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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) has multiple roles in the development and progression of atherosclerosis. Recent studies have indicated an association of PCSK9 with thrombotic process. Purpose We aimed to examine whether there exists a relationship between plasma PCSK9 concentration and the most commonly coagulation parameters including prothrombin time (PT) and activated partial thromboplastin time (APTT). Methods A total of 2293 consecutive patients with angina-like chest pain who had no treatment of lipid-lowering drugs were enrolled in this study. The baseline clinical and laboratory data were collected. PT and APTT tests were performed. Circulating PCSK9 concentrations were determined by ELISA and classified into three subgroups according to their levels of PCSK9 tertiles. The relation of PCSK9 concentration to PT or APTT were analyzed. Results Firstly, we found that the patients with high PCSK9 levels trended to have lower PT and APTT (p Conclusion Circulating PCSK9 concentration was independently negative associated with PT, suggesting a potential link between PCSK9 and PT that may be involved in atherogenesis and atherothrombosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences

Ti-based metallic glass matrix composites (MGMCs) with a composition of Ti50Zr20V10Cu5Be15 (atomic percent, at. %) exhibit excellent tensile ductility and distinct work-hardening capability. A dislocation pile-up model (DPM) has been established to elaborate the dislocation motion near the yield point and to theoretically derive a linear Hall-Petch-like relationship between the yield strength, σ, and the inverse square root of the diameter of dendrite arms, d−1/2. The materials constant, k, in the present Hall-Petch-like relationship can be calculated on the basis of the pile-up model, and is very close to the experimental value. The hardness variation in the dendrites and the strengthening effect from unloading-reloading tests prove the reasonability of the DPM during tension. The Hall-Petch-like relationship is verified for a variety of MGMCs, whose plastic deformation is only dominated by dislocation motion. Mean-field theory (MFT) has been first utilized to build a relationship between the critical diameter of dendrites, dc, and the composition in MGMCs with the similar atomic percentages of low solubility elements. By tuning the composition, one can universally scale the Hall-Petch-like relationship, and accurately predict the yield strength of such in-situ MGMCs.

Objectives For patients with recurrent/metastatic cervical cancer, incorporation of anti-angiogenesis therapy with chemotherapy yields a modest survival benefit of 3.7 months over chemotherapy alone (Tewari et al. NEJM. 2014). The rationale for checkpoint inhibition is supported by programmed death ligand-1 (PD-L1) expression in some cervical cancers (∼70%), with a higher proportion noted in squamous cell carcinoma vs adenocarcinoma. Based on the 14.3% objective response in KEYNOTE-158, the US FDA granted accelerated approval to pembrolizumab for PD-L1–positive cervical cancer for second-line therapy and beyond. Methods KEYNOTE-826 is a phase 3, randomized, double-blind, placebo-controlled, multinational trial of chemotherapy with pembrolizumab or placebo for first-line treatment of recurrent, persistent, or metastatic cervical cancer. Patients not previously treated with chemotherapy for recurrence and not amenable to curative treatment will be randomized 1:1 to chemotherapy + pembrolizumab 200 mg or placebo every 3 weeks. The chemotherapy regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by investigators pre-randomization. Stratification factors include metastatic status at diagnosis (yes/no), bevacizumab use (yes/no), and tumor PD-L1 status (combined positive score

To address high HIV prevalence, the District of Columbia (DC) Department of Health has implemented multiple strategies to increase routine HIV testing since 2006. Examination of delayed HIV diagnosis over time can demonstrate population-level impact of public health strategies to promote HIV testing. Using HIV surveillance data, we examined delayed HIV diagnosis in DC (stage 3 within 90 days of diagnosis), CD4 count at HIV diagnosis, linkage to HIV care, and time to viral suppression among DC residents age 13 and above who were diagnosed from 2006 to 2016. We used the Cochran-Armitage test of trend, Cuzick's test of trend, and Chi-square for univariate analyses, and we examined factors associated with delayed HIV diagnosis using a log-binomial multivariate model. 7,937 DC residents were diagnosed with HIV and had available data. Between 2006 and 2016, delayed HIV diagnoses declined from 36.4% to 25.5%, median CD4 count increased from 190 cells/µl to 426 cells/µl, and median time from HIV diagnosis to viral suppression declined from 1,136 days to 84 days. Women, youth ages 13-29, and men who have sex with men had lower proportions with delayed HIV diagnosis. In the multivariate models, racial/ethnic disparities in delayed HIV diagnoses were apparent during 2006-2008 but not during 2009-2016. Continued efforts around earlier HIV testing are needed in DC.

