Immune checkpoint inhibitors as the second-line treatment for advanced esophageal squamous cell carcinoma: a cost-effectiveness analysis based on network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system. METHODS: A network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Five clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%. CONCLUSIONS AND RELEVANCE: Among the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen as the second-line treatment for locally advanced or metastatic ESCC in China.

Optimized optical system with a 1.65 m wide-field corrector for the 6.5 m high-performance MUltiplexed Survey Telescope.

The development of modern large-scale spectroscopic survey telescopes responds to the urgent demand for spectral information in astronomical research. Tsinghua University has previously proposed a 6.5 m MUltiplexed Survey Telescope consisting of a Ritchey-Chretien configuration and a 1.8 m multi-element wide-field corrector, achieving excellent performance and world-leading survey efficiency. However, an optimized 1.65 m multi-element corrector with five lenses is proposed to overcome the constraints on glass uniformity and verification in fabrication of the previous corrector design. It maintains outstanding image quality, with the 80% enclosed energy diameter not more than 0.559 arcsec within 3° FoV over up to a 55° zenith angle. The optimized optical system does not revise the working mode of the ADC or the curvature of the primary mirror while ensuring the reasonability and accuracy of manufacturing of large corrector elements. It provides a more feasible reference optical design for the MUltiplexed Survey Telescope in subsequent iterations and communications with manufacturers.

Untargeted metabolomic analysis of metabolites related to body dysmorphic disorder (BDD).

Body dysmorphic disorder (BDD) is a disorder associated with depression and eating disorders. It often arises from minor defects in appearance or an individual imagining that he or she is defective. However, the mechanisms causing BDD remain unclear, and its pathogenesis and adjuvant treatment methods still need to be explored. Here, we employed a liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach to identify key metabolic differences in BDD versus healthy patients. We obtained plasma samples from two independent cohorts (including eight BDD patients and eight healthy control patients). Raw data were analyzed using Compound Discoverer to determine peak alignment, retention time correction, and extraction of peak areas. Metabolite structure identification was also obtained using Compound Discoverer by of accurate mass matching (< 10 ppm) and secondary spectral matching queries of compound databases. Next, multidimensional statistical analyses were performed using the ropls R package. These analyses included: unsupervised principal component analysis, supervised partial Least-Squares Discriminant Analysis, and orthogonal partial Least-Squares Discriminant Analysis. We then identified the most promising metabolic signatures associated with BDD across all metabolomic datasets. Principal component analysis showed changes in small-molecule metabolites in patients, and we also found significant differences in metabolite abundance between the BDD and normal groups. Our findings suggest that the occurrence of BDD may be related to metabolites participating in the following KEGG pathways: ABC transporters, purine metabolism, glycine, serine and threonine metabolism, pyrimidine, pyrimidine metabolism, biosynthesis of 12-, 14-, and 16-membered macrolides, microbial metabolism in diverse environments, biosynthesis of secondary metabolites, and caffeine and insect hormone biosynthesis.

Hybrid ball-hinged secondary mirror assembly for high-precision surface shape maintenance.

As an essential part of optical telescope, the secondary mirror is subject to the influence of ambient temperature, which leads to temperature-induced distortion on the surface shape. A hybrid ball-hinged secondary mirror assembly (HSMA) is proposed to achieve thermal adaptation over a wide range of temperature. Simulation investigation on the temperature-induced surface shape distortion of the HSMA were carried out by using the finite element model. Simulation results show that the change of secondary mirror surface distortions over a wide range of temperature are minimal and negligible. For the wide ambient temperature range from -30°C to 70°C, the PV and RMS values of the maximum residual distortions can reach as small as 16.31 nm and 3.005 nm, respectively. Furthermore, the influence of gravity-induced distortion on the surface shape is also carried out. Both simulation and experiment results show that the HSMA is able to maintain high-precision surface shape of the secondary mirror over a wide range of temperature and at different attitudes from 0 to 90 ∘.

