Search

Graphical abstract, Highlights • A herb-based formula delivers positive clinical outcomes on COVID-19 patients. • The formula inhibits SARS-CoV-2 pathogenesis in anti-viral & -inflammatory assays. • Real-world-evidence offers insights to inform drug development. • Bed-to-bench approach shortens the time required for finding effective therapeutics., COVID-19 is a global pandemic, with over 50 million confirmed cases and 1.2 million deaths as of November 11, 2020. No therapies or vaccines so far are recommended to treat or prevent the new coronavirus. A novel traditional Chinese medicine formula, Taiwan Chingguan Yihau (NRICM101), has been administered to patients with COVID-19 in Taiwan since April 2020. Its clinical outcomes and pharmacology have been evaluated. Among 33 patients with confirmed COVID-19 admitted in two medical centers, those (n = 12) who were older, sicker, with more co-existing conditions and showing no improvement after 21 days of hospitalization were given NRICM101. They achieved 3 consecutive negative results within a median of 9 days and reported no adverse events. Pharmacological assays demonstrated the effects of the formula in inhibiting the spike protein/ACE2 interaction, 3CL protease activity, viral plaque formation, and production of cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. This bedside-to-bench study suggests that NRICM101 may disrupt disease progression through its antiviral and anti-inflammatory properties, offering promise as a multi-target agent for the prevention and treatment of COVID-19.

Aortic aneurysms are morbid conditions that can lead to rupture or dissection and are categorized as thoracic (TAA) or abdominal aortic aneurysms (AAA) depending on their location. While AAA shares overlapping risk factors with atherosclerotic cardiovascular disease, TAA exhibits strong heritability. Human genetic studies in the past two decades have successfully identified numerous genes involved in both familial and sporadic forms of aortic aneurysm. In this review we will discuss the genetic basis of aortic aneurysm, focusing on the extracellular matrix and how insights from these studies have informed our understanding of human biology and disease pathogenesis.

Background Adults with congenital heart disease (ACHD) have traditionally been viewed as an underinsured population. Whether this is true in the Affordable Care Act era is unknown. We determined insurance patterns in ACHD patients compared to the non-ACHD cardiology population in a contemporary cohort. Methods All cardiology outpatient visits between July 2016 and February 2017 to a large referral center in the United States were reviewed. The primary payer was categorized as health maintenance organization (HMO), preferred provider organization (PPO), Medicare, Medicaid, self-pay, or other. Diagnosis and lesion severity of ACHD were extracted from ICD-10 diagnostic codes and assigned according to the 2008 American College of Cardiology/American Heart Association ACHD guidelines. Age-matching was used to account for baseline age differences between ACHD and non-ACHD patients. Results E ACHD and 17 154 non-ACHD patients were identified. Without age-matching, ACHD patients were significantly younger than non-ACHD patients (mean age 38.5 vs 63.8 years). After age-matching (N = 805 in each group), mean age was 39.5 years in both groups. ACHD patients had less HMO (29.1% vs 34.7%, P = .012) and Medicaid (12.4% vs 17.3%, P = .006) coverage, but more PPO (34.4% vs 27.5%, P = .003) and Medicare (23.2% vs 18.1%, P = .005) coverage compared to non-ACHD patients. No differences were found in private insurance, public insurance, or self-pay. Lesion complexity had no effect on insurance in ACHD patients. Eligibility of parental plan coverage did not affect use of private insurance. ACHD patients in states with Medicaid expansion had higher rates of Medicaid (15.6% vs 10.6%, P = .045) but lower rates of HMO coverage (24.5% vs 31.7%, P = .036) and self-pay (0% vs 3.3%, P

BACKGROUND The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen–matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy–based HCT. METHODS A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model. RESULTS Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non–PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy. CONCLUSIONS The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy–based HCT. Cancer 2017;123:1800–1809. © 2017 American Cancer Society.

Not all patients with angina pectoris have coronary artery stenosis. To facilitate the diagnosis of coronary artery disease (CAD), we sought to identify predictive factors of pulse spectrum analysis, which was developed by Wang and is one technique of modern pulse diagnosis. The patients suffered from chest pain and received cardiac catheterization to confirm the CAD diagnosis and Gensini score were recruited. Their pulse waves of radial artery were recorded. Then, by performing a fast Fourier transform, 10 amplitude values of frequency spectrum harmonics were obtained. Each harmonic amplitude was divided by the sum of all harmonic amplitude values, obtaining the relative percentages of 10 harmonics (C1-C10). Subsequently, multivariate logistic regression was conducted with two models and the areas under the receiver operating characteristic curves (ROC) of these 2 models were compared to see if combining the pulse diagnosis parameters with the risk factor of CAD can increase the prediction rate of CAD diagnosis. The predictive factors of CAD severity were analyzed by multivariate linear regression. A total of 83 participants were included; 63 were diagnosed CAD and 20 without CAD. In the CAD group, C1 was greater and C5 was lower than those of the non-CAD group. The CAD risk factors were put alone in Model 1 to perform the multivariate logistic regression analysis which had a prediction rate of 77.1%; while putting the C1 and C5 harmonics together with the risk factors into Model 2, the prediction rate increased to 80.7%. Finally, the area under ROC of Model 1 and Model 2 was 0.788 and 0.856, respectively. Furthermore, left C1, left C5, gender, and presence of hyperlipidemia were predictors of CAD severity. Therefore, pulse spectrum analysis may be a tool to facilitate CAD diagnosis before receiving cardiac catheterization. The harmonics C1 and C5 were favorable predictive indicators.

Background. Identifying patients with high risk of coronary artery disease (CAD) is often difficult in outpatient clinic settings. This study aimed to explore if the measurement of body constitution can be adopted to predict the risk of CAD diagnosis. The objective of this study is to conduct a prospective observational study and a case-control study to answer the research question. Study Design. Part 1 (prospective observational study): a total of 143 patients with chest pain and admitted to receive cardiac catheterization were enrolled, and 108 of them were diagnosed with CAD. Part 2 (case-control study): the above 108 CAD patients and 476 healthy controls matched by age and gender from the participants of Taiwan Biobank were adopted for comparison. Main Outcome Measures. The body constitution of both patients and healthy controls were measured by the Body Constitution Questionnaire (BCQ). Each one received scores of Yang-Xu (Yang-deficiency), Yin-Xu (Yin-deficiency), and Stasis. These 3 scores together with demographic characteristics and CAD risk factors were used in the logistic multiple regression model to predict the risk of CAD. Results. (Part 1) No difference was found between the scores of Yang-Xu, Yin-Xu, and Stasis between the patients with and without CAD. (Part 2) The scores of Yang-Xu, Yin-Xu, and Stasis of the CAD patients were significant higher those of the healthy controls. Yang-Xu and Stasis scores were obtained with age, BMI, and hypertension in the model with prediction rate 89.0%. The area under receiver operating characteristic curve of this model was 0.896. Conclusions. This study is the first to apply Chinese body constitution concepts and measurable variables to assess the risk of having CAD of the patients with chest pain prior to receiving cardiac catheterization. The higher scores of Yang-Xu and Stasis were found to be risk factors. Our results revealed that BCQ has the potential to be a first-line diagnostic tool for patients with chest pain to facilitate early recognition and diagnosis of CAD.

Left ventricular assist device (LVAD) has been increasingly utilized in the past decade for patients with end stage heart failure. The clinical course of acute myocardial infarction (AMI) after LVAD remains unclear. LVAD provides complete hemodynamic support irrespective of cardiac rhythm or

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

Neointimal hyperplasia causes arterial obstruction, responsible for significant morbidity and mortality worldwide. Animal models for neointimal hyperplasia may provide an important platform for preclinical and mechanistic studies. Current animal models for neointimal hyperplasia require surgical

Heart malformations are common congenital defects in humans. Many congenital heart defects involve anomalies in cardiac septation or valve development, and understanding the developmental mechanisms that underlie the formation of cardiac septal and valvular tissues thus has important implications for the diagnosis, prevention and treatment of congenital heart disease. The development of heart septa and valves involves multiple types of progenitor cells that arise either within or outside the heart. Here, we review the morphogenetic events and genetic networks that regulate spatiotemporal interactions between the cells that give rise to septal and valvular tissues and hence partition the heart.

Importance The incremental benefit of noninvasive testing in addition to clinical evaluation (history, physical examination, an electrocardiogram [ECG], and biomarker assessment) vs clinical evaluation alone for patients who present to the emergency department (ED) with acute chest pain is unknown. Objective To examine differences in outcomes with clinical evaluation and noninvasive testing (coronary computed tomographic angiography [CCTA] or stress testing) vs clinical evaluation alone. Design, Setting, and Participants This study was a retrospective analysis of data from the randomized multicenter Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT-II) trial. Data for 1000 patients who presented with chest pain to the EDs at 9 hospitals in the United States were evaluated. Interventions Clinical evaluation plus noninvasive testing (CCTA or stress test) vs clinical evaluation alone. Main Outcomes and Measures Primary outcome was length of stay (LOS). Secondary outcomes included hospital admission, direct ED discharge, downstream testing, rates of invasive coronary angiography, revascularization, major adverse cardiac events (MACE), repeated ED visit or hospitalization for recurrent chest pain at 28 days, and cost. Safety end points were missed acute coronary syndrome (ACS) and cumulative radiation exposure during the index visit and follow-up period. Results Of the 1000 patients randomized, 118 patients (12%) (mean [SD] age, 53.2 [7.8]; 49 [42%] were female) did not undergo noninvasive testing, whereas 882 (88%) (mean [SD] age, 54.4 [8.14] years; 419 [48%] were female) received CCTA or stress testing. There was no difference in baseline characteristics or clinical presentation between groups. Patients who underwent clinical evaluation alone experienced a shorter LOS (20.3 vs 27.9 hours;P Conclusions and Relevance In patients presenting to the ED with acute chest pain, negative biomarkers, and a nonischemic ECG result, noninvasive testing with CCTA or stress testing leads to longer LOS, more downstream testing, more radiation exposure, and greater cost without an improvement in clinical outcomes. Trial Registration clinicaltrials.gov Identifier:NCT01084239

Aims Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin–NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries. Methods and results Using tissue-specific gene deletion, we found that calcineurin–NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 ( Cnb1 ), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin–NFAT signals within a narrow time window at embryonic Day 12.5–13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2 , whose gene product is critical for transducing transforming growth factor β (TGFβ)–Alk5 signalling to control coronary development. Conclusion Our findings demonstrate new spatiotemporal and molecular actions of calcineurin–NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin–NFAT integrates with TGFβ signalling during embryonic development.

Bai-Hu-Tang(BHT) has been broadly applied to treating the early stage of acute infection with systemic inflammation for two thousand years in Chinese medicine. We explore whether BHT is beneficial in treating sepsis and its effects on proinflammatory cytokine, interleukin-6, and anti-inflammatory cytokine interleukin-10, in which both play key roles in the progress of sepsis. Thirty-six male Sprague-Dawley rats were randomized into six groups, with cecal ligation and puncture (CLP) performed in all but the sham-control group. Rats in CLP + BHT-L6and CLP + BHT-H6groups, respectively, received a low (0.45 g/kg) and high doses (0.9 g/kg) of BHT, 6 hrs postoperatively. CLP + BHT-L12and CLP + BHT-H12groups, respectively, received low and high doses of BHT, 12 hrs postoperatively. Sham-control and sepsis-control groups received distilled water (1 mL) as vehicle, 6 hrs postoperatively. Serial blood samples were drawn before operation, as baseline, and at 4, 8, and 12 hrs postoperatively for IL-6 and IL-10 assay. All rats were monitored for 3 days for survival study. Rats in the CLP + BHT-H6group had significantly higher survival rate (80%) and significantly lower levels of both IL-6 and IL-10 at 12 hrs postoperatively than those in the sepsis-control group. Results suggested that BHT may be a new complementary treatment option for sepsis.