Discrete, jerky stress-drop bursts (serrated flows) during plastic deformation of a Zr-based bulk metallic glass exhibit different magnitudes in response to variant strain rates. Through the classical statistical analysis of stress-strain curves during serrated flow, plastic dynamic behavior changes from Gauss to the power-law distribution with increasing the strain rates. In addition, a quantitative liner relation between mean stress drops and the logarithm of strain rates is obtained to describe the influence of strain rates on mean amplitudes of the stress drop. The power-law scaling behavior is illustrated in different views including the strain-rate dependence, energy dynamics, the Poisson's ratio of material, and shear-banding operation. These results are helpful for understanding the serration behavior at room temperature.

To understand the causes of the past water cycle variations and the influence of climate variability on the streamflow, lake storage, and flood potential, we analyze the changes in streamflow and the underlying drivers in four typical watersheds (Gaosha, Meigang, Saitang, and Xiashan) within the Poyang Lake Basin, based on the meteorological observations at 79 weather stations, and datasets of streamflow and river level at four hydrological stations for the period of 1961-2000. The contribution of different climate factors to the change in streamflow in each watershed is estimated quantitatively using the water balance equations. Results show that in each watershed, the annual streamflow exhibits an increasing trend from 1961–2000. The increases in streamflow by 4.80 m3 s−1 yr−1 and 1.29 m3 s−1 yr−1 at Meigang and Gaosha, respectively, are statistically significant at the 5% level. The increase in precipitation is the biggest contributor to the streamflow increment in Meigang (3.79 m3 s−1 yr−1), Gaosha (1.12 m3 s−1 yr−1), and Xiashan (1.34 m3 s−1 yr−1), while the decrease in evapotranspiration is the major factor controlling the streamflow increment in Saitang (0.19 m3 s−1 yr−1). In addition, radiation and wind contribute more than actual vapor pressure and mean temperature to the changes in evapotranspiration and streamflow for the four watersheds. For revealing the possible change of streamflow due to the future climate change, we also investigate the projected precipitation and evapotranspiration from of the Coupled Model Intercomparison Project phase 3 (CMIP3) under three greenhouse gases emission scenarios (SRESA1B, SRESA2 and SRESB1) for the period of 2061–2100. When the future changes in the soil water storage changes are assumed ignorable, the streamflow shows an uptrend with the projected increases in both precipitation and evapotranspiration (except for the SRESB1 scenario in Xiashan watershed) relative to the observed mean during 1961–2000. Furthermore, the largest increase in the streamflow is found at Meigang (+4.31%) and Xiashan (+3.84%) under the SRESA1B scenario, while the increases will occur at Saitang (+6.87%) and Gaosha (+5.15%) under the SRESB1 scenario.

The array dielectric tool (ADT) can be used in situations where the formation water resistivity is variable or unknown. However, few laboratory measurements of the dielectric dispersion properties at wide frequencies (20 MHz–1 GHz) have been reported to date, which hinders our understanding of the petrophysical mechanisms. In this study, we introduce the dielectric constant measurements of a sweep frequency in the range of 20–1000 MHz based on the parallel-disk capacitor method. In order to control the variables, artificial rocks were manufactured from glass beads. The relationships between the rock dielectric constant and the frequency, saturation, salinity were investigated in the MHz to GHz range. It is shown that the frequency, water saturation, salinity control the dielectric dispersion of rocks. The dielectric constant is found to have a power law dependence on the frequency and a linear dependency between the rock's dielectric constant and the saturation is observed experimentally. Additionally, the dielectric constant increases with increasing salinity.

Objective The study was conducted to inform area-based prevention intervention programs and plan resource allocation to reduce new infections in the District of Columbia (DC), United States of America. Study design The analysis used spatial regression to evaluate the spatial heterogeneity of the new HIV rate and its association with sexually transmitted infection repeaters (STIREPs) and socio-economic as well as demographic characteristics. The HIV and STIREP data were obtained from the DC Department of Health surveillance data (2010–2016). Other covariates were obtained from the American Community Survey, 2016. Methods Ordinary least squares (OLS) and geographically weighted regression (GWR) were used to compare global and local relationships. GWR-computed robust results were compared with other spatial regression methods such as spatial lag or spatial error methods. Results For the OLS model, age, high school dropouts (NHSD), and the black population had an association with new HIV diagnoses (HIVDVi). The results from the GWR model demonstrate spatial variations of association of STIREPs; mean age of each block group; and percentage of female population, NHSD, unemployment, and poverty with HIVDVi. Akaike information criterion (AICc) value for the global model was 2770.99, and R2 was 0.54 (54%). The R2 and AICc of the GWR model was 0.81 (81%) and 2580.84, respectively, where the latter showed a 0.27 (27%) increase in R2 and a decreased AICc. Conclusion These results will assist in planning HIV prevention and intervention strategies. These results will also be used for targeted testing, planning pre-exposure prophylaxis, and access to health care. The results will help plan resource allocation to community-based providers for prevention intervention programs and fund public health programs such as condom distribution, mobile vans, and youth-based sex education.

