Quantification of functional hemodynamics in aortic valve disease using cardiac computed tomography angiography.

BACKGROUND AND OBJECTIVE: Cardiac computed tomography angiography (CTA) is the preferred modality for preoperative planning in aortic valve stenosis. However, it cannot provide essential functional hemodynamic data, specifically the mean transvalvular pressure gradient (MPG). This study aims to introduce a computational fluid dynamics (CFD) approach for MPG quantification using cardiac CTA, enhancing its diagnostic value. METHODS: Twenty patients underwent echocardiography, cardiac CTA, and invasive catheterization for pressure measurements. Cardiac CTA employed retrospective electrocardiographic gating to capture multi-phase data throughout the cardiac cycle. We segmented the region of interest based on mid-systolic phase cardiac CTA images. Then, we computed the average flow velocity into the aorta as the inlet boundary condition, using variations in end-diastolic and end-systolic left ventricular volume. Finally, we conducted CFD simulations using a steady-state model to obtain pressure distribution within the computational domain, allowing for the derivation of MPG. RESULTS: The mean value of MPG, measured via invasive catheterization (MPGInv), echocardiography (MPGEcho), and cardiac CTA (MPGCT), were 51.3 ± 28.4 mmHg, 44.8 ± 19.5 mmHg, and 55.8 ± 25.6 mmHg, respectively. In comparison to MPGInv, MPGCT exhibited a higher correlation of 0.91, surpassing that of MPGEcho, which was 0.82. Moreover, the limits of agreement for MPGCT ranged from -27.7 to 18.7, outperforming MPGEcho, which ranged from -40.1 to 18.0. CONCLUSIONS: The proposed method based on cardiac CTA enables the evaluation of MPG for aortic valve stenosis patients. In future clinical practice, a single cardiac CTA examination can comprehensively assess both the anatomical and functional hemodynamic aspects of aortic valve disease.

A phase 3 randomized, open-label study evaluating the immunogenicity and safety of concomitant and staggered administration of a live, pentavalent rotavirus vaccine and an inactivated poliomyelitis vaccine in healthy infants in China.

This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from - 4.3% to - 1.6%, for all poliovirus types, p < .001. At PD3, geometric mean titers (GMTs) of nAb responses to poliovirus types 1, 2, and 3 in the concomitant-use group and the staggered-use group were comparable; 100% of participants had nAb titers ≥1:8 and ≥1:64 for all poliovirus types. Anti-rotavirus serotype-specific IgA GMTs and participants with ≥3-fold rise in postvaccination titers from baseline were comparable between groups. Administration of RV5 and IPV was well tolerated with comparable safety profiles in both groups. The immunogenicity of IPV in the concomitant-use group was non-inferior to the staggered-use group and RV5 was immunogenic in both groups. No safety concerns were identified. These data support the concomitant use of RV5 and IPV in healthy Chinese infants.

Initial establishment and validation of a predictive model for preeclampsia in twin pregnancies based on maternal characteristics and echocardiographic parameters.

INTRODUCTION: The primary objective of this study was to evaluate the association between maternal echocardiographic changes and the occurrence of preeclampsia (PE) in twin pregnancies. Additionally, we established and validated a prediction model for PE in twin pregnancies. MATERIAL AND METHODS: The first part of this study was retrospective and included data from 854 twin pregnancies that received antenatal care at Peking University Third Hospital from April 2017 to April 2021 (training cohort). Overall, 159 women who underwent transthoracic echocardiography were included in the analysis. To build a predictive model, cardiac findings were compared between normotensive women and those with PE. The model was then validated in a prospective longitudinal cohort (test cohort) that included 109 women with twin pregnancies who underwent two consecutive transthoracic echocardiography examinations during the second and third trimesters. RESULTS: Fifty-four normotensive women and 105 women with PE were analyzed in the retrospective cohort that was used to build the model in which later preeclampsia was associated with higher left ventricular mass index (>61 g/m2 ), interventricular septal thickness (>7.87 mm), left atrial anteroposterior diameter (>33.5 mm), mitral inflow late diastolic velocity (A) (>0.685 m/s), ratio of early diastolic velocity (E) and peak early diastolic myocardial velocity of the lateral mitral annulus (>6.5), and lower peak early diastolic myocardial velocity (<13.1 cm/s). The optimized PE prediction model based on the interventricular septal thickness, left atrial anteroposterior diameter, A, peak early diastolic myocardial velocity and pre-pregnancy bodyweight index was then established (area under the curve [AUC] = 0.840, 95% CI 0.778-0.903, P < 0.001). The model was tested in the prospective cohort including 87 normotensive women and 22 women with PE; the validation test showed that the prediction model in the second (AUC = 0.801) and third (AUC = 0.811) trimesters had high discriminative ability and calibration. CONCLUSIONS: Maternal echocardiographic changes in twin pregnancies are associated with the development of preeclampsia. The model constructed, based on the echocardiographic parameters and body mass index, provides novel ideas for the prediction of PE.