2023 HRS/EHRA/APHRS/LAHRS Expert Consensus Statement on Practical Management of the Remote Device Clinic.

Remote monitoring is beneficial for the management of patients with cardiovascular implantable electronic devices by impacting morbidity and mortality. With increasing numbers of patients using remote monitoring, keeping up with higher volume of remote monitoring transmissions creates challenges for device clinic staff. This international multidisciplinary document is intended to guide cardiac electrophysiologists, allied professionals, and hospital administrators in managing remote monitoring clinics. This includes guidance for remote monitoring clinic staffing, appropriate clinic workflows, patient education, and alert management. This expert consensus statement also addresses other topics such as communication of transmission results, use of third-party resources, manufacturer responsibilities, and programming concerns. The goal is to provide evidence-based recommendations impacting all aspects of remote monitoring services. Gaps in current knowledge and guidance for future research directions are also identified.

Experimental Study of Skin Contraction Induced by Bipolar Radiofrequency.

Background: Facial skin relaxation has become an important part in solving the problem of facial rejuvenation. Minimally invasive or noninvasive skin-tightening procedures have become a trend for facial rejuvenation. Bipolar radiofrequency (RF) is a new option for treating skin relaxation and is more effective than noninvasive surgery without surgical incision. Objective: To explore the effect of different bipolar RF powers on the area of the original box, changes of skin and subcutaneous tissue thickness and numbers of fibroblasts in rabbits. Design: The research team performed an animal study. Setting: This study took place in Affiliated Hospital of Nanjing University of Chinese Medicine. Participants: Eighteen common-grade adult New Zealand rabbits (female, 2.5-3.0 kg). Methods: Bipolar radiofrequency therapy was given to a girl rabbit on the left side of the treatment area. Standard HE and Masson staining were performed to assess the pathological changes, area of the original box and the number of fibroblasts in skin and subcutaneous tissues. Outcome Measures: (1) The area of the original box, changes of skin and subcutaneous tissue thickness, and numbers of fibroblasts under different bipolar RF temperatures or under different bipolar RF powers immediately after surgery, 1 month after surgery and 3 months after surgery were observed. (2) Standard HE and Masson staining results. Results: Under the condition of certain instrument power, at 36de 38d and 40nd the area of the original box shrank to different degrees immediately after surgery (16.54±0.37, 17.78±0.03, 17.19±0.01), 1 month after surgery (16.59±0.31, 17.82±0.01, 18.34±0.30) and 3 months after surgery (16.89±0.12, 18.16±0.14, 19.23±0.32) compared with that before surgery (P < .05). Under specific temperature conditions, at 16 W, 18 W, 20 W, and 22 W, the area of the original box shrank to different degrees immediately after surgery (16.40±0.49, 15.55±0.57, 17.54±0.12, 16.19±0.27), 1 month after surgery (16.88±0.12, 17.46±0.02, 18.05±0.35, 19.41±0.08) and 3 months after surgery (19.09±1.01, 18.30±0.69, 20.00±0.29, 21.20±0.90) compared with that before surgery (P < .05). When the power was fixed, the thickness of skin and subcutaneous tissue decreased immediately after surgery (6.7, 6.8, 7), 1 month after surgery (6, 6.1, 6.3) and 3 months after surgery (6.4, 6.5, 6.2) at different temperatures (P < .05). When the temperature was fixed, the thickness of skin and subcutaneous tissue decreased immediately after surgery (6.1, 6.08, 6.03), 1 month after surgery (6.2, 6.15, 6.13), and 3 months after surgery (6.2, 6.23, 6.03) under different powers (P < .05). Under the condition of certain instrument power, at 36de 38d and 40n, the number of fibroblasts increased to different degrees immediately after surgery (26.54±2.37, 30.78±3.03, 37.19±4.01), 1 month after surgery (28.59±2.31, 34.82±3.01, 40.34±4.30), and 3 months after surgery (30.89±0.12, 38.16±0.14, 42.23±0.32) compared with that before surgery, and all were statistically significant (P < .05). Under specific temperature conditions, at 16 W, 18 W, 20 W, and 22 W, the number of fibroblasts increased to different degrees immediately after surgery (28.29±2.49, 30.97±3.57, 38.74±3.12, 45.68±4.27), 1 month after surgery (30.88±3.12, 32.46±4.02, 41.05±0.35, 50.41±0.08), and 3 months after surgery (29.99±2.01, 33.30±2.69, 39.00±3.29, 23.20±2.90) compared with that before surgery, and all were statistically significant (P < .05). Conclusions: Our study clarifies that bipolar RF can decrease the skin and subcutaneous tissue thickness and increase the numbers of fibroblasts at the temperature of 36°C, 38°C, and 40°C and frequency of 16-22 W, which has a therapeutical effect on skin contraction. Our study might effectively improve the skin slack of patients, and the postoperative maintenance rate is high, and will not cause obvious complications. This study may provide a theoretical direction for clinicians to tighten the skin of patients using bipolar RF.

Identification of sex pheromone of red swamp crayfish Procambarus clarkii and exploration of the chemosensory mechanism of their antennae.

Red swamp crayfish, Procambarus clarkii, is a globally invasive species, which has caused great damage to biodiversity, agriculture, and fishing. Therefore, the development of effective management methods, such as pheromone control, is necessary for biological control and biodiversity protection. However, the components of P. clarkii sex pheromones have not yet been explored, and the chemosensory mechanism of the P. clarkii antennae after stimulation by sex pheromone also remains unknown. In this study, we isolated and identified the candidate bioactive component of the female P. clarkii sex pheromone using ultrafiltration centrifugation, semi-preparative liquid phase separation and omics technologies and conducted bioassays to determine its attraction ability. Meanwhile, RNA-Seq technology was used to analyze the potential chemosensory mechanism of antennae. Our results indicated that the male P. clarkii were uniaxially attracted to the female crude conditioned water (FCW), medium fraction (MF, isolated by ultrafiltration centrifugation), and preparative fragment 6 of females (PFF6, isolated by semi-preparative liquid phase separation). Metabolomic analysis revealed the presence of 18 differential metabolites between the PFF6 and PFM6 samples, among which 15 were significantly upregulated in the PFF6 sample. Bioassay test also showed that mestranol, especially at concentrations of 10-5-10-2 mol∙l-1, could significantly attract P. clarkii males; therefore, mestranol was identified as the candidate sex pheromone component of P. clarkii females. Furthermore, RNA-Seq results showed that most differentially expressed genes (DEGs) enriched in lipid metabolism and signal transduction pathways were up-regulated in P. clarkii males. In addition, high expressions of Ca2+-binding protein and ion transporting ATPases may enhance the sensitivity of the antennae of P. clarkii males towards sex pheromones. Our study provides data on P. clarkii sex pheromone composition and reveals the molecular mechanism of sex pheromone response in P. clarkii. Moreover, our study provides a referable method for the isolation of candidate bioactive molecules from the P. clarkii sex pheromone.

2023 Consensus of Taiwan Society of Cardiology on the Pharmacological Treatment of Chronic Heart Failure.

The prevalence of heart failure is increasing, causing a tremendous burden on health care systems around the world. Although mortality rate of heart failure has been significantly reduced by several effective agents in the past 3 decades, yet it remains high in observational studies. More recently, several new classes of drugs emerged with significant efficacy in reducing mortality and hospitalization in chronic heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). To integrate these effective therapies and prioritize them in the management of Asian patients, Taiwan Society of Cardiology has recently appointed a working group to formulate a consensus of pharmacological treatment in patients with chronic heart failure. Based on most updated information, this consensus provides rationales for prioritization, rapid sequencing, and in-hospital initiation of both foundational and additional therapies for patients with chronic heart failure.

PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy.

BACKGROUND & AIMS: Although the treatment of hepatocellular carcinoma (HCC) has been revolutionized by the advent of effective systemic therapies, the prognosis of patients with HCC remains dismal. Herein, we examined the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy. METHODS: The oncogenic function of PARG was evaluated in 2 orthotopic xenograft models and a Pargflox/flox mice model. The therapeutic efficacy of PARG inhibitors in combination with an anti-PD-1 antibody were assessed in murine orthotopic models. Microarray analysis was used to evaluate the pathological relevance of the PARG/DDB1/c-Myc/MMR axis. RESULTS: High PARG expression was strongly associated with poor HCC prognosis. Hepatocyte-specific PARG deletion significantly impaired liver tumorigenesis. PARG promoted HCC growth and metastasis through DDB1-dependent modulation of c-Myc. Specifically, PARG dePARylated DDB1 and consequently promoted DDB1 autoubiquitination, thus stabilizing the c-Myc protein in HCC cells. PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was correlated with a favorable prognosis in patients with HCC treated with anti-PD-1-based immunotherapy. In addition, PARG inhibitors could act in synergy with anti-PD-1 antibodies in orthotopic mouse models. CONCLUSIONS: PARG can act as an oncogene in HCC by modulating PARG/DDB1/c-Myc signaling and could be used as a biomarker to identify patients with HCC who may benefit from anti-PD-1 treatment. Our findings suggest that co-inhibition of PARG and PD-1 is an effective novel combination strategy for patients with HCC. LAY SUMMARY: The increase in deaths due to hepatocellular carcinoma (HCC) is a growing concern, with the mechanisms responsible for HCC development still incompletely understood. Herein, we identify a novel mechanism by which the protein PARG contributes to HCC development. Inhibition of PARG increased the efficacy of anti-PD-1 therapy (a type of immunotherapy) in HCC. These findings support the future clinical development of PARG inhibitors, potentially in combination with anti-PD-1 inhibitors.

Clinical impacts of scar reduction on gated myocardial perfusion SPECT after cardiac resynchronization therapy.

BACKGROUND: It had not been reported that myocardial scar shown on gated myocardial perfusion SPECT (GMPS) might reduce after cardiac resynchronization therapy (CRT). In this study, we aim to investigate the clinical impact and characteristic of scar reduction (SR) after CRT. METHODS AND RESULTS: Sixty-one heart failure patients following standard indication for CRT received twice GMPS as pre- and post-CRT evaluations. The patients with an absolute reduction of scar ≥ 10% after CRT were classified as the SR group while the rest were classified as the non-SR group. The SR group (N = 22, 36%) showed more improvement on LV function (∆LVEF: 18.1 ± 12.4 vs 9.4 ± 9.9 %, P = 0.007, ∆ESV: - 91.6 ± 52.6 vs - 38.1 ± 46.5 mL, P < 0.001) and dyssynchrony (ΔPSD: - 26.19 ± 18.42 vs - 5.8 ± 23.0°, P < 0.001, Δ BW: - 128.7 ± 82.8 vs - 25.2 ± 109.0°, P < 0.001) than non-SR group (N = 39, 64%). Multivariate logistic regression analysis showed baseline QRSd (95% CI 1.019-1.100, P = 0.006) and pre-CRT Reduced Wall Thickening (RWT) (95% CI 1.016-1.173, P = 0.028) were independent predictors for the development of SR. CONCLUSION: More than one third of patients showed SR after CRT who had more post-CRT improvement on LV function and dyssynchrony than those without SR. Wider QRSd and higher RWT before CRT were related to the development of SR after CRT.

Fasudil on Myocardial Injury in Rats with Myocardial Ischemia and Reperfusion through Rho-ROCK Signal Pathway.

Cardiovascular diseases are very harmful to human life and health. Reperfusion therapy is a standard method to treat cardiovascular diseases and has achieved high clinical effects. However, this treatment method is likely to cause myocardial ischemia-reperfusion injury. It has been reported that the Rho kinase inhibitor fasudil can interfere with cardiomyocyte apoptosis through the Rho-ROCK signaling pathway, so it is often used to treat cardiovascular diseases. The essay aims to research this specific influence of fasudil on cardiac damage in myocardial ischemia-reperfusion mouses through the Rho-ROCK signal path and its related mechanisms. Forty rats were taken as the research object, and the mouses were separated into control clusters. In the observation cluster of fasudil, the rat heart device was perfused by surgery. The rat coronary artery was ligated for 20 minutes to make the rat myocardial ischemia. Then, the ligation was loosened for myocardial perfusion to create a rat myocardial ischemia-reperfusion model. Observation group rats were perfused with quantitative fasudil, 80 minutes after ischemia-reperfusion, the ultrastructural changes and myocardial ischemic area of the rat myocardium were observed under a microscope, and the dynamic changes of the mouse heart were examined by flow cytometry. The PCR fluorescence method was used to explore the outlook layer of Rho-ROCK kinase activity to detect rat cardiomyocyte apoptosis. It is shown that under this intervention of fasudil, this expression level of Rho-ROCK kinase activity in the observation group was reduced by 18.3%, the myocardial cell apoptosis rate was decreased by 26.4%, and one area of myocardial ischemia can be reduced by 32.5%. The ultrastructure of the new object in rats is improved, and the left ventricular diastolic and systolic effect is enhanced. Therefore, the fasudil may decrease cardiac ischemia and focus on injured Rho-ROCK signal path activity.

Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression.

Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9-/-) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil-/-) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.

Epigenetic silencing of E-cadherin gene induced by lncRNA MALAT-1 in acute myeloid leukaemia.

BACKGROUND: Epigenetic abnormalities in acute myeloid leukaemia provide us with a target for novel therapeutic strategies. The aim of the study was to verify the epigenetic regulatory mechanism of E-cadherin gene silencing induced by long non-coding RNA MALAT-1 in AML. METHODS: Expression of MALAT-1, E-cadherin, EZH2, SUZ12 and EED genes in AML patients was detected by RT-qPCR. After MALAT-1 silencing in AML cell lines, levels of the E-cadherin, EZH2, SUZ12, EED, DNMT1, DNMT3A and DNMT3B genes and encoded proteins were detected by RT-qPCR and Western blotting. The level of CpG island methylation and trimethylation modification of histone H3K27 in the promoter region of E-cadherin was detected by pyrosequencing and ChIP-qPCR. RIP-qPCR was used to detect the interaction between MALAT-1 and proteins. RESULTS: MALAT-1, EZH2 and EED gene expression was markedly increased in AML patients with E-cadherin down-regulation. A positive correlation between EZH2 or SUZ12 and MALAT-1 expression was observed. After MALAT-1 silencing, the expression of E-cadherin was up-regulated, whereas the expression of EZH2, SUZ12, DNMT1, DNMT3A and DNMT3B was down-regulated. Results of Western blotting were consistent with those of RT-qPCR. Methylation levels of E-cadherin in AML patients were higher than that in normal controls, which appeared to increase with age. Methylation of the CpG island and H3K27 trimethylation of E-cadherin were decreased after MALAT-1 silencing. RIP-qPCR suggested that MALAT-1 might be enriched by EZH2 and SUZ12. CONCLUSION: Our findings verified that MALAT-1 might lead to the transcriptional silencing of E-cadherin gene through the trimethylation of H3K27 mediated by recruiting EZH2 and SUZ12.

Reliability and Validity of the Self-Report Chinese Version of the Yale-Brown Obsessive-Compulsive Scale Modified for Body Dysmorphic Disorder (BDD-YBOCS) in Patients Undergoing Plastic Surgery.

BACKGROUND: To develop a self-report Chinese version of the Yale-Brown Obsessive-Compulsive Scale Modified for Body Dysmorphic Disorder (BDD-YBOCS) and determine its validity and reliability in patients seeking a consultation with a plastic surgeon or undergoing plastic surgery in China. METHODS: Forward and backward translation and cultural adaptation of the BDD-YBOCS were performed according to recommended guidelines. The self-report Chinese version of the BDD-YBOCS was psychometrically tested using data collected from a cross-sectional validation study, which included 240 patients seeking a consultation with a plastic surgeon or undergoing plastic surgery at the Department of Plastic Surgery, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China, between May and September 2020. Item analysis used the independent sample t test and bivariate Pearson test. Content validity was established through expert interviews. Construct validity was measured with exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Convergent validity and discriminant validity were analyzed using Pearson's correlation to evaluate the association between the self-report Chinese version of the BDD-YBOCS and the Body Dysmorphic Disorder Questionnaire (BDDQ). Internal reliability was assessed using Cronbach's α. RESULTS: No items were removed from the original English version of the BDD-YBOCS based on expert interviews and factor analysis. A total of 220 patients completed the study survey (91.7%). EFA extracted 3 factors, which accounted for 64.50% of the variance. CFA supported a 3-factor structure (χ2/df = 1.322, RMSEA = 0.054, GFI = 0.904, NFI = 0.902, CFI = 0.974 and TLI = 0.966). The scale had good convergent and discriminant validity. Cronbach's α for the scale was 0.871 (P < 0.001) and ranged from 0.852 to 0.873 when individual items were removed. CONCLUSION: The self-report Chinese version of the BDD-YBOCS shows good validity and reliability for use in patients seeking a consultation with a plastic surgeon or undergoing plastic surgery in China. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[The destructive role of soluble Robo4 secreted by the M1-polarized-microglia during cerebral ischemia-reperfusion in blood-brain barrier integrity].

This project was aimed to investigate the role and the underlying mechanism of microglia polarization on blood-brain barrier (BBB) during cerebral ischemia-reperfusion. After construction of the mouse model of cerebral ischemia-reperfusion, upregulated IL-6 and TNF-α in peripheral blood and increased IL-6 and iNOS in ischemia tissues were confirmed. The supernatant expression of TNF-α and IL-6, as well as IL-6, iNOS and CD86 mRNA, was significantly increased in the of Bv-2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) model was constructed in vitro. For further understanding the expression pattern of RNAs, the next-generation RNA sequencing was performed and upregulation of Robo4 (roundabout guidance receptor 4) was found both in M1-polarized and OGD/R treated Bv-2 cells, which was also confirmed by RT-qPCR. Extracellular soluble Robo4 (sRobo4) protein also increased in the supernatant of M1-polarized and OGD/R treated Bv-2 cells. Treating bEND3 cells with the Robo4 recombinant protein, M1-polarized Bv-2 cell supernatant or OGD/R Bv-2 cell supernatant decreased trans-endothelial electrical resistance (TEER), suggesting the injury of BBB. In addition, Robo4 was also highly expressed in the serum of patients who experienced acute ischemia stroke and mechanical thrombectomy operation. All the results suggest that increased secretion of Robo4 by M1-polarized-microglia during cerebral ischemia-reperfusion is most likely one of the causes of BBB injury, and Robo4 may be one of the therapeutic targets for BBB functional protection.

Effects of Ivabradine on Patients with Depressed Left Ventricular Function after Cardiac Resynchronization Therapy.

Background: The potential synergistic effect of ivabradine and cardiac resynchronization therapy (CRT) in heart failure (HF) patients has rarely been studied. We aimed to evaluate the clinical benefits of ivabradine in patients with left ventricular dysfunction following CRT implantation. Methods: Two hundred and thirty-one patients receiving CRT were consecutively enrolled between January 2014 and December 2018 from two HF centers. A total of 123 patients had left ventricular ejection fraction (LVEF) < 40% and resting sinus heart rate (HR) ≥ 75 bpm after six months of CRT implantation. Among these patients, 45 were treated with ivabradine (Group 1), and 78 did not receive ivabradine treatment (Group 2). Results: Baseline characteristics and prescription rates of HF medications other than ivabradine were similar between the two groups. In Group 1, the mean HR decreased from 82.2 ± 11.4 bpm to 76.3 ± 10.5 bpm (p = 0.012), and the mean LVEF increased from 29.9 ± 6.5% to 38.8 ± 12.4% (p < 0.001). Atrial pacing percentage, biventricular pacing percentage, and burden of atrial fibrillation (AF) were not significantly different between the two groups during the study period. The patients' daily physical activity increased significantly in Group 1 compared to Group 2 (Δ daily activity 0.4 ± 0.7 hours/day vs. -0.1 ± 7.2 hours/day, p < 0.001). Conclusions: Ivabradine could effectively reduce HR and improve physical activity. It was safe to use and did not increase AF burden or affect biventricular pacing percentage in CRT recipients.

Intranasal delivery of plasmids expressing bovine herpesvirus 1 gB/gC/gD proteins by polyethyleneimine magnetic beads activates long-term immune responses in mice.

BACKGROUND: DNA vaccine is one of the research hotspots in veterinary vaccine development. Several advantages, such as cost-effectiveness, ease of design and production, good biocompatibility of plasmid DNA, attractive biosafety, and DNA stability, are found in DNA vaccines. METHODS: In this study, the plasmids expressing bovine herpesvirus 1 (BoHV-1) gB, gC, and gD proteins were mixed at the same mass ratio and adsorbed polyethyleneimine (PEI) magnetic beads with a diameter of 50 nm. Further, the plasmid and PEI magnetic bead polymers were packaged into double carboxyl polyethylene glycol (PEG) 600 to use as a DNA vaccine. The prepared DNA vaccine was employed to vaccinate mice via the intranasal route. The immune responses were evaluated in mice after vaccination. RESULTS: The expression of viral proteins could be largely detected in the lung and rarely in the spleen of mice subjected to a vaccination. The examination of biochemical indicators, anal temperature, and histology indicated that the DNA vaccine was safe in vivo. However, short-time toxicity was observed. The total antibody detected with ELISA in vaccinated mice showed a higher level than PBS, DNA, PEI + DNA, and PBS groups. The antibody level was significantly elevated at the 15th week and started to decrease since the 17th week. The neutralizing antibody titer was significantly higher in DNA vaccine than naked DNA vaccinated animals. The total IgA level was much greater in the DNA vaccine group compared to other component vaccinated groups. The examination of cellular cytokines and the percentage of CD4/CD8 indicated that the prepared DNA vaccine induced a strong cellular immunity. CONCLUSION: The mixed application of plasmids expressing BoHV-1 gB/gC/gD proteins by nano-carrier through intranasal route could effectively activate long-term humoral, cellular, and mucosal immune responses at high levels in mice. These data indicate PEI magnetic beads combining with PEG600 are an efficient vector for plasmid DNA to deliver intranasally as a DNA vaccine candidate.

Drought losses in China might double between the 1.5 °C and 2.0 °C warming.

We project drought losses in China under global temperature increase of 1.5 °C and 2.0 °C, based on the Standardized Precipitation Evapotranspiration Index (SPEI) and the Palmer Drought Severity Index (PDSI), a cluster analysis method, and "intensity-loss rate" function. In contrast to earlier studies, to project the drought losses, we predict the regional gross domestic product under shared socioeconomic pathways instead of using a static socioeconomic scenario. We identify increasing precipitation and evapotranspiration pattern for the 1.5 °C and 2.0 °C global warming above the preindustrial at 2020-2039 and 2040-2059, respectively. With increasing drought intensity and areal coverage across China, drought losses will soar. The estimated loss in a sustainable development pathway at the 1.5 °C warming level increases 10-fold in comparison with the reference period 1986-2005 and nearly threefold relative to the interval 2006-2015. However, limiting the temperature increase to 1.5 °C can reduce the annual drought losses in China by several tens of billions of US dollars, compared with the 2.0 °C warming.

Application of Autologous Cartilage Transplantation in the Reconstruction of Congenital Nasal Soft Triangle Deformities in Asians.

BACKGROUND: Nasal soft triangle is one of the areas usually left unattended in most rhinoplasties, whereas its unique anatomy puts it at great risk of deformities. Its appearance is critical to the natural contour of the nasal tip lobule. The purpose of this study was to evaluate the outcome of autologous cartilage transplantation in treating congenital nasal soft triangle deformities in Asians. METHODS: From January 2016 to January 2018, 32 patients underwent the procedure, in which costal cartilage, septal cartilage, or conchal cartilage was taken. All cases were operated upon using the external rhinoplasty approach. The cartilage was carved into battens as the lateral and intermediate crura grafts to reconstruct the dome of alar cartilage and treat the soft triangle deformities. The costal cartilage or septal cartilage was used as a columella strut. At the same time, a prosthesis or costal cartilage scaffold was placed onto the nasal dorsum, and finally the fascia was placed on the tip of the nose to relieve tension. The changes of the angle between the intermediate and lateral crura of the alar cartilage before and after cartilage graft and the difference between the greatest distance from the long axis of the nostrils to the alar rim before and after surgery were statistically analyzed. In addition, we compared the preoperative and postoperative nasal contour and evaluated the outcome of soft tissue triangle deformities and asymmetry correction and the whole procedure. RESULTS: The angle between the lateral and medial crura of the 32 patients decreased from 51.5 ± 10.9 degrees preoperatively to 37.2 ± 5.9 degrees at completion of the nasal dome reconstruction (P < 0.05). The maximum distance from the long axis of the nostrils to the alar rim was 3.3 ± 0.6 mm preoperatively and 1.9 ± 0.7 mm postoperatively (P < 0.05). The patients were followed up for 6 to 18 months, and the noses were with natural contour and tactile impression and without any serious complications. The degree of satisfaction was 87.5%. CONCLUSIONS: The application of autologous cartilage is an ideal choice to treat soft triangle deformities, which can result in significant improvement of the nasal contour and high degree of satisfaction postoperatively.

The Characteristics and Outcomes of Patients with Heart Failure and Reduced Ejection Fraction: The Eligibility of Novel Heart Failure Medications.

BACKGROUND: Renin-angiotensin system inhibitors and beta-blockers are the initial treatment of choice for heart failure with reduced ejection fraction (HFrEF), whereas sacubitril/valsartan (SAC/VAL) and ivabradine are considered to second-line therapies. The eligibility of SAC/VAL and ivabradine according to the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) labels, Taiwan National Health Insurance (TNHI) reimbursement regulations, and European Society of Cardiology (ESC) heart failure (HF) guidelines are diverse, and they may not fulfill the needs of real-world HFrEF patients. METHODS: Patients hospitalized for HF with left ventricular ejection fraction (LVEF) ≤ 40% were recruited from 21 hospitals in Taiwan between 2013 and 2014. The criteria for SAC/VAL and ivabradine according to the different regulations were applied. RESULTS: Of 1,474 patients, 86.8%, 29.4%, and 9.5% met the EMA/FDA label criteria, TNHI-regulation, and ESC guidelines for SAC/VAL, compared to 47.1%, 37.2%, and 45.6% for ivabradine, respectively. Ineligible reasons for the TNHI regulations included LVEF > 35% (19.9%, for SAC/VAL and ivabradine) and sinus rate < 75 beats per minute (bpm) (29.9%, for ivabradine). Although not meeting the TNHI regulations, patients with LVEF 35-40% had a similar 1-year mortality rate (15.6% vs. 15.8%, p = 0.876) to those with LVEF ≤ 35%, whereas patients with a sinus rate 70-74 bpm had a similar 1-year mortality rate (15.3% vs. 16.1%, p = 0.805) to those with a sinus rate ≥ 75 bpm. CONCLUSIONS: Approximately 70% and 63% of TSOC-HFrEF registry patients were ineligible for SAC/VAL and ivabradine, respectively, according to current TNHI regulations. Regardless of the eligibility for novel HFrEF medications, the high incidence of adverse events suggests that all patients should be treated cautiously.