Background Patients with advanced cervical cancer comprise a high-risk, poor prognostic group. Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target for these patients, though incorporation of the anti-VEGF agent bevacizumab to platinum- and taxane-based chemotherapy (CT) is associated with a modest OS benefit vs CT alone (median OS, 16.8 vs 13.3 mo; hazard ratio, 0.77, 95% CI, 0.62-0.95; P = 0.007; Tewari et al. Lancet. 2017). On the basis of an ORR of 14.3% (95% CI, 7.4-24.1) among 77 pretreated women with PD-L1–positive tumors in the cervical cancer cohort of KEYNOTE-158 (Chung et al. J Clin Oncol. 2019), the PD-1 inhibitor pembrolizumab was granted accelerated approval by the US FDA for patients with PD-L1–positive (combined positive score [CPS] of > 1) cervical cancer who had progressed during or after first-line CT. KEYNOTE-826 (NCT03635567) is a phase 3, randomized, double-blind, multinational study designed to evaluate the efficacy and tolerability of CT with or without pembrolizumab and/or bevacizumab in the first-line setting. Trial design Eligible patients with recurrent, persistent, or metastatic cervical cancer not previously treated with CT in a recurrent or metastatic setting who are not amenable to curative treatment will be randomized 1:1 to CT + pembrolizumab 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification will be performed by metastasis status at diagnosis, planned bevacizumab use (yes/no), and tumor PD-L1 CPS ( Clinical trial identification NCT03635567. Legal entity responsible for the study Merck & Co., Inc. Funding Funding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure K. Fujiwara: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharpe & Dohme Corp.; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Advisory / Consultancy: Takeda; Honoraria (self): Bayer; Honoraria (self): Daiichi Sankyo; Honoraria (self): Janssen Oncology; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Lilly Japan; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Zeria Pharmaceutical; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Kaken Pharmaceutical; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Oncotherapeutics. R. Shapira-Frommer: Honoraria (self): MSD Oncology; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Vascular Biogenics; Advisory / Consultancy: Clovis Oncology. J. Alexandre: Honoraria (self): Roche/Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis ; Honoraria (self): Sanofi/Aventis; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. B. Monk: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Advaxis; Advisory / Consultancy: Agenus; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Conjupro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Gradalis; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Immunomedics; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen/JohnsonJ Advisory / Consultancy: Mateon (formally Oxigene); Advisory / Consultancy: Merck; Advisory / Consultancy: Myriad; Advisory / Consultancy: Perthera; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Precison Oncology. T. Fehm: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer. N. Colombo: Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): TESARO, Inc.; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Takeda; Advisory / Consultancy: TESARO, Inc.; Advisory / Consultancy: BioCad. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy: Merck Sharpe & Dohme Corp.; Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Research grant / Funding (self): Yakult Honsha; Research grant / Funding (self): Pfizer. J.J. Li: Travel / Accommodation / Expenses, Full / Part-time employment: Merck & Co., Inc.; Travel / Accommodation / Expenses, Spouse / Financial dependant: Celgene. K. Stein: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.; Shareholder / Stockholder / Stock options: Novartis. S.M. Keefe: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. K. Tewari: Honoraria (self): TESARO, Inc.; Honoraria (self): Clovis Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Speaker Bureau / Expert testimony: AstraZeneca ; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Morphotek; Research grant / Funding (institution): Regeneron. All other authors have declared no conflicts of interest.

