Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Reduced expression of HCN channels in sinoatrial node of streptozotocin-induced diabetic rats

Diabetes mellitus (DM) is associated with an electrical remodeling of the heart, increasing risk of arrhythmias. However, knowledge of electrical remodeling in sinoatrial node (SAN) by DM is limited. We investigated the expression of HCN channel isoforms, HCN1-HCN4, in SAN from streptozotocin (STZ)-induced diabetic rats and the age-matched controls. We found that the STZ-induced diabetic rats have a lower intrinsic heart rate, a lengthened sinoatrial conduction time and rate-corrected maximal sinoatrial node recovery time in vivo as well as a longer cycle length (CL) in vitro as compared with the control. Optical mapping of the SAN demonstrated an inferior leading pacemaker site, a reduced SAN conduction velocity and diastolic depolarization slope, a longer action potential duration in the STZ-induced diabetic rats than the control. The transcripts and proteins of HCN2 and HCN4 in diabetic SAN were reduced. Specific blockade of HCN channels by 3uM ivabradine significantly prolonged CL of Langendorff heart by 18 % in the diabetic rats and 26 % in the control. The reduced expression of HCN channel isoforms in SAN of the STZ-induced diabetic rat may be an important contributor to the reduced SAN function in DM.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Identification of SPRYD4 as a tumour suppressor predicts prognosis and correlates with immune infiltration in cholangiocarcinoma

Abstract Cholangiocarcinoma (CCA) is an aggressive solid tumour with a 5-year survival rate ranging from 7% to 20%. It is, therefore, urgent to identify novel biomarkers and therapeutic targets to improve the outcomes of patients with CCA. SPRY-domain containing protein 4 (SPRYD4) contains SPRY domains that modulate protein–protein interaction in various biological processes; however, its role in cancer development is insufficiently explored. This study is the first to identify that SPRYD4 is downregulated in CCA tissues using multiple public datasets and a CCA cohort. Furthermore, the low expression of SPRYD4 was significantly associated with unfavourable clinicopathological characteristics and poor prognosis in patients with CCA, indicating that SPRYD4 could be a prognosis indicator of CCA. In vitro experiments revealed that SPRYD4 overexpression inhibited CCA cells proliferation and migration, whereas the proliferative and migratory capacity of CCA cells was enhanced after SPRYD4 deletion. Moreover, flow cytometry showed that SPRYD4 overexpression triggered the S/G2 cell phase arrest and promoted apoptosis in CCA cells. Furthermore, the tumour-inhibitory effect of SPRYD4 was validated in vivo using xenograft mouse models. SPRYD4 also showed a close association with tumour-infiltrating lymphocytes and important immune checkpoints including PD1, PD-L1 and CTLA4 in CCA. In conclusion, this study elucidated the role of SPRYD4 during CCA development and highlighted SPRYD4 as a novel biomarker and tumour suppressor in CCA

Markers of Autolysis in Acute ST Elevation Myocardial Infarction – A Comparative Analysis

Introduction: The availability of reliable noninvasive markers for infarct-related artery patency status are very limited, otherwise could allow early identification of patients with patent IRA, for whom repeat thrombolysis or rescue percutaneous coronary intervention are not necessary. 
 Methods: We conducted a single centered retrospective study of STEMI patients undergoing primary PCI to determine how various factors such as demographic characteristics, risk markers of coronary heart disease, clinical and blood parameters present differently in patients with higher coronary flow and patent infarct related artery from patients with total occlusion at the time of initial angiography and how they affect in outcome of the disease. 
 Results: MPV level (11.96 fL vs. 10.92 fL, P < 0.001), Lp (a) level (179.57 nmol/l vs 141.16 nmol/l , p < 0.001), CK-MB (290.2 vs. 190.98, P < 0.001), total cholesterol level (4.11 mmol/L vs. 3.8 mmol/L, p < 0.02) in total occlusion group were higher than in the patent IRA group. Wall motion abnormality was 77.2% for 203 patients with total occlusion group and 54.2% for 83 patients with patent IRA group (P<0.01). Mean hospital stay days were higher in total occlusion group as compared to the patent IRA group P < 0.01. 
 Conclusions: MVP, Lp (a), TC, and CK-MB levels and myocardial wall motion at the presentation may play the role of markers for IRA patency status that will help in early identification of patients with IRA, for whom repeat thrombolysis or rescue PCI may not be required. 
 Keywords: acute coronary syndrome; infarct related artery; myocardial infarction

Identification of Prognostic and Therapeutic Biomarkers among FAM83 Family Members for Pancreatic Ductal Adenocarcinoma

Family with sequence similarity 83 (FAM83) members were shown recently to have oncogenic effect in a variety of cancer types, but the biological roles and prognostic value of FAM83 family in pancreatic ductal adenocarcinoma remain unknown. In the current study, the clinical significance and molecular function of the FAM83 family were assessed by multiple bioinformatics analysis. Besides, potential associations between differentially expressed genes (DEGs) of FAM83 family and antitumor immunity were evaluated using TIMER and TISIDB analyses. As the results show, FAM83A, FAM83D, FAM83E, and FAM83H were significantly upregulated in PDAC and were identified as DEGs. Higher expression of FAM83A, FAM83B, FAM83D, FAM83E, and FAM83H were associated with advanced tumor stage or worse patient prognosis. Importantly, the overexpression of DEGs was found to be significantly correlated with activated KRAS and loss of SMAD4, which are important drivers for PDAC. Further, FAM83A, FAM83D, and FAM83H were associated with CD8+ T cell, Gamma Delta T cell, and CD4+ T cell infiltration in PDAC and FAM83H was found closely correlated with some immunomodulators including immunoinhibitors, immunostimulators, and MHC molecules. In conclusion, FAM83A, FAM83D, FAM83E, and FAM83H have significant prognostic value in PDAC and they may play important roles in regulating tumor progression and the immune cell infiltration

Markers of Autolysis in Acute ST Elevation Myocardial Infarction – A Comparative Analysis

Introduction: The availability of reliable noninvasive markers for infarct-related artery patency status are very limited, otherwise could allow early identification of patients with patent IRA, for whom repeat thrombolysis or rescue percutaneous coronary intervention are not necessary. Methods: We conducted a single centered retrospective study of STEMI patients undergoing primary PCI to determine how various factors such as demographic characteristics, risk markers of coronary heart disease, clinical and blood parameters present differently in patients with higher coronary flow and patent infarct related artery from patients with total occlusion at the time of initial angiography and how they affect in outcome of the disease. Results: MPV level (11.96 fL vs. 10.92 fL, P < 0.001), Lp (a) level (179.57 nmol/l vs 141.16 nmol/l , p < 0.001), CK-MB (290.2 vs. 190.98, P < 0.001), total cholesterol level (4.11 mmol/L vs. 3.8 mmol/L, p < 0.02) in total occlusion group were higher than in the patent IRA group. Wall motion abnormality was 77.2% for 203 patients with total occlusion group and 54.2% for 83 patients with patent IRA group (P<0.01). Mean hospital stay days were higher in total occlusion group as compared to the patent IRA group P < 0.01. Conclusions: MVP, Lp (a), TC, and CK-MB levels and myocardial wall motion at the presentation may play the role of markers for IRA patency status that will help in early identification of patients with IRA, for whom repeat thrombolysis or rescue PCI may not be required.  Keywords: acute coronary syndrome; infarct related artery; myocardial infarction

Prognostic Nomogram for Patients With Pancreatic Ductal Adenocarcinoma of Pancreatic Head After Pancreaticoduodenectomy

Background: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) of pancreatic head remains poor, even after potentially curative R0 resection. The aim of this study was to develop an accurate model to predict patients’ prognosis for PDAC of pancreatic head following pancreaticoduodenectomy. Methods: We retrospectively reviewed 112 patients with PDAC of pancreatic head after pancreaticoduodenectomy in Guangdong Provincial People’s Hospital between 2014 and 2018. Results: Five prognostic factors were identified using univariate Cox regression analysis, including age, histologic grade, American Joint Committee on Cancer (AJCC) Stage 8th, total bilirubin (TBIL), CA19-9. Using all subset analysis and multivariate Cox regression analysis, we developed a nomogram consisted of age, AJCC Stage 8th, perineural invasion, TBIL, and CA19-9, which had higher C-indexes for OS (0.73) and RFS (0.69) compared with AJCC Stage 8th alone (OS: 0.66; RFS: 0.67). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve for the nomogram for OS and RFS were significantly higher than other single parameter, which are AJCC Stage 8th, age, perineural invasion, TBIL, and CA19-9. Importantly, our nomogram displayed higher C-index for OS than previous reported models, indicating a better predictive value of our model. Conclusions: A simple and practical nomogram for patient prognosis in PDAC of pancreatic head following pancreaticoduodenectomy was established, which shows satisfactory predictive efficacy and deserves further evaluation in the future

A Novel Prognostic Nomogram for Gallbladder Cancer after Surgical Resection: A Single-Center Experience

Background. Gallbladder cancer (GBC), which accounts for more than 80% of biliary tract malignancies, has a poor prognosis with an overall 5-year survival less than 10%. The study aimed to identify risk factors and develop a predictive model for GBC following surgical resection. Methods. 98 GBC patients who underwent surgical resection from Guangdong Provincial People’s Hospital were enrolled in the study. Cox-regression analysis was performed to identify significant prognostic factors. A nomogram was constructed and Harrell’s concordance index, calibration plot, and decision cure analysis were used to evaluate the discrimination and calibration of the nomogram. Results. Liver resection, tumor size, perineural invasion, surgical margin, and liver invasion were identified as independent risk factors for overall survival (OS) in GBC patients who underwent surgical resection. Based on the selected risk factors, a novel nomogram was constructed. The C-index of the nomogram was 0.777, which was higher than the American Joint Committee on Cancer (AJCC) staging system (0.724) and Nevin staging system (0.659). Decision cure analysis revealed that the nomogram had a better net benefit and the calibration curves for the 1-, 3-, and 5-year survival probabilities were also well matched with the actual survival rates. Lastly, high-risk GBC were stratified based on the scores of the nomogram and we found high-risk GBC were associated with both worse OS and disease-free survival (DFS). Conclusion. We developed a nomogram showing a better predictive capacity for patients’ survival of resected GBC than the AJCC staging systems. The established model may help to stratify high-risk GBC and facilitate decision-making in the clinic

Optimizing an Emergency Medical Dispatch System to Improve Prehospital Diagnosis and Treatment of Acute Coronary Syndrome: Nationwide Retrospective Study in China

BackgroundAcute coronary syndrome (ACS) is the most time-sensitive acute cardiac event that requires rapid dispatching and response. The medical priority dispatch system (MPDS), one of the most extensively used types of emergency dispatch systems, is hypothesized to provide better-quality prehospital emergency treatment. However, few studies have revealed the impact of MPDS use on the process of ACS care. ObjectiveThis study aimed to investigate whether the use of MPDS was associated with higher prehospital diagnosis accuracy and shorter prehospital delay for patients with ACS transferred by an emergency medical service (EMS), using a national database in China. MethodsThis retrospective analysis was based on an integrated database of China’s MPDS and hospital registry. From January 1, 2016, to December 31, 2020, EMS-treated ACS cases were divided into before MPDS and after MPDS groups in accordance with the MPDS launch time at each EMS center. The primary outcomes included diagnosis consistency between hospital admission and discharge, and prehospital delay. Multivariable logistic regression and propensity score–matching analysis were performed to compare outcomes between the 2 groups for total ACS and subtypes. ResultsA total of 9806 ACS cases (3561 before MPDS and 6245 after MPDS) treated by 43 EMS centers were included. The overall diagnosis consistency of the after MPDS group (Cohen κ=0.918, P<.001) was higher than that of the before MPDS group (Cohen κ=0.889, P<.001). After the use of the MPDS, the call-to-EMS arrival time was shortened in the matched ACS cases (20.0 vs 16.0 min, P<.001; adjusted difference: –1.67, 95% CI –2.33 to –1.02; P<.001) and in the subtype of ST-elevation myocardial infarction (adjusted difference: –3.81, 95% CI –4.63 to –2.98, P<.001), while the EMS arrival-to-door time (20.0 vs 20.0 min, P=.31) was not significantly different in all ACS cases and subtypes. ConclusionsThe optimized use of MPDS in China was associated with increased diagnosis consistency and a reduced call-to-EMS arrival time among EMS-treated patients with ACS. An emergency medical dispatch system should be designed specifically to fit into different prehospital modes in the EMS system on a regional basis