Exploratory use of intraprocedural transesophageal echocardiography to guide implantation of the leadless pacemaker.

Background: Fluoroscopy is the standard tool for transvenous implantation of traditional and leadless pacemakers (LPs). LPs are used to avoid complications of conventional pacemakers, but there still is a 6.5% risk of major complications. Mid-right ventricular (RV) septal device implantation is suggested to decrease the risk, but helpful cardiac landmarks cannot be visualized under fluoroscopy. Transesophageal echocardiography (TEE) is an alternative intraprocedural imaging method. Objective: The purpose of this study was to explore the spatial relationship of the LP to cardiac landmarks via TEE and their correlations with electrocardiographic (ECG) parameters, and to outline an intraprocedural method to confirm mid-RV nonapical lead positioning. Methods: Fifty-six patients undergoing implantation of LP with TEE guidance were enrolled in the study. Device position was evaluated by fluoroscopy, ECG, and TEE. Distances between the device and cardiac landmarks were measured by TEE and analyzed with ECG parameters with and without RV pacing. Results: Mid-RV septal positioning was achieved in all patients. TEE transgastric view (0°-40°/90°-130°) was the optimal view for visualizing device position. Mean tricuspid valve-LP distance was 4.9 ± 0.9 cm, mean pulmonary valve-LP distance was 4.2 ± 1 cm, and calculated RV apex-LP distance was 2.9 ± 1 cm. Mean LP paced QRS width was 160.8 ± 28 ms and increased from 117.2 ± 34 ms at baseline. LP RV pacing resulted in left bundle branch block pattern on ECG and 37.8% QRS widening by 43.5 ± 29 ms. Conclusion: TEE may guide LP implantation in the nonapical mid-RV position. Further studies are required to establish whether this technique reduces implant complications compared with conventional fluoroscopy.

Risk Factors Associated With Postoperative Pulmonary Infection in Elderly Patients With Hip Fracture: A Longitudinal Study.

This study aimed to conduct a longitudinal study to explore the influencing factors of pulmonary infection in elderly patients with hip fracture after surgery, to provide evidence and reference for the early identification and nursing care of patients at high risk of postoperative pulmonary infection.A secondary analysis was conducted of electronic medical record data from elderly patients with hip fractures treated in a tertiary hospital from January 1, 2020 to June 30, 2021.A total of 526 patients were included. Age ≥70 years (odd ratio [OR] 2.042, 95% confidence interval [CI] [1.516-4.022]), history of smoking (OR 2.755, 95% CI [2.009-3.175]), time from fracture to operation ≥5 days (OR 3.117, 95% CI [1.925-3.911]), American Society of Anesthesiologists grade ≥II (OR 1.254, 95% CI [1.053-1.921]), chronic obstructive pulmonary disease (OR 2.832, 95% CI [1.775-3.808]), hypoproteinemia (OR 1.395, 95% CI [1.022-1.841]), red blood cell distribution width >15% (OR 3.142, 95% CI [2.104-4.172]), intensive care unit stay (OR 2.174, 95% CI [1.083-3.718]) and duration of mechanical ventilation ≥180 minutes (OR 3.117, 95% CI [2.199-4.807]) were the independent risk factors (all p < .05).Early nursing care should be taken for patients with risk factors to reduce the pulmonary infection.

Diversity-Oriented Metal-Free Synthesis of Nitrogen-Containing Heterocycles Using Atropaldehyde Acetals as a Dual C3/C2-Synthon.

A highly efficient and elegant diversity-oriented reaction paradigm employing atropaldehyde acetals as new dual C2/C3 synthons was developed under metal-free conditions using glycine esters as the counterpart reagents, which allowed rapid synthesis of two important nitrogen-containing heterocycles, pyrrolo[1,2-a]quinolines and 3,5-diarylpyridines. The divergent products are subtly controlled by the manipulation of the substitutional groups of glycine esters. When a N-arylglycine ester was used, pyrrolo[1,2-a]quinolines can be formed through cascade oxidative C-C cleavage/multiple cyclization. Instead, N-benzylglycine ester as the counter-reagent led to the synthesis of 3,5-diarylpyridines via two key C-N cleavages. Mild conditions, broad substrate scope, scalability and environmentally acceptable organic solvents rendered this method practical and attractive.

Nicorandil Improves Left Ventricular Myocardial Strain in Patients With Coronary Chronic Total Occlusion.

Background: Nicorandil is recommended as a second-line treatment for stable angina; however, randomized-controlled trials to evaluate the benefit of nicorandil for patients with chronic total occlusion (CTO) are lacking. Objective: To determine whether nicorandil can improve left ventricular (LV) myocardial strain in patients with CTO. Methods: Patients with CTO were included and randomized to the nicorandil group (n = 31) and the control group (n = 30). Nicorandil was given orally at 15 mg/day for 3 months in the nicorandil group. Three-dimensional speckle-tracking echocardiography and the Seattle Angina Questionnaire (SAQ) survey were performed at baseline and at 3 months. The primary study endpoint was the LV global area strain (GAS) at 3 months. Results: The nicorandil and the control groups were well-matched at baseline, including the mean GAS and SAQ scores. At 3 months, GAS in the nicorandil group was significantly higher than that in the control group (-23.7 ± 6.3% vs. -20.3 ± 5.6%, respectively; p = 0.033). There were no significant differences in LV global longitudinal strain, global circumferential strain, global radial strain, LV ejection fraction, LV end-diastolic volume, and LV end-systolic volume at 3 months between the two groups. At 3 months, the SAQ scores for angina stability, angina frequency, and treatment satisfaction in the nicorandil group were significantly higher than those in the control group. Conclusion: Nicorandil treatment can improve GAS and angina symptoms in patients with CTO. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT05087797.

Cardioprotection of Repeated Remote Ischemic Conditioning in Patients With ST-Segment Elevation Myocardial Infarction.

Background: Repeated remote ischemic conditioning (RIC) after myocardial infarction (MI) has been shown to improve left ventricular (LV) remodeling in the experimental studies, but its cardioprotective effect in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown. Objective: To investigate whether repeated RIC started early after primary percutaneous coronary intervention (PCI) can improve LV function in patients with STEMI. Methods: Patients with STEMI treated by primary PCI were included and randomized to the repeated RIC group (n = 30) or the control group (n = 30). RIC was started within 24 h after PCI and repeated daily for 1 week, using an Auto RIC device. 3D speckle-tracking echocardiography (STE) was used to assessed LV function. The primary study endpoint was the change in LV global longitudinal strain (GLS) from baseline to 1 month after PCI. Results: The repeated RIC group and the control group were well-matched at baseline including mean GLS (-9.8 ± 2.6% vs. -10.1 ± 2.5%, P = 0.62). Despite there was no significant difference in mean GLS at 1 month between the two groups (-11.9 ± 2.1% vs. -10.9 ± 2.7%, P = 0.13), the mean change in GLS from baseline to 1 month was significantly higher in the treatment group than in the control group (-2.1 ± 2.5% vs. -0.8 ± 2.3%, P = 0.04). There were no significant differences in the changes in global circumferential strain (GCS), global area strain (GAS), global radial strain (GRS), LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) between the two groups. Peak creatine kinase isoenzyme-MB, peak high-sensitivity troponin T, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 24 h after PCI did not differ significantly between the two groups, but NT-proBNP levels at 1 week were significantly lower in the treatment group than in the control group [357.5 (184.8-762.8) vs. 465.0 (305.8-1525.8) pg/ml, P = 0.04]. Conclusion: Daily repeated RIC started within 24 h after PCI can improve GLS and reduce plasma NT proBNP levels in patients with STEMI.

Safety and immunogenicity of a quadrivalent influenza vaccine in adults aged 60 years or above: a phase III randomized controlled clinical study.

To control seasonal influenza epidemics in elders, a quadrivalent, inactivated, split-virion influenza vaccine (IIV4) comprising A and B lineages is produced for young individuals and adults aged ≥60 years. In this phase III, randomized, double-blind, active-controlled trial, we compared safety and immunogenicity of IIV4 with a licensed quadrivalent inactivated vaccine (IIV4-HL) produced by Hualan Biological Engineering during the 2019 influenza season. Participants were randomly assigned to receive IIV4 (n = 959) or IIV4-HL (n = 959). Compared to IIV4-HL, geometric mean titers (GMT) of hemagglutination inhibition (HAI) titers and seroconversion rate (SCR) of IIV4 demonstrated better antibody responses in A lineages (H1N1 and H3N2) (P < .01) and equivalent antibody responses in B lineages (B/Yamagata and B/Victoria) (P > .01) in both age groups. After immunization, IIV4 provided a satisfactory SCR and seroprotection rate (SPR) in elders. No discernible variation in immunogenicity was observed between the two age cohorts. In both age groups, IIV4 and IIV4-HL recipients experienced similar levels of solicited and unsolicited adverse events (AEs), and the incidence of AEs was low in both vaccine groups. Most AEs were of mild-to-moderate severity and no grade 3 AEs in IIV4 group, but AEs in adults aged 60-65 were little higher than in adults over 65 years in IIV4 and IIV4-HL groups (IIV4: 14.66% vs. 10.36%; IIV4-HL:14.67% vs. 11.43%). Totally, IIV4 was generally well tolerated and induced high antibody titers against all four influenza strains in elderly, making it a compelling alternative for the elderly aged ≥60 years.Trial registration: Clinical Trials.gov: 2015L00649-2.

Pregnancy Outcomes in Females with Stage 1 Hypertension and Elevated Blood Pressure Undergoing In Vitro Fertilization and Embryo Transfer.

Objective: To determine whether stage 1 hypertension and elevated blood pressure (BP), as defined by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, prior to pregnancy contributes to adverse pregnancy outcomes in females who conceived by in vitro fertilization and embryo transfer (IVF-ET). Methods: This retrospective cohort study involved 2239 females who conceived by IVF-ET and delivered live neonates. BPs recorded before IVF-ET were collected. Elevated BP was defined as at least two systolic BPs of 120 to 129 mmHg. Stage 1 hypertension was defined as at least two systolic BPs of 130 to 139 mmHg or diastolic BPs of 80 to 89 mmHg. Results: Among the females included in this study, 18.5% (415/2239) had elevated BP and 10.0% (223/2239) had stage 1 hypertension. Multiple logistic regression analysis showed that females with stage 1 hypertension had higher risks of hypertensive disorders in pregnancy (HDP) [adjusted odds ratio (aOR) 1.65; 95% confidence interval (CI) 1.16-2.35] and preeclampsia (aOR 1.52; 95% CI 1.02-2.26) than normotensive females. However, the risks of HDP (aOR 0.88; 95% CI 0.64-1.21) and preeclampsia (aOR 0.83; 95% CI, 0.57-1.20) in females with elevated BP were not significantly different from those in normotensive females. The females were then categorized into five groups by systolic and diastolic BP; females with systolic BP of 130 to 139 mmHg or diastolic BP of 85 to 89 mmHg had significantly increased risks of HDP and preeclampsia. Conclusion: Stage 1 hypertension before IVF-ET was an independent risk factor for HDP and preeclampsia.

Acid-catalyzed cleavage of C-C bonds enables atropaldehyde acetals as masked C2 electrophiles for organic synthesis.