Background Pembro, a PD-1 inhibitor, confers durable benefit in many tumor types but has limited efficacy in non–microsatellite instability–high (MSI-high)/pMMR mCRC. Chemotherapies that include 5-fluorouracil (5-FU), oxaliplatin and irinotecan, which are commonly used to treat mCRC, may modulate intrinsic tumor immunogenicity and sensitize tumors to immunotherapy agents. In the phase 1b KEYNOTE-651 study (NCT03374254), pembro + mFOLFOX7 (cohort B) or pembro + FOLFIRI (cohort D) was evaluated in patients with non–MSI-high/pMMR mCRC. Methods Patients were ≥18 years with non–MSI-high/pMMR mCRC, Eastern Cooperative Oncology Group performance status 0/1, and no prior systemic chemotherapy for stage IV mCRC (cohort B) or 1 prior therapy including a fluoropyrimidine + oxaliplatin-based regimen (cohort D). Patients received pembro 200 mg every 3 weeks (Q3W) + mFOLFOX7 (oxaliplatin [85 mg/m2]; leucovorin [400 mg/m2]; 5-FU [2400 mg/m2]) Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI (irinotecan [180 mg/m2]; leucovorin [400 mg/m2]; 5-FU [2400 mg/m2]) Q2W (cohort D). Primary objectives were safety/tolerability and establishment of the recommended phase 2 dose (RP2D); the secondary objective was objective response rate. Results At data cutoff (Feb 18, 2019), 15 patients in cohort B and 16 in cohort D started treatment; median follow-up was 6.8 months (cohort B) and 5.7 months (cohort D). Treatment was discontinued in 4 patients (27%) in cohort B (adverse event [AE], n = 1 [7%]; PD, n = 3 [20%]) and 9 patients (56%) in cohort D (AEs, PD, patient withdrawal; n = 3 [19%] each). There was 1 dose-limiting toxicity in cohort D: grade 3 small-intestinal obstruction. See RP2Ds for cohorts B and D in the Methods section. All patients had ≥1 treatment-related AE (TRAE). Grade 3 TRAEs occurred in 8 patients each in cohort B (53%) and cohort D (50%), most commonly anemia and neutropenia (13% each) in cohort B and neutropenia, diarrhea, fatigue, and leukopenia (13% each) in cohort D. There were no grade 4-5 TRAEs. Efficacy results will be presented. Conclusions Pembro in combination with mFOLFOX7 or FOLFIRI was safe and tolerable in patients with mCRC. Clinical trial identification NCT03374254; Release date: December 15, 2017. Editorial acknowledgement Jacqueline Kolston, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA); Funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Array BioPharma. Disclosure R. Kim: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Research grant / Funding (institution): Eisai. J. Kortmansky: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche. L. Wong: Research grant / Funding (institution): Astellas Pharma Global Development, Inc./Astellas US, Inc.; Research grant / Funding (institution): BeiGene, Ltd; Research grant / Funding (institution): Exelixis, Inc.; Research grant / Funding (institution): Merck; Research grant / Funding (institution): NovoCure, Inc.; Research grant / Funding (institution): Pierre Fabre Medicament; Research grant / Funding (institution): PledPharma AB; Research grant / Funding (institution): SynCore Biotechnology Co., Ltd.; Research grant / Funding (institution): Halozyme, Inc.; Research grant / Funding (institution): Pharmacyclics, Inc.; Research grant / Funding (institution): TESARO; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Array. M. Tehfe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self): Ipsen; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Taisho. J.J. Li: Full / Part-time employment: Merck & Co., Inc. M. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. C. Mayo: Full / Part-time employment: Merck & Co., Inc. P. Marinello: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. E. Chiorean: Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Halozyme; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Array; Advisory / Consultancy: Five Prime; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Halozyme; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Ignyta/Roche; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Macrogenetics. All other authors have declared no conflicts of interest.

The development of nanotechnology has endowed the light-matter interaction with more degrees of freedom, and made the manipulation of optical phenomena more precise and arbitrary. Fano resonance is a type of resonant scattering phenomenon with asymmetric line profile, which was firstly studied in atomic physics and then introduced to photonics and plasmonics. This phenomenon is due to the interference between a discrete bound state and a continuum state, thus a two-body or few-body system is needed to provide different types of states that are necessary in this phenomenon. Artificial metamaterial is a very good candidate to generate Fano resonances because of its designable configuration. In this paper, a new type of structure—3D folding metamaterial—is introduced for Fano resonance generation and application. The structure, fabricated by focused-ion-beam based folding technique, is composed of planar and out-of-plane parts, which are essential for the excitation of the discrete bound states and continuum states. The intensity, frequency and quality factor of the Fano resonances can be modulated by the configuration of the 3D folding structures (shape, size, inclined angle, etc.), thus enlarges its application potential such as index sensing and surface enhanced Raman scattering.

This study investigated the effects of angiotensin II (AngII) intervention, using captopril and losartan, on the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in rats with pulmonary hypertension, in an effort to understand mechanisms underlying pulmonary vascular remodeling. A total of 40 male Sprague-Dawley rats were randomly divided into normal group, model group, captopril group, and losartan group. After 5 weeks, the mean pulmonary arterial pressure (mPAP), right ventricular index, and neointima formation in each group were determined. Immunohistochemical analysis was performed to determine the degree of pulmonary arterial muscularization as well as MMP-2, MMP-9, and TIMP-1 protein expression in lung tissue. Real-time fluorescent quantitative PCR was used to detect MMP2, MMP9, TIMP1, COL1A1, and COL4A1 mRNA expression. Picro-sirius red staining was performed to detect collagen protein expression. Neointima formation was observed in the model group. Moreover, the mPAP, right ventricular index, degree of arterial muscularization, and collagen deposition, as well as mRNA and protein expression of MMP2, MMP9, and TIMP1 were significantly higher than those in the other groups (P < 0.05). The mPAP, right ventricular index, degree of arterial muscularization, and mRNA and protein expression in the captopril and losartan groups were significantly decreased compared with those of the model group (P < 0.05). AngII regulates MMP-2, MMP-9, and TIMP-1 expression and affects collagen deposition. Thus, this hormone is involved in pulmonary vascular remodeling, indicating a possible mechