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Background Comitant esotropia is the most common form of strabismus. It is caused by heterogeneous environmental and genetic risk factors. The pure duplication of the long arm of chromosome 19 is a rare abnormality. Only 8 patients with partial trisomy of the long arm of chromosome 19q have been reported to date. Here, we describe a girl with pure duplication of 19q, who was diagnosed with congenital esotropia, microcephaly, and gallbladder agenesis. Case summary The patient was diagnosed with esotropia when she was 1-year-old. The Krimsky method showed +50 prism diopters in the primary gaze position. No additional abnormal findings were observed following slit lamp and fundus examination, but the features of the full-field electroretinogram showed a decreased amplitude and increased implicit times. Magnetic resonance imaging showed ventriculomegaly with thinning of the corpus callosum and splenium in her brain. A 4.42 Mb mosaic duplication within 19q13.2-q13.31 region (chr19:39,343,725 to 43,762,586) was detected by microarray comparative genomic hybridization. Conclusion Strabismus is reported in many live borns with pure duplication of 19q. This important clinical characteristic indicates that the candidate genes fundamental for this phenotype may be narrowed to genes within the 19q13.3-q13.31 region. There were two candidate genes observed that may contribute to the comitant esotropia phenotype, namely XRCC1 (19:43,543,311) and SMG9 (19:43,727,991).

Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. In this study, we explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Our results indicate that keloid fibroblasts can be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory. Interestingly, the percentage of mesenchymal fibroblast subpopulation is significantly increased in keloid compared to normal scar. Functional studies indicate that mesenchymal fibroblasts are crucial for collagen overexpression in keloid. Increased mesenchymal fibroblast subpopulation is also found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis. These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies., Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. Here the authors employ scRNA-seq to explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases.

Background Dysregulated microRNAs are involved in the macrophage polarization and atherosclerotic development. Apart from microRNAs, alteration in DNA methylation is considered as one of the most frequent epigenetic changes. The purpose of the research is to investigate the altered methylation status of miR-181b in the circulating monocytes from patients with coronary artery disease (CAD) and explore the underlying mechanisms. Methods We examined the methylation status of miR-181b in purified circulating monocytes from patients with CAD and healthy controls. We then transfected monocytes with miR-181b mimics and determined the role of miR-181b on the phenotypic switch of macrophages and inflammatory response. DNA methylation levels determined by MethyLight PCR and pyrosequencing at the promoter of miR-181b significantly increased in CAD patients. Based on TargetScan database, we identified PIAS1 as the target gene of miR-181b and explored the interaction of miR-181b and PIAS1 by Dual-Luciferase assay, quantitative PCR and immunoblots. We also investigated the role of miR-181b and PIAS1 on macrophage polarization and inflammation. Results Hypermethylation at the promoter of miR-181b directly contributed to the decrease of miR-181b activity and expression. Overexpression of miR-181b reduced M1 polarization and facilitated M2 polarization determined by quantitative PCR. While knockdown of PIAS1 induced KLF4 degradation and SUMOylation in monocytes, miR-181b mimics reverse the KLF4 SUMOylation via suppression of PIAS1. Moreover, KLF4 SUMOylation by PIAS1 reversed M1 polarization induced by depletion of miR-181b in monocytes. Conclusions Hypermethylation of miR-181b induces M1 polarization and promotes atherosclerosis through activation of PIAS1 and KLF4 SUMOylation in macrophages.

Purpose: Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive and metastatic disease, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Hence, developing effective targeted therapy using potent proteasome inhibitor is required. Methods: We evaluated anti-cancer activity of a potent proteasome inhibitor, marizomib, in vitro using breast cancer lines and in vivo using 4T1.2 murine syngeneic model, MDA-MB-231 xenografts, and patient-derived tumor xenografts. Global proteome profiling, western blots, and RT-qPCR were used to investigate the mechanism of action for marizomib. Effect of marizomib on lung and brain metastasis was evaluated using syngeneic 4T1BR4 murine TNBC model in vivo. Results: We show that marizomib inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, we show that marizomib is a dual inhibitor of proteasome and oxidative phosphorylation (OXPHOS) in TNBCs. Marizomib reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of genes involved in the epithelial-to-mesenchymal transition. We demonstrate that marizomib-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and combined inhibition of glycolysis with marizomib leads to a synergistic anti-cancer activity. Conclusions: Our data provide a strong rationale for a clinical evaluation of marizomib in primary and metastatic TNBC patients.

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.

BACKGROUND Hepatitis C virus (HCV) infection is an important health threat in China to which direct acting antivirals (DAAs) are very effective. In 2019, another novel DAA glecaprevir/pibrentasvir (GLE/PIB) was officially approved. Knowledge of its cost-effectiveness would be informative for clinical decision-making but has not been evaluated. This study aims to evaluate the cost-effectiveness of GLE/PIB to inform policy-making on drug reimbursement and HCV eradication. METHODS Markov models were developed from the payers' perspective and simulated the lifetime experience of adult patients chronically infected with HCV genotype 1 or genotype 2. Two regimens, GLE/PIB and pegylated interferon (pegIFN) plus ribavirin (RBV), were compared in cost and quality adjusted life years (QALY) with both outcomes being discounted to 2020 values. The incremental cost-effectiveness ratio (ICER) was computed to reflect the incremental benefit of GLE/PIB versus pegIFN + RBV. The robustness of the model outcomes was examined using deterministic and probabilistic sensitivity analysis (PSA) to identify influential parameters and to assess the probability of GLE/PIB being cost-effective. The GDP per capita in China in 2019 ($10,275) was used as the threshold for cost-effectiveness. RESULTS For the entire target population, GLE/PIB was the dominant regimen attaining a cost-saving of $255 and 1.17 more QALYs relative to pegIFN + RBV. The finding was more pronounced for HCV genotype 1 infection by saving $1,656 and creating 1.37 more QALYs. At the $10,275 threshold, the probability of GLE/PIB being cost-effective was 99.32% overall and 99.85% for HCV genotype 1 infection. The age of starting DAA treatment, price of pegIFN + RBV, cost of cirrhosis treatment and duration of the GLE/PIB regimen were the five most influential factors. For the patients with HCV genotype 2 infection, the ICER of GLE/PIB was $12,914/QALY with 95% confidence interval of $4,047/QALY to $37,640/QALY. The GLE/PIB regimen statistically cannot be ruled out as a cost-effective option for HCV genotype 2 infection. CONCLUSIONS GLE/PIB is a cost-effective strategy to treat chronic HCV genotype 1 and HCV genotype 2 infection in China. This regimen should be initiated at a younger age to maximize its value. To achieve national eradication, it may be timely to consider replacing pegIFN + RBV with DAAs, such as GLE/PIB, as the first-line treatment.