Acid-catalyzed tandem reactions of atropaldehyde acetals were established for the synthesis of three important molecules, 2,2-disubstituted indolin-3-ones, naphthofurans and stilbenes. The synthesis was realized using novel reaction cascades, which involved the same two initial steps: (i) SN2' substitution, in which the atropaldehyde acted as an electrophile; and (ii) oxidative cleavage of the carbon-carbon bond of the generated phenylacetaldehyde-type products. Compared with literature methods, the present protocol not only avoided the use of expensive noble metal catalysts, but also enabled a simple operation.

Immunogenicity and safety of a recombinant fusion protein vaccine (V-01) against coronavirus disease 2019 in healthy adults: a randomized, double-blind, placebo-controlled, phase II trial.

BACKGROUND: Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study. METHODS: A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18-59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 µg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 µg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization. RESULTS: V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 [95% confidence interval [CI]: 133.3-196.7] and 149.3 [95%CI: 123.9-179.9] in 10 and 25 µg V-01 group of younger adults, respectively; 111.6 [95%CI: 89.6-139.1] and 111.1 [95%CI: 89.2-138.4] in 10 and 25 µg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3-91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 µg V-01 two-dose group, and 50 µg V-01 one-dose group, respectively. CONCLUSIONS: The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 µg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).

Effectiveness of a home-based exercise program among patients with lower limb spasticity post-stroke: A randomized controlled trial.

PURPOSE: To evaluate the effectiveness of advanced practice nurse-guided home-based rehabilitation exercise program (HREPro) among patients with lower limb spasticity post-stroke. METHODS: This randomized controlled study recruited 121 patients with lower limb spasticity post-stroke. Intervention (n = 59) and control (n = 62) groups underwent 12-month HREPro and conventional rehabilitation, respectively, after discharge. The Fugl-Meyer assessment of spasticity measurement, modified Ashworth scale of motor function, 10-Meter Walk Test of walking ability, and Barthel index of activities of daily living (ADL) were evaluated at 0, 3, 6, and 12 months after discharge. RESULTS: Significant differences were found in spasticity degree, motor function, walking ability, and ADL at 6 and 12 months after discharge between the control and intervention groups. Lower limb spasticity and ADL in the intervention group were significantly improved. CONCLUSION: HREPro is effective for rehabilitation of patients with lower limb spasticity post-stroke and has favorable home application.

Evaluation of left ventricular systolic function in patients with different types of ischemic heart disease by two-dimensional speckle tracking imaging.

BACKGROUND: The purpose of this study was to evaluate left ventricular systolic function in patients with different types of ischemic heart disease using two-dimensional speckle tracking imaging (2D-STI). METHODS: We retrospectively studied patients who were admitted to Peking University Third Hospital from January 2011 to December 2017 due to chest tightness and chest pain. Two hundred forty-two patients were divided into control group, CMD group and obstructive CAD group. The main coronary artery stenosis was confirmed by coronary angiography or coronary computed tomography and coronary flow reserve (CFR) in patients was measured by transthoracic Doppler echocardiography. Left ventricular strain and strain rate (SR) measured by 2D-STI. Cardiac structure and function were measured by conventional echocardiography. RESULTS: Conventional echocardiography showed that there was no significant difference in cardiac structure and function among the three groups (P > 0.05). Moreover, the longitudinal strain (LS) of each ventricular wall in CMD group was notably lower than that in control group (P < 0.01). In addition, global longitudinal SR and longitudinal SR in CMD group and obstructive CAD group were obviously lower than those in control group (P < 0.01). GLS, endocardial LS and epicardial LS were negatively correlated with CFR (P < 0.01). CONCLUSIONS: Early left ventricular systolic dysfunction was found in patients with CMD and patients with obstructive CAD, with similar degree. CFR is an independent influencing factor of GLS. GLS and stratified LS have certain diagnostic value for CMD.

Higher serum angiopoietin 2 levels are independently associated with coronary microvascular dysfunction in patients with angina in the absence of obstructive coronary artery disease.

BACKGROUND: Angiopoietin-2 (Ang-2) is a type of endothelial growth factor involved in angiogenesis and vascular remodeling. Circulating Ang-2 levels are elevated in patients with obstructive coronary artery disease (CAD). This study aimed to evaluate the association between serum Ang-2 levels and coronary microvascular dysfunction in patients without obstructive CAD. METHODS: A total of 125 patients with angina in the absence of obstructive CAD were included in this cross-sectional study. Coronary flow reserve (CFR) was measured in the distal left anterior descending coronary artery by trans-thoracic Doppler echocardiography. The patients were divided into the following two sub-groups according to CFR: the impaired CFR group with CFR values <2.5 and the preserved CFR group with CFR values ≥2.5. Serum Ang-2 levels were determined using enzyme-linked immunosorbent assay. Independent predictors for impaired CFR were identified by binary logistic regression analysis. The receiver-operating characteristic curve was determined to evaluate the ability of serum Ang-2 in predicting impaired CFR. RESULTS: We found that age, percentage of female sex, N-terminal pro-B-type natriuretic peptide levels, Ang-2 levels (763.3 ±â€Š264.9 vs. 579.7 ±â€Š169.3 pg/mL, P < 0.001), and the left atrial volume index were significantly higher in patients with impaired CFR than in patients with preserved CFR. Serum Ang-2 levels were negatively correlated with CFR (r = -0.386, P < 0.001). Binary logistic regression analysis showed that Ang-2 (odds ratio: 1.004, 95% confidence interval [CI]: 1.001-1.006, P = 0.003) and age (odds ratio: 1.088, 95% CI: 1.023-1.156, P = 0.007) were independently associated with impaired CFR. Furthermore, Ang-2 was a significant predictor of impaired CFR on the receiver-operating characteristic curve (P < 0.001). The area under the curve was 0.712 (95% CI: 0.612-0.813). CONCLUSIONS: High serum Ang-2 levels are independently associated with impaired CFR in patients with angina in the absence of obstructive CAD.

Identification and functional analysis of long non-coding RNAs in the synovial membrane of osteoarthritis patients.

Osteoarthritis (OA), the most common chronic joint disease in the elderly, has become a significant economic burden for families and societies worldwide. Although treatments are continually improving, current drugs only target joint pain, with no effective therapies modifying OA progression. Long noncoding RNAs (lncRNAs), which have received increasing attention in recent years, are abnormally expressed in OA cartilage. In the present study, weighted coexpression network analysis (WGCNA) was applied to identify modules related to certain OA clinical traits. In total, 4404 coding genes and 161 lncRNAs were differentially expressed based on two OA expression profile data sets and normal control samples. Subsequently, 11 independent modules were acquired, and the green module, with a total of 49 hub genes, was identified as the most relevant to OA. These hub genes were validated using the GSE12021 data set. There was only one lncRNA among the hub genes, namely, NONHSAG034351. Thus, we further explored the function of NONHSAG034351-related genes in the network. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that NONHSAG034351-associated genes are involved in the response to lipopolysaccharide, angiogenesis, tumour necrosis factor (TNF) signalling, and mitogen-activated protein kinase (MAPK) signalling pathways. In conclusion, we identified modules through WGCNA related to OA clinical traits. NONHSAG034351, the only hub-lncRNA, was downregulated in OA synovial tissue and might play a significant role in the pathological progression of this disease. Our findings have important clinical implications and could provide novel biomarkers that indicate the molecular mechanisms of OA and act as potential therapeutic targets. SIGNIFICANCE OF THIS STUDY: Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in osteoarthritis (OA), which is the most common chronic joint disease among the elderly. In the present study, we report the expression profiles of lncRNAs in OA and the identification of modules through WGCNA related to OA clinical traits. NONHSAG034351, the only hub-lncRNA identified to be downregulated in the synovial tissue of OA patients, might play a significant role in the pathological progression of OA. Furthermore, our findings provide novel biomarkers associated with the molecular mechanisms underlying OA pathogenesis, thus implying potential therapeutic targets with important clinical implications.

4-Aminoindoles as 1,4-bisnucleophiles for diversity-oriented synthesis of tricyclic indoles bearing 3,4-fused seven-membered rings.

A straightforward access to tricyclic indoles bearing 3,4-fused seven-membered rings has been established by using 4-aminoindoles as 1,4-bisnucleophiles in three-component reactions. 1H-Azepino[4,3,2-cd]indoles, 4,6-dihydro-1H-azepino[4,3,2-cd]indoles and 1,3,4,6-tetrahydro-5H-azepino[4,3,2-cd]indol-5-ones could thus be synthesized in one pot in moderate to good yields. Beyond opening access to 3,4-fused tricyclic indoles, the use of easily accessible 4-aminoindoles as C,N-1,4-bisnucleophiles also provides a new platform to be used in a diversity-oriented synthesis strategy, fully displaying its benefits of maximizing molecular complexity and reaction diversity.

Mechanical behavior of ctenoid scales: Joint-like structures control the deformability of the scales in the flatfish Solea solea (Pleuronectiformes).

Ctenoid scales protect the fish body against predators and other environmental impacts. At the same time, they allow for sufficient degree of flexibility to perform species-specific locomotion. The scales of the flatfish Solea solea were chosen to study the specific mechanical behavior and material properties of the ctenoid scales. Using scanning electron microscopy and micro-computed tomography, three-dimensional asymmetric structures of the stacked mineralized ctenial spines in the posterior field, which is a part of the scales exposed to the environment, were examined in detail. Nanoindentations on the surface of the ctenial spines indicated that the elastic modulus and hardness of these mineralized structures are about 14 GPa and 0.4 GPa, respectively. The spines appeared to be connected to each other by means of joint-like structures containing soft tissues. Bending tests showed that the ctenoid scales have two functional zones: a stiff supporting main body and an anisotropically deformable posterior field. While the stiff plate-like main body provides support for the whole scale, the deformable joint-like structures in the ctenial spines increase the deformability of the posterior field in downward bending. During upward bending, however, the spines prevent complete folding of the posterior field by an interlocking effect. STATEMENT OF SIGNIFICANCE: In contrast to the continuously mineralized cycloid scales, ctenoid scales combine two conflicting properties: They are hard to protect the body of fish against predators and other environmental impacts, yet flexible enough to allow for sufficient degree of body bendability for locomotion. To understand the structural background underlying this specific biomechanical feature, here we investigated the scales of the flatfish Solea solea. For the first time, we demonstrated the presence of joint-like structures within the scales, which increase scale deformability during downward bending, but prevent scale deformation during upward bending by interlocking. Our results shed lights on the material-structure-function relationships in ctenoid scales, as well as on their functional adaptations to the specific environment.

Knockdown of lncRNA NEAT1 inhibits Th17/CD4+ T cell differentiation through reducing the STAT3 protein level.

CD4+ T cells differentiated into Th17 cells are a main cause for occurrence and development of rheumatoid arthritis (RA). This study aims to define the role of long noncoding RNA nuclear-enriched abundant transcript 1 (lncRNA NEAT1) and its downstream molecule in Th17 cell differentiation. Determination of lncRNA NEAT1 expression in the peripheral blood mononuclear cells (PBMCs) of patients with RA and in Th17 cells induced differentiation in vitro used quantitative real-time polymerase chain reaction. Lentivirus-constructed short hairpin RNA interference for NEAT1 (Lenti-siRNA-NEAT1) was pretransfected into CD4+ T cells before inducing treatment of Th17 cell differentiation. NEAT1 targets STAT3 protein was proved by RNA pull down. Lenti-siRNA-NEAT1 was injected into the joint of the mice arthritis model to verify the function of NEAT1 knockdown. Our results showed that NEAT1 is significantly upregulated in the PBMCs of RA patients, as well as in Th17 cells in vitro induced from CD4+ T cells. The knockdown of NEAT1 restrains CD4+ T cells differentiate into Th17 cells. STAT3 protein, a critical molecule for Th17 cell differentiation, is a downstream molecule for NEAT and its cellular level can be positively targeted and regulated by NEAT via reducing the ubiquitination level. Moreover, the cotreatment of NEAT1 knockdown and STAT3 overexpression promotes Th17 cell differentiation compared with NEAT1 knockdown alone. Knockdown of Th17 by in vivo injection of lenti-siRNA-NEAT1 relieves arthritis degree in II type collagen induced mice arthritis model. These data concluded that NEAT1 is auxo-active molecule for CD4+ T cells differentiating into Th17 cells and knockdown of NEAT1 positively inhibits Th17/CD4+ T cell differentiation through reducing the STAT3 protein level.