Semilunar valve malformations are common human congenital heart defects. Bicuspid aortic valves occur in 2–3% of the population, and pulmonic valve stenosis constitutes 10% of all congenital heart disease in adults (Brickner et al., 2000) [1] . Semilunar valve defects cause valve regurgitation, stenosis, or calcification, leading to endocarditis or congestive heart failure. These complications often require prolonged medical treatment or surgical intervention. Despite the medical importance of valve disease, the regulatory pathways governing semilunar valve development are not entirely clear. In this report we investigated the spatiotemporal role of calcineurin/Nfatc1 signaling in semilunar valve development. We generated conditional knockout mice with calcineurin gene disrupted in various tissues during semilunar valve development. Our studies showed that calcineurin/Nfatc1 pathway signals in the secondary heart field (SHF) but not in the outflow tract myocardium or neural crest cells to regulate semilunar valve morphogenesis. Without SHF calcineurin/Nfatc1 signaling, the conal endocardial cushions—the site of prospective semilunar valve formation—first develop and then regress due to apoptosis, resulting in a striking phenotype with complete absence of the aortic and pulmonic valves, severe valve regurgitation, and perinatal lethality. This role of calcineurin/Nfatc1 signaling in the SHF is different from the requirement of calcineurin/Nfatc1 in the endocardium for semilunar valve formation (Chang et al., 2004) [2] , indicating that calcineurin/Nfatc1 signals in multiple tissues to organize semilunar valve development. Also, our studies suggest distinct mechanisms of calcineurin/Nfat signaling for semilunar and atrioventricular valve morphogenesis. Therefore, we demonstrate a novel developmental mechanism in which calcineurin signals through Nfatc1 in the secondary heart field to promote semilunar valve morphogenesis, revealing a new supportive role of the secondary heart field for semilunar valve formation.

In order to provide a faster and easier way for outcome prediction of sepsis, this study aimed to characterize the pattern of arterial pulse spectrum by a rat cecum ligation and puncture (CLP) model and explore whether specific harmonic components of pulse spectrum are associated with the mortality of CLP rats, followed by the comparison of accuracy between these specific variables and IL-6.Nineteen Sprague-Dawley rats receiving CLP were analyzed. Femoral artery of each rat was catheterized for blood pressure recording and blood sampling in the first 24 hours after CLP. The former was for off-line pulse spectrum analysis, and the latter for IL-6 assay. These rats were observed for 3-day mortality after CLP, and were divided into survivor or non-survivor groups. Differences of the hemodynamic profile, IL-6, and changes of the harmonics between the 2 groups were analyzed by using the Mann-Whitney test. Kaplan-Meier curves were constructed to characterize cumulative survival with the best prognostic cutoff point.The characteristic changes of pulse spectrum were different between survivors and non-survivors. The percentage differences of the 2nd harmonic proportion (C2) increased significantly from the 10th hour after CLP, and was higher in the non-survivors. Serum levels of IL-6 were also higher in the non-survivor group. Analyzed by Kaplan-Meier survival curve for 3-day mortality, C2 had a higher accuracy than IL-6 as a predictor.The pulse spectrum analysis may be applied to evaluate the prognosis of CLP rats, and the rapidly and highly elevated C2 harmonic had a strong association with the 3-day mortality of CLP rats.

Background: Anemia and oral mucositis are main side effects of radiotherapy (RT) and are important factors affecting the quality of life (QOL) in head and neck cancer (HNC) patients treated with RT. This study aimed to explore the safety and therapeutic efficacy of Tianwang Buxin Mini-pills (＂TWBXM＂) for the prevention of acute RT toxicity in HNC patients by using a randomized, double-blind and placebo-controlled study design. Patients and Methods: Seventy-three HNC patients participated the study. They were randomized into a treatment group (n = 38) and a control group (n = 35). All patients received daily either ＂TWBXM＂ treatment or placebo starting from the initiation of RT until 1-month follow-up after RT completion. All patients were evaluated for QOL, acute RT toxicities and laboratory data (hemoglobin [Hgb], white blood cell and platelet) at 3 time points: Pre-RT, upon RT completion and at ＂TWBXM＂ completion. Results: The ＂TWBXM＂ group maintained normal levels of Hgb during the duration of the study while the placebo group showed a decrease in Hgb (P = 0.035). Conclusions: This study demonstrated the safety and efficacy of ＂TWBXM＂ applied in the HNC patients receiving RT. It prevented the decrease of Hgb in HNC patients undergoing RT treatment as well 1-month-post-RT treatment. Further studies are needed to assess the effects of ＂TWBXM＂ for the prevention of other RT toxicities.