Objective A 29-year-old male from Guizhou, China, had been suffering from obsessive–compulsive disorder since graduation from junior high school at 14 years. He was afraid of putting glass substances in his mouth. His main symptoms were repetitive thoughts, inquiries and examinations for more than 6 hours a day. He dropped out of school and stayed at home. He had been taking 60 mg/day paroxetine for 7 consecutive years. Over the past 2 years, his obsessive–compulsive symptoms had increased and were present for 12 hours a day. Methods The patient was treated using a combination of drugs, transcutaneous electrical acupoint stimulation–exposure and response prevention therapy (TEAS–ERP) and parental involvement. Results After 28 days, his Yale–Brown Obsessive Compulsive Scale score dropped from 40 to 11 points. After 1 month, telephone follow-up showed that he was able to do housework and was ready to go to work. After 6 months, he was able to easily work, and his compulsive behaviour only occurred 1 to 2 times each day for about 0.5 minutes each time. Conclusions The combination of TEAS–ERP, sertraline and clomipramine had a rapid effect. There was no resumption of obsessive–compulsive symptoms during post-treatment follow-up.

There are limited evidence on the association between short-term exposure to ambient particulate matter (PM) and overall hospital outpatient visits for respiratory system disease (RESD) and cardio-cerebrovascular system disease (CCD) in high-polluted countries like China. Though previous epidemiological studies of RESD and CCD generally applied a linear relationship of the acute PM effects, it is unclear whether this linear exposure-response relationship holds in high pollution area. In this study, a Lime-series study during 2013 through 2016 was conducted to investigate 245,442 and 430,486 hospital visits for RESD and CCD respectively from Nanjing city, China. A combination of logistic generalized additive model (GAM) was used to evaluate the exposure-response associations. The results disclosed that a 10 mu g/m(3) increase in PM2.5 and PM10 concentration on the current day of exposure (lag 0) was associated with 036% (95% CI: -0.02%-0.73%) and 033% (0.07%-0.60%) increase in RESD; and 042% (0.00%-0.85%) and 0.37% (0.08%-0.67%) increase in CCD. The exposure-response association was approximately linear within 0-150 mu g/m(3) of PM concentration and non-linear across the full range of exposures. The effects of PM on RESD and CCD were sensitive to additional adjustment for co-pollutants, indicating the health effects of air pollution mixture in Nanjing city. There was no evidence of potential effect modification of RESD and CCD by season (cold and warm), age (5-64, 65-74, >= 75 years) and sex (male and female) groups. Though not statistically significant, the estimated risks in warm season were higher than those in cold season, suggesting potential synergistic effects of ambient PM pollution and temperature on triggering RESD and CCD. (C) 2019 Elsevier B.V. All rights reserved.

BACKGROUND Unstable carotid atherosclerotic plaques are prone to cause ischemic stroke. Contrast-enhanced ultrasound (CEUS) is the primary method of assessing plaque stability, but CEUS cannot be a method for screening for unstable plaque. The emergence of superb micro-vascular imaging (SMI) offers the possibility of clinically screening for unstable plaque AIM To investigate the value of SMI in predicting ischemic stroke in patients with carotid atherosclerotic plaques. METHODS Patients with carotid atherosclerotic plaques (luminal stenosis of 50%-70%) were enrolled into the present study. All patients received conservative medication. The patient's clinical baseline data, serological data, CEUS and SMI data were analyzed. All patients underwent a 3-year follow-up. The follow-up endpoint was the occurrence of ischemic stroke and patients were divided into stroke group and non-stroke group according to whether the prognosis occurred or not. Subsequently, the difference in clinical data was compared, the correlation of SMI and CEUS was analyzed, and multiple Cox regression and receiver operating characteristic curve were applied to investigate the value of SMI and CEUS in predicting cerebral arterial thrombosis in three years. RESULTS In this study, 43 patients were enrolled in the stroke group and 82 patients were enrolled in the non-stroke group. Cox regression revealed that SMI level (P = 0.013) and enhancement intensity (P = 0.032) were the independent factors influencing ischemic stroke. There was a positive correlation between SMI level and enhancement intensity (r = 0.737, P = 0.000). The area under curve of SMI level predicting ischemic stroke was 0.878. The best diagnostic point was ≥ level II, and its sensitivity and specificity was 86.05% and 79.27%. The area under curve of enhancement intensity predicting ischemic stroke was 0.890. The best diagnostic point was 9.92 db, and its sensitivity and specificity was 88.37% and 89.02%. As the SMI level gradually increased, the incidence of ischemic stroke increased gradually (X2 = 108.931, P = 0.000). CONCLUSION SMI can be used as a non-invasive method of screening for unstable plaques and may help prevent ischemic stroke.

Objective The aim of this study was to investigate value of superb microvascular imaging (SMI) and contrast-enhanced ultrasonography (CEUS) in evaluating the neovascularization of early bone regeneration. Methods Twenty-five Sprague-Dawley male rats were implanted with recombinant human bone morphogenetic protein-2/calcium phosphate cement (rhBMP-2/) in the muscle space of the left hind limb near the femoral head to establish the rat model of intramuscular ectopic osteogenesis. Ultrasonography and pathologic analysis were performed on the 3rd, 7th, 14th, 21st, and 28th days after modeling. Two-dimensional ultrasonography, SMI, and CEUS were used to assess neovascularization and bone formation. Results Pathologic examination showed that different levels of neovascularization were observed in the graft bone over time after modeling, which increased significantly from the 3rd to 14th day, and then gradually decreased. CEUS and SMI showed no obvious microvessels inside the graft bone on the 3rd day. On the 7th day after modeling, a small number of neovascular vessels were observed around the graft bone. On the 14th day, neovascularization was observed in both the peripheral and inner parts of the graft bone. The number of neovascular vessels inside the graft bone had decreased gradually by the 21st and 28th days. The results of SMI and CEUS indexes showed that the vascular index, peak intensity, enhancement intensity, and enhancement rate first increased and then decreased with time. Their peak points were found on the 14th day. Arrival time, time to peak, and enhancement time decreased gradually over time (P Conclusion The combined application of SMI and CEUS may be useful in evaluating the neovascularization of early osteoanagenesis.

Nonalcoholic fatty liver disease (NAFLD) is significantly on the rise, which will seriously affect human health; yet, there is no approved drug for the treatment of NAFLD currently. Recently, more and more studies have demonstrated that intestinal bacteria affect liver function through the gut-liver axis, and that the imbalance of intestinal bacterial composition is essential in the pathogenesis of NAFLD. Correcting intestinal bacterial imbalance, therefore, may prevent the development and attenuate the progression of NAFLD. Fecal microbiota transplantation (FMT) is considered the most effective method to correct intestinal bacteria imbalance, but its therapeutic role in NAFLD has not been established. Moreover, the potential molecular mechanisms of FMT for NAFLD have not been elucidated. This review paper summarizes the currently available experimental and clinical research results on the therapeutic effects of FMT for NAFLD. In addition, the underlying molecular mechanisms are proposed, which would provide theoretical support for FMT as a useful modality for the treatment of NAFLD.

© The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. BACKGROUND Cirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features. AIM To delineate the liver features between WD-associated cirrhosis and hepatitis Bassociated cirrhosis in the Chinese population. METHODS In this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups. RESULTS No inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WDassociated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.38-12.45, P = 0.011). CONCLUSION WD-associated cirrhosis presents a higher risk of splenomegaly associated with leukopenia and thrombocytopenia, although revealing milder liver dysfunction and portal hypertension symptoms, which recommends WD patients to be monitored for associated complications.

Objective: To evaluate the effect of selenium supplementation on autoantibody titers, thyroid ultrasonography and thyroid function in patients with Hashimoto's thyroiditis (autoimmune thyroiditis) and normal thyroid reference range. Methods: A total of 100 patients were given 200 ug/d selenium yeast orally, their thyroid function, levels of serum selenium, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb) and urine iodine were measured and thyroid ultrasonography was performed before administration and three and six months afterwards, and the data were statistically analysed. Results: The subjects exhibited a selenium deficiency before the administration of selenium, and the serum levels increased to moderate levels three and six months after the selenium supplementation (p

Background Contrast-enhanced spectral mammography (CESM) is a new image examination technology that has developed over the past few years. As CESM technology keeps improving, a current meta-analysis review is needed to systematically evaluate the potential diagnostic value of CESM. Methods A total of 18 studies were included in the review. Sensitivity, specificity, and other important parameters of CESM accuracy for breast cancer diagnosis were pooled and analyzed using random-effects models. Summary receiver operating characteristic curves were calculated for overall accuracy estimation. Results The summary estimates for CESM in the diagnosis of breast cancer were as follows: the pooled sensitivity and specificity were 0.89 (95% confidence interval [CI], 0.88-0.91) and 0.84 (95% CI, 0.82-0.85), respectively. Positive likelihood ratio was 3.73 (95% CI, 2.68-5.20), negative likelihood ratio was 0.10 (95% CI, 0.06-0.15), and diagnostic odds ratio was 71.36 (95% CI, 36.28-140.39). The area under the curve was 0.96 (standard error = 0.011). Conclusion CESM has a high diagnostic accuracy for evaluating breast cancer and can be considered as a useful test for initial assessment of breast lesions.

Accurate observation and understanding of diffuse radiation is of vital importance for solar energy applications. Numerous empirical models have been developed for estimating solar radiation in regional and global scales, owing to the relatively sparse radiation measurements. The main objective of this study was to conduct a comprehensive evaluation of 15 typical empirical models for estimating diffuse radiation in different climate zones over mainland China. The result showed that the model in form of second order polynomial performed superior than other models, with mean MBE, MAE, MARE, RMSE, RRMSE, t-stat, STD, and R at all 17 CMA stations were − 0.125 MJ m−2day−1, 1.331 MJ m−2 day−1, 0.208 MJ m−2 day−1,1.807 MJ m−2 day−1, 24.889%, 10.866, 0.941 MJ m−2 day−1, and 0.792, respectively. By contrast, the model in form of fractional first order polynomial showed the poorest performance than other models, with mean MAE, MARE, RMSE, RRMSE, t-stat, STD, and R of − 0.699 MJ m−2day−1, 2.508 MJ m−2day−1, 0.397 MJ m−2 day−1, 6.779 MJ m−2 day−1, 102.716%, 6.709, 1.773 MJ m−2 day−1, and 0.519, respectively. All models generally showed poor accuracies in arid areas with warm-temperate climate, due to the frequent dust occurrences in the air. The estimation errors in Qinghai-Tibet Plateau were also relatively larger, owing to the strong heating atmosphere there. This study would assist in the selection of the most appropriate models for solar energy applications.

PurposeDiffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis. The current study aimed to evaluate the clinical characteristics and profile of molecular markers on patients with a DMG harboring H3K27M mutations, and explore the impact of this genetic makeup on overall survival.MethodsWe retrospectively analyzed 43 consecutive patients diagnosed with a DMG harboring H3K27M mutations (age range 3 to 75 years) and treated in a tertiary institution within China between January 2017 to December 2019. Various clinical and molecular factors were evaluated to assess their prognostic value in this unique patient cohort.ResultsThe median overall survival (OS) was 12.83 months. Preoperative Karnofsky Performance Score (KPS) and adjuvant radiotherapy were found to be independent clinical parameters influencing the OS by multivariate analysis (p = 0.027 and p < 0.001 respectively). Whereas extent of tumor resection failed to demonstrate statistical significance. For molecular markers, P53 overexpression was identified as a negative prognostic factor for overall survival by multivariate analysis (p = 0.030).ConclusionLow preoperative KPS, absence of radiotherapy and P53 overexpression were identified as predictors of a dismal overall survival in patients with DMG and H3K27M mutations.

World Standards Day was established by the International Organization for Standardization (ISO) on October 14 to enhance awareness on the significance of international standardization to respond to the needs of businesses, industries, governments and consumers worldwide Since its rejoining the ISO in 1978, China held various presentations, symposiums, and commemorative events for World Standards Day in major and medium-sized cities nationwide to publicize the role of standardization in societal development and enhance the awareness of standardization among the people The theme for the 51st World Standards Day in this year is “Protecting the planet with standards” Since the coronavirus disease 2019 (COVID-19) pandemic emerged, practitioners in standardization took immediate actions to respond China’s State Standardization Administration, National Health Commission, local governments, and social organizations took emergency actions to formulate and publish a series of relevant national standards, industry standards, local standards, and organization standards for the prevention and control of COVID-19, which played an essential role in regulating and directing efforts in the prevention and control of the outbreak and in protecting the people’s health and safety

Background/Aims: Because the prevalence of age-related cardiac impairment increases as the human lifespan increases, it is important to combat the effects of aging. Recently, the cardiac M3 muscarinic acetylcholine receptor (M3-mAChR) has been demonstrated to play important roles in cardiac development and in the pathogenesis of cardiac diseases. However, the role of M3-mAChR in aging remains largely unknown. Therefore, the aim of this study was to investigate the involvement of M3-mAChR in the progression of cardiac aging. Methods: We established a cardiac aging model in mice through subcutaneous injection with D-galactose at a dose of 100 mg/kg/day for 6 weeks. D-galactose was also used to induce aging in primary cultured neonatal mouse cardiomyocytes. The myocardium from mice was stained with hematoxylin and eosin for histological analysis. The protein expression levels of p53 and p21 were determined using western blotting. The mRNA and protein expression levels of M3-mAChR, caspase-1, and interleukin (IL)-1β were determined using real-time PCR, immunohistochemical staining, and western blotting. Results: The expression of M3-mAChR was down-regulated in the myocardium from aged mice and D-galactose-treated mice, while the expression levels of caspase-1 and its downstream molecule IL-1β were significantly increased. The M3-mAChR agonist choline reduced the increase in caspase-1 in cardiomyocytes induced by D-galactose, which was reversed by the M3-mAChR antagonist 4-DAMP. Moreover, 4-DAMP promoted D-galactose-induced cardiomyocyte aging, which was attenuated by a caspase-1 inhibitor. Conclusion: Activation of M3-mAChR delayed cardiac aging by inhibiting the caspase-1/IL-1β signaling pathway.

Purpose. This study aimed to explore the effects of ticagrelor (a P2Y12 receptor inhibitor) on interleukin (IL)-17 and myeloperoxidase (MPO) expression in coronary thrombus as well as on the coronary blood flow in ST-segment elevation myocardial infarction (STEMI) patients following percutaneous coronary intervention (PCI). Methods. Forty STEMI patients who were admitted to the First Affiliated Hospital of Harbin Medical University between August 1, 2014 and December 30, 2014 were enrolled in this study according to a set inclusion criteria. They were randomized to ticagrelor and clopidogrel groups and treated with 180 mg ticagrelor and 600 mg clopidogrel before PCI, respectively. Intracoronary thrombus aspiration was performed by a physician during PCI. Immunohistochemistry and Western blot analysis were carried out to detect the expression of IL-17 and MPO in the thrombus. Corrected thrombolysis in myocardial infarction frame count (CTFC) was used to evaluate blood flow after PCI. Results. Immunohistochemistry results showed that the average positive staining area percentage of IL-17 and MPO in the clopidogrel group was significantly higher than that in the ticagrelor group. Western blot analysis also showed similar results for IL-17 (clopidogrel 0.71 ± 0.036, ticagrelor 0.50 ± 0.56) and MPO (clopidogrel 0.50 ± 0.040; ticagrelor 0.38 ± 0.06). CTFC was lower in the ticagrelor group than that in the clopidogrel group (P < 0.05). Conclusions. Ticagrelor is more effective than clopidogrel in reducing inflammation thrombosis and improving postprocedural PCI blood flow in STEMI patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

BACKGROUND The aims of this study were to examine the expression of miRNA-21 in the serum of elderly patients (>65 years) with acute myocardial infarction (AMI) and to investigate the potential role of serum miRNA-21 as a marker of early cardiac myocyte damage. MATERIAL AND METHODS Thirty-eight elderly patients with recent AMI, 27 elderly patients with unstable angina pectoris, and 25 healthy elderly individuals were included in the study. Serum miRNA-21 expression was determined following total RNA extraction and reverse-transcribed into cDNA, followed by reverse transcription-polymerase chain reaction (RT-PCR). Serum creatine kinase MB isoenzyme (CK-MB) and cardiac troponin I (cTnI) levels were analyzed by electrochemiluminescence. Apoptosis of human cardiac myocytes (HCM) was analyzed using fluorescence-activated cell sorting (FACS), and protein expression of caspase-3 was detected using Western blot. RESULTS Expression levels of miRNA-21 in the serum of elderly patients with AMI were positively correlated with serum levels of CK-MB (r=0.3683, P=0.0229) and cTnI (r=0.5128, P=0.009). Following tumor necrosis factor (TNF)-α induction, the apoptosis rates of HCM transfected with the miRNA-21 mimic short hairpin RNA (shRNA) were downregulated by 39.1% compared with control HCM cells, and protein expression of c-Jun N-terminal kinases (JNK) and p38 were unchanged (P>0.05); protein expression of p-JNK, p-p38 and caspase-3 were downregulated by 37.1%, 35.8%, and 36.0%, respectively. CONCLUSIONS Expression of miRNA-21 was upregulated in the serum of elderly patients with AMI, which inhibited TNF-a induced apoptosis in HCM by activating the JNK/p38/caspase-3 signaling pathway.

The coastal wetland ecosystems are the critical ecological infrastructure and have a close relation to coastal sustainability. Rapid urbanization lead to a big demand of coastal reclamation in China thereafter caused the loss and degradation of coastal wetlands. In this study, we presented modified model suitable for quantifying ecosystem service values of different coastal system subtypes and assessing their loss due to coastal reclamations with a case of coastal agriculture-dominated city of Eastern China (Lianyungang). We focused on four major agriculture-related ecosystem services as follows: food production, raw material supply, disturbance regulation, and water purification. The results showed that: 32,346 ha of loss in coastal wetlands resulted in US$ 806 million year−1 loss in ecosystem service. The modified ecosystem service valuing models enable achieving categorized management of coastal ecological infrastructures. Furthermore, this study showed how to integrate the ecosystem service estimate into assessment, management, planning, restoration, and compensations of coastal ecological infrastructures.

A novel high-impedance compound film material has been developed to satisfy the reservoir of many kinds of space liquid in space station. Considering the high gas-resistance and liquid-resistance, and its compatibility with the liquid in space station, the complex film was designed using 9 layers materials. The compatibility experiment and mechanical properties experiment showed that the high-impedance complex film has good compatibility with drinking water in space station. It also has excellent heat seal ability, physical and mechanical properties. The complex film also has high gas-resistance and water-resistance property, as well as great chemical corrosion-resistance property. The high-impedance complex film material offers a new method for the design and application of liquid container in space station.

Background Hypothermic circulatory arrest is usually used in aortic surgery, congenital heart defect repairs and other complex surgeries. It is frequently associated with excessive postoperative bleeding and the transfusion of allogeneic blood products. The physiopathology of hypothermic circulatory arrest-induced coagulopathy has never been systematically studied. The aim of the study was to investigate this phenomenon in a pig model. Methods Ten pigs were randomly assigned to 30 min of hypothermic circulatory arrest at either 15 °C (n = 5) or 25 °C (n = 5). Detection of apoptosis and haemostatic system assays were performed in this experiment. Enzyme-linked immunosorbent assays were performed at ten time points in each group to study the changes in the coagulation system in hypothermic circulatory arrest. All of the statistical analyses were performed in SPSS software, version 18.0, and as bilateral tests, and p Results There was no significant difference in the effect of different types of hypothermic circulatory arrest on routine laboratory tests and tissue sample analysis (p > 0.05, for all). Our results demonstrated that more severe systemic activation of the coagulation system (TAT and F1+2) was applied in the deep hypothermic circulatory arrest group but not in the moderate hypothermic circulatory arrest group (TAT/p = 0.01, F1+2/p = 0.03). However, this activation of the coagulation system (AT III and PC) was not associated with changes in the anticoagulation pathway (AT III/p = 0.24, PC/p = 0.33). In addition, analysis of biomarkers of the haemostatic system revealed that the consumption of coagulation is more concentrated on extrinsic coagulation factors (FVII/p = 0.01). Conclusions Moderate hypothermic circulatory arrest is more suitable for patients with coagulation dysfunction. We believe the application of deep hypothermic circulatory arrest should pay more attention to changes in coagulation rather than the anticoagulation pathway. Extrinsic coagulation factor supplementation is more effective after deep hypothermic circulatory arrest.

In this paper, the SEIR model is generalized by introducing an asymptomatic class to quantify the influence of wearing N95 facemasks in reducing the spread of influenza H1N1. What's more, we explain the control reproduction number Rc according to the biological meaning reasonably. Without any intervention, the basic reproduction number R0=1.83 and there will be a large outbreak of infectious diseases. If N95 facemasks are 50% effective in reducing susceptibility and infectivity, 50% of population wear them on the first day, the basic reproduction number will be decreased from 1.83 to 1.17 and the final size reduced from 73% to 2%.

Osteoporotic vertebral compression fracture (OVCF) is a common disease in senior patients. Conservative treatments (usual care) and percutaneous vertebroplasty (PVP) are typically applied to treat OVCFs; however, their efficacies are not fully satisfactory. While Teriparatide (TPTD) is effective in both anti-osteoporosis and bone healing, whether TPTD could be applied as a conservative treatment for acute OVCFs remains unclear.This investigation represents a real-world prospective cohort study, where 60 postmenopausal women (≥55 years old) with acute OVCFs were equally assigned to a TPTD conservative group or PVP (plus alendronate) group based on the patient's choice. TPTD (20 μg, s.c., once daily) or alendronate (70 mg, p.o., once weekly) were administrated together with 0.6 mg Caltrate and 500 iu Vitamin D3 per day. A health survey (SF-36) was conducted at 0-, 1- and 3-months post-treatment. Back pain and the Oswestry Disability Index (ODI) were measured at 0-week, 1-week, 1-month and 3-months after treatment, while the direct medical cost was analyzed at the end of the third month.Both treatments with TPTD and PVP significantly and similarly improved the patients' health quality, with reduced visual analogue and ODI scores at the end of the first and third months. PVP was more effective in reducing pain at the early time point (1 week, p 0.05). 24 of 27 patients who were rescanned with magnetic resonance imaging in the TPTD group showed bone healing. The mid-vertebral height was increased by PVP (p 0.05) but not by TPTD. The cost of TPTD treatment was 21,868.61 ± 167.05 RMB per capita, while the cost for PVP treatment was 33,265.95 ± 1491.11 RMB per capita (p 0.05).TPTD conservative treatment obtained similar therapeutic effects but cost less than PVP in terms of treating acute OVCF.

Background and purpose To evaluate the prognostic value of MRI-detected residual retropharyngeal lymph node (RRLN) at three months after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC) and second, to establish a nomogram for the pretherapy prediction of RRLN. Materials and methods We included 1103 patients with NPC from two hospitals (Sun Yat-Sen University Cancer Center [SYSUCC, n = 901] and Dongguan People's Hospital [DGPH, n = 202]). We evaluated the prognostic value of RRLN using Cox regression model in SYSUCC cohort. We developed a nomogram for the pretherapy prediction of RRLN using logistic regression model in SYSUCC training cohort (n = 645). We assessed the performance of this nomogram in an internal validation cohort (SYSUCC validation cohort, n = 256) and an external independent cohort (DGPH validation cohort, n = 202). Results RRLN was an independent prognostic factor for OS (HR 2.08, 95% CI 1.32–3.29), DFS (HR 2.45, 95% CI 1.75–3.42), DMFS (HR 3.31, 95% CI 2.15–5.09), and LRRFS (HR 3.04, 95% CI 1.70–5.42). We developed a nomogram based on baseline Epstein–Barr virus DNA level and three RLN status-related features (including minimum axial diameter, extracapsular nodal spread, and laterality) that predicted an individual's risk of RRLN. Our nomogram showed good discrimination in the training cohort (C-index = 0.763). The favorable performance of this nomogram was confirmed in the internal and external validation cohorts. Conclusion MRI-detected RRLN at three months after IMRT was an unfavorable prognostic factor for patients with NPC. We developed and validated an easy-to-use nomogram for the pretherapy prediction of RRLN.

Background: MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/glucagon receptor activity that is under development for type 2 diabetes mellitus. This study was conducted in subjects of Japanese and Chinese descent to facilitate expansion of its global clinical development in Japan and China. Methods: This phase 1, randomized, blinded study evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of single subcutaneous (SC) doses of MEDI0382. In part A, 24 subjects of Japanese descent across 3 cohorts (8 per cohort) received single SC doses of MEDI0382 at a dose of 50 µg (cohort 1), 100 µg (cohort 2), or 150 µg (cohort 3) or placebo in a 3:1 ratio. In part B, 8 subjects of Chinese descent received a single SC dose of MEDI0382 at 100 µg or placebo in a 3:1 ratio (cohort 4). Results: In part A, the incidence of treatment-emergent adverse events (TEAEs) was highest in the 150-μg group (5 of 6 subjects). In part B, 2 of 6 subjects in the MEDI0382 group reported TEAEs. Nausea, headache, and vomiting were most common. A trend of increased pulse rate post-dose was seen in subjects of Japanese descent in the MEDI0382 100- and 150-µg groups. No clinically meaningful changes from baseline in vital signs were observed in part B. Median tmax values were 6.15-8.16 h at doses of 50-150 μg, both in subjects of Japanese and Chinese descent. In part A subjects receiving MEDI0382 100 and 150 µg, postprandial mean glucose levels remained closer to baseline levels as compared with changes seen with MEDI0382 50 µg or placebo. Discussion: The safety profile of single doses of MEDI0382 at doses of 50, 100, and 150 µg supports its further development in subjects of Japanese and Chinese descent. The pharmacokinetic data for MEDI0382 in the range of 50-150 µg also support its further clinical development in subjects of Japanese and Chinese descent. Disclosure D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. M. Petrone: Employee; Self; MedImmune. L. Tsai: Employee; Self; MedImmune. Other Relationship; Self; AstraZeneca. R.A. Gasser: Employee; Self; AstraZeneca, MedImmune. Funding AstraZeneca

Different kinds of radiative transfer models, including a relative sunshine-based model (BBM), a physical-based model for tropical environment (PBM), an efficient physical-based model (EPP), a look-up-table-based model (LUT), and six artificial intelligence models (AI) were introduced for modeling the daily photosynthetically-active radiation (PAR, solar radiation at 400⁻700 nm), using ground observations at twenty-nine stations, in different climatic zones and terrain features, over mainland China. The climate and terrain effects on the PAR estimates from the different PAR models have been quantitatively analyzed. The results showed that the Genetic model had overwhelmingly higher accuracy than the other models, with the lowest root mean square error (RMSE = 0.5 MJ m−2day−1), lowest mean absolute bias error (MAE = 0.326 MJ m−2day−1), and highest correlation coefficient (R = 0.972), respectively. The spatial⁻temporal variations of the annual mean PAR (APAR), in the different climate zones and terrains over mainland China, were further investigated, using the Genetic model; the PAR values in China were generally higher in summer than those in the other seasons. The Qinghai Tibetan Plateau had always been the area with the highest APAR (8.668 MJ m−2day−1), and the Sichuan Basin had always been the area with lowest APAR (4.733 MJ m−2day−1). The PAR datasets generated by the Genetic model, in this study, could be used in numerous PAR applications, with high accuracy.

This study enrolled 3266 pregnant women, to explore the relationship of prenatal phthalate exposure with the risk of preterm birth and gestational age. All participants filled questionnaires and provided with up to three urine samples during three trimesters. Seven phthalate metabolites in urines were measured. The incidences of very preterm, late preterm, early-term, late-term and postterm births were 0.58%, 3.52%, 24.22%, 10.53%, and 0.34%, respectively. Non-linear relationships were shown between phthalate metabolites and gestational age. Except for monomethyl phthalate (OR = 1.65, 95%CI = 1.17–2.34), the average concentrations of phthalate metabolites were associated with a slightly and insignificantly increased risk of overall preterm birth ( 0.05) or a non-linear manner (p-value

Introduction:Taiwan is an Asian country with speedy aging. Healthcare demands are also changing dramatically, which make a huge grow of healthcare expenditure. Therefore, we need to re-design a more patient-centered and integrated care models to support for high quality healthcare delivery. We launched in our hospital a vertical integration health care system (VIHCS) since 2015.The case managers are the souls of the care plans. They will provide individual and diversified care management services, so as to reduce the rates of repeated outpatient visits, emergency visits, and hospitalizations. This study aims to evaluate the efficiency of VIHCS and the role of case managers in this program.Methods:Our VIHCS program was carried on in a 32-bed hospitalist ward. Six dedicated attending physicians, nurse specialist practitioners, case managers, clinical pharmacists, and nursing staffs as key members in the VIHCS program. The job description of case managers are: (1) to make clarifications for the patient's multiple chronic disease histories and medication details. (2) To link the cooperation resources. (3) To discuss the aims of care and draft the discharge preparation plans. (4) To establish a multi-dimensional communication channel, contact the community hospitals and physicians at the primary care clinics which the patients are accustomed to seek medical treatment or near their homes, and hold a meeting for discussions. (5) To provide disease-related educations. (6) To perform regular monthly telephone visits, provide consulting services, and assist the patients in seeking medical treatment when necessary.Results:We successfully recruited 54 patients with multiple chronic diseases as the majority disease pattern. The number of emergency department visits within 6 months decreased by 75%, the rates of successful primary-care referral to the hospitals reached 19% (54/284), and the patient satisfaction rate was up to 96%.Conclusion:Our newly designed caring model, the VIHCS, can successfully prevent re-entry of discharge patients, reduce healthcare expenditure, and improve patient satisfaction. The case managers play an important role and function in this program.Keywords:case managers, hospitalist, vertical integration healthcare service, integrated care

Purpose In populations without contrast enhancement, the imaging features of atypical brain parenchyma inflammations can mimic those of grade II gliomas. The aim of this study was to assess the value of the conventional MR-based radiomics signature in differentiating brain inflammation from grade II glioma. Methods Fifty-seven patients (39 patients with grade II glioma and 18 patients with inflammation) were divided into primary (n = 44) and validation cohorts (n = 13). Radiomics features were extracted from T1-weighted images (T1WI) and T2-weighted images (T2WI). Two-sample t-test and least absolute shrinkage and selection operator (LASSO) regression were adopted to select features and build radiomics signature models for discriminating inflammation from glioma. The predictive performance of the models was evaluated via area under the receiver operating characteristic curve (AUC) and compared with the radiologists’ assessments. Results Based on the primary cohort, we developed T1WI, T2WI and combination (T1WI + T2WI) models for differentiating inflammation from glioma with 4, 8, and 5 radiomics features, respectively. Among these models, T2WI and combination models achieved better diagnostic efficacy, with AUC of 0.980, 0.988 in primary cohort and that of 0.950, 0.925 in validation cohort, respectively. The AUCs of radiologist 1’s and 2’s assessments were 0.661 and 0.722, respectively. Conclusion The signature based on radiomics features helps to differentiate inflammation from grade II glioma and improved performance compared with experienced radiologists, which could potentially be useful in clinical practice.

When the ratio of W/S in ADS mode LCD is tuned, V-T Curve symmetry is altered by splay deformations in areas above the pixel electrode and slit, and flicker shift and DC image sticking are changed by bend deformations in area above the border of the pixel electrode and slit.

This study aimed to investigate the association of epidermal growth factor receptor (EGFR) mutation status with treatment outcome for patients with stage 3 non-small cell lung cancer (NSCLC) who had undergone a complete (R0) resection. The study identified 3445 NSCLC patients tested for EGFR mutations between September 2001 and December 2011 at the Sun Yat-Sen University Cancer Center. Of these patients, 224 were stage 3 patients who had undergone R0 resections. These 224 R0-resected, pathologic stage 3A and 3B patients included 150 patients with wild-type EGFR and 74 patients with EGFR mutations. During a median follow-up period of 42 months (range, 4–133 months), pathologic stage was shown to be the only prognostic factor. The 3-year overall survival (OS) rates did not differ significantly from the OS rates for the wild-type and mutant EGFR groups (62.0 vs 67.2 %; p = 0.789). Multivariate analyses indicated that the patients in the mutant EGFR group with EGFR exon 19 mutations had a better OS rate (73.0 vs 61.1 %; p = 0.026). Cancer stage remained the significant prognostic factor in R0-resected stage 3 NSCLC patients. The presence of an EGFR mutation is more likely to be a predictive marker for the response to treatment with tyrosine kinase inhibitors. In the EGFR mutant group, the patients with an exon 19 mutation had better 3-year OS rates. These findings might be considered in future study designs.

Urbanization processes affect the ecosystem through alterations in ecological functions and landscape patterns. Currently, analysis of the total ecosystem services value (ESV) has targeted the overall benefits which human beings obtain from the regional ecosystem but does not generally include information regarding ecological structures and patterns. Therefore, the results cannot reflect the comprehensive state of the local ecosystem. We propose a new, integrative ecosystem quality indicator based on the ESVand landscape metrics for evaluating the quality of the regional ecosystem. We adopted the method of a coupled degree of coordination for evaluating the interrelationship between urbanization and ecosystem quality in Lianyungang City from 1985 to 2010. The coupling degree of coordination between urbanization and ecosystem quality showed an inverse U-shaped curve. At the primary stage of urbanization (1985‒1995), the degree of coupling of urbanization and the ecosystem was just barely balanced. From 1995 until 2000, the coupling system reached a balanced condition, in which the urbanization level increased. Since 2000, the urbanization process has accelerated. The coordination between urbanization and the ecosystem achieved the optimum condition in 2005. A turning point appeared at the same time, and the degree of coupling coordination began falling from the optimum. Subsequently, the coupled system once more entered a barely balanced state. Overall, the comprehensive level of ecosystem quality decreased since 1985 and degraded sharply after 2005, suggesting an overall degradation of the local ecosystem quality.

This paper systematically introduces a three-dimensional transmission and transformation engineering auxiliary design software, and analyses its function, structure and technical characteristics. The main feature of this software is that it has a relatively powerful three-dimensional auxiliary design capability, which can help designers quickly generate a three-dimensional model of power transmission and transformation projects. The three-dimensional model can not only give the project investor an overall image and visual effect of the project during the design bidding stage, but also serve as a reference for the design of the relevant drawings in the later period. At the same time, after having an accurate model, the designer can verify the correctness and reliability of the design, can directly obtain some spatial information, and can dynamically modify, adjust and verify the model as needed. The software also provides related information statistics, query, modification, retrieval and other functions, and provides corresponding drawing management tools according to drawing management specifications. (With the actual application of the system, the design level and technical capabilities of designers will be further improved to ensure that the design work can be completed with high quality and efficiency.

Background Previous reports found that cinnamaldehyde has effects on anti-respiratory syncytial virus (ARSV). However, their results are still contradictory. Therefore, this study will systematically address the effects of cinnamaldehyde on ARSV. Methods The following electronic bibliographic databases will be retrieved from their outset to the March 31, 2020: MEDLINE, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Technology Periodical Database, China Biology Medicine, and China National Knowledge Infrastructure. No language and publication time limitations will be exerted in this study. All relevant case-controlled studies or randomized controlled studies exploring the effects of cinnamaldehyde on ARSV will be included. Study quality of case-controlled studies will be assessed by Newcastle-Ottawa scale, and that of randomized controlled studies will be identified by Cochrane risk of bias tool. All data pooling and analysis will be performed using RevMan 5.3 software. Results This study will summarize the up-to-date high-quality evidence to synthesize outcome data on the effects of cinnamaldehyde on ARSV. Conclusion Findings of this study may provide beneficial evidence for both clinicians and future studies regarding the effects of cinnamaldehyde on ARSV. Systematic review registration INPLASY202040074.

Recently, the negative absorption in graphene-based metamaterials became a very attractive direction of THz electronic devices. Here we propose a graphene-dielectric hybrid meta-structure to realize photo-induced enhanced negative absorption in the THz regime, which results from strong graphene-light interaction. The negative absorption is derived from the degradation of the conductivity of graphene under optical pump. Meanwhile, the graphene-dielectric hybrid meta-structure introduces dispersion relation and resonance mode, which can couple with the incident wave to construct a strong resonance. In this case, both the dispersion of the propagating waves and resonance are contributed to the graphene-light interaction and enhance the negative absorption, in which the resonance coupling determines the distribution of negative absorption, and the maximum is dominated by dispersion. More importantly, compared with the previous work, the negative absorption is increased by nearly 100 times by adopting this meta-structure.

MEDI0382 is a balanced GLP-1/glucagon receptor dual agonist in development for type 2 diabetes mellitus (T2DM). We investigated the effects of MEDI0382 on hepatic fat content in overweight/obese subjects with T2DM and a BMI of 27-40 kg/m2. In a phase 2a study (NCT02548585), 51 subjects were randomized to receive MEDI0382 200 μg or placebo daily during a 41-day treatment period. Quantification of liver proton density fat fraction, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) was performed as an exploratory analysis in a subset of patients (MEDI0382 n = 17, placebo n = 21) who had MRI scans taken at baseline and day 41. Mean (SD) liver fat content at baseline was 15.7% (8.97) and 18.1% (8.38) in the MEDI0382 and placebo groups, respectively. Patients treated with MEDI0382 showed a highly significant relative reduction from baseline in hepatic fat content vs. placebo (Table). This was positively correlated with reductions in both body weight (r = 0.49, P = 0.002) and alanine aminotransferase (r = 0.42, P = 0.009). Treatment with MEDI0382 was also associated with reductions in both SAT and VAT vs. placebo. These data demonstrate the efficacy of MEDI0382 in reducing liver fat and its potential for the treatment of nonalcoholic fatty liver disease, including steatohepatitis.MeasurementChange from Baseline, LS Mean (90% CI)P MEDI0382 (n - 17)Placebo (n = 21)Hepatic fat content, absolute change (%)-5.98 (-7.67, -4.29)-3.17 (-4.68, -1.65)0.017Hepatic fat content, relative change (%)-39.12 (49.11, -29.14)-19.51 (-28.49, -10.53)0.006SAT (L)-0.39 (-0.48, -0.30)-0.21 (-0.30, -0.13)0.008VAT (L)-0.36 (-0.52, -0.19)-0.14 (-0.29, 0.01)0.057 Disclosure M. Jain: Employee; Self; MedImmune. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. P. Hockings: Other Relationship; Self; MedImmune, AstraZeneca. L. Johansson: Stock/Shareholder; Self; Antaros Medical. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.

MEDI0382 is a GLP-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus (T2DM). This double-blind study (NCT02548585) evaluated MEDI0382 in T2DM patients with BMI 27-40 kg/m2. Subjects (n = 61) were randomized to once-daily subcutaneous MEDI0382 or placebo (PBO) at different dosing levels and uptitration schedules (100 μg [C1], 150 μg [C2], 200 μg [C3], and 300 μg (2 uptitration schedules, C4 and C5). Marked reduction in fasting and postprandial glucose was achieved with a ∼40% decrease in glucose AUC0-4h after mixed-meal testing across all cohorts (P ≤ 0.0102) (Figure 1A). Weight loss was observed at all dose levels and reached statistical significance (P = 0.024) at 300 μg (C4) (Figure 1B). Ambulatory systolic blood pressure decreased nonsignificantly from baseline in the 300-μg cohort (C4, -4.9 vs. -6.5 mmHg; C5, -9.1 vs. -5.0 mmHg). Similar to other marketed GLP-1 analogs, MEDI0382 increased pulse rate vs. PBO (C4, 8.4 vs. -2.4 BPM, P = 0.0039; C5, 5.8 vs. 0.2 BPM, P = 0.0796). Treatment-related adverse events occurred more often with MEDI0382 vs. PBO (86% [36/42] vs. 47% [9/19]); most events were mild or moderate in severity. In conclusion, MEDI0382 administered for up to 22 days showed a marked reduction in both fasting and postprandial glucose with weight reduction and an acceptable tolerability profile. Disclosure D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M.W. Stumvoll: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Foundation. M.G. Posch: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. G. Klein: None. L. Tsai: Employee; Self; MedImmune. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.

MEDI0382 is under development for the treatment of type 2 diabetes mellitus (T2DM). In a double-blind study (NCT02548585), 51 T2DM patients with BMI 27-40 kg/m2 were randomized (1:1) to daily SC MEDI0382 200 μg or placebo (PBO). Based on ANCOVA with treatment and baseline (BL) values as covariates, MEDI0382 markedly reduced fasting glucose (change from BL at day 41, -49.9 vs. -19.2 mg/dL; P < 0.0001) and postprandial glucose in a mixed-meal tolerance test (percent change from BL in glucose AUC0-4h, -32.8 vs. -10.2; P < 0.0001) (Figure 1) with no increase in hypoglycemia. HbA1c levels decreased -0.9% with MEDI0382 and -0.6% with PBO (P = 0.0004). Weight loss was 3.8 kg vs. BL (1.7 kg vs. PBO; P = 0.0008); 92% of MEDI0382 patients lost >2 kg. Mean reduction in ambulatory systolic BP was -4.2 for MEDI0382 vs. -1.5 mmHg for PBO (P = ns). As with marketed GLP-1 analogs, a mean pulse increase of 6.8 BPM for MEDI0382 vs. a fall of 2.0 BPM for PBO was seen (P < 0.0001). Treatment-related AEs such as decreased appetite, vomiting, and headache were seen in more patients on MEDI0382 (20 vs. 15); 0 were grade >3 severity, 3 led to study discontinuation for MEDI0382 vs. 1 for PBO, and 1 SAE in the PBO arm. Overall, MEDI0382 normalized fasting and postprandial blood glucose, significantly reduced body weight, and had an acceptable safety profile over 41 days of dosing in obese/overweight T2DM patients. Disclosure P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. M.W. Stumvoll: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Foundation. M.G. Posch: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.

MEDI0382, a GLP-1/glucagon dual receptor agonist, is being developed for the treatment of T2DM. GLP-1 receptor agonists promote glucose-dependent insulin release, suppress glucagon, and increase or have minimal effect on glucose-dependent insulinotropic polypeptide (GIP); knowledge of the effect on GLP-1 is limited. We characterized fasting and postprandial hormone profiles associated with MEDI0382 therapy. In a phase 2a study (NCT02548585), 51 subjects with T2DM and BMI 27-40 kg/m2 received MEDI0382 (uptitrated to 200 µg) or placebo (PBO) daily for 41 days. Glucose, insulin, glucagon, GIP, and GLP-1 were measured at baseline (day -1) and day 41 during a liquid mixed-meal tolerance test. MEDI0382 significantly reduced fasting glucose (-49.9 vs. -19.2 mg/dL for PBO; P < 0.0001) and glucose AUC0-4h (-32.8 vs. -10.2% for PBO; P < 0.0001) in association with increased fasting insulin (2.2 mU/L vs. -3.9 mU/L for PBO; P = 0.016), but postprandial insulin AUC was unchanged. In contrast, fasting and postprandial endogenous glucagon, GIP (Figure), and active and inactive GLP-1 were suppressed, and a delay in their kinetics was observed after MEDI0382 therapy. The results suggest that MEDI0382 is insulinotropic and might also cause delayed gastric emptying. The effects of MEDI0382 on GIP have not been observed with GLP-1 receptor mono-agonists and may represent a footprint of dual GLP-1/glucagon receptor agonism in this complex hormone signaling network. Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.

We present the design and characterization of a CMOS pixel direct charge sensor, Topmetal-IIa, fabricated in a standard 0.35µm CMOS process. The sensor features a 45 × 216 pixel array with a 40µm pixel pitch which collects and measures external charge directly through exposed metal electrodes in the topmost metal layer. Each pixel contains a low-noise charge-sensitive preamplifier to establish the analog signal, which is read out through time-shared multiplexing over the entire array. Compared to the earlier Topmetal-II- chip, the analog readout noise of Topmetal-IIa is reduced by 10.8% from 13.9e- to 12.4e-, and the DC voltage variation noise is reduced by 21% from 1.2mV down to 0.946mV. The sensor is capable of detecting both electrons and ions drifting in gas. These characteristics enable its use as the charge readout device in future Time Projection Chambers without gaseous gain mechanism, which has unique advantages in low background and low rate-density experiments.

The predictive value of four-dimensional speckle tracking imaging (4D-STI) risk classification and TIMI risk scores for the prognosis of patients with ST-segment elevation myocardial infarction (STEMI) after reperfusion therapy were investigated. One hundred and twenty patients with STEMI after reperfusion therapy were involved. At 12 h after reperfusion therapy, 2nd and 3rd day, the three-dimensional longitudinal strain (LS), circumferential strain (CS) and radial strain (RS), area strain (AS), as well as other 4D-STI detection indicators, were collected. The patients were followed up for one year, and were divided into good prognosis group and poor prognosis group. LS, CS, RS and AS indicators were analyzed between these two groups. The ROC curve was drawn to establish the 4D-STI risk classification and its predictive value for poor prognosis and mortality were compared with TIMI risk scores. AS, LS and RS at 12 h after reperfusion treatment, and AS and RS at 2nd and 3rd day had a certain degree of prediction accuracy in STEMI patients in the poor prognosis group. In the 4D-STI and TIMI risk scores, the risk of death and adverse prognosis significantly increased as the risk scores increased (P