Pooled odds ratios (ORs) of AF occurrence were calculated using random-effects models to explore the significance of PTFV1. RESULTS: A total of 12 studies examining 51,372 participants were included, with 9 studies analyzing PTFV1 as a categorical variable and 4 studies analyzing PTFV1 as a continuous variable. As a categorical variable, abnormal PTFV1 (>0.04 mm s) was significantly associated with AF occurrence with a pooled OR of 1.39 (95% confidence interval [CI] 1.08-1.79, p = .01). Subgroup analysis found that ORs of studies in hemodialysis patients (OR = 4.89, 95% CI 2.54-9.90, p < .001) and acute ischemic stroke patients (OR = 1.60, 95% CI 1.14-2.25, p = .007) were higher than general population (OR = 1.15, 95% CI 1.03-1.29, p = .01). Studies from Europe (OR = 1.05, 95% CI 0.91-1.20, p = .51) yielded lower OR of endpoints compared with Asia (OR = 1.89, 95% CI 1.38-2.60, p < .001) and United States (OR = 1.43, 95% CI 1.19-1.72, p < .001). As a continuous variable, PTFV1 was also significantly associated with AF occurrence with a polled OR per 1 standard deviation (SD) change of 1.27 (95% CI 1.02-1.59, p = .03). CONCLUSIONS: PTFV1 was significantly associated with the risk of AF and was considered to be a good predictor of AF occurrence in population with or without cardiovascular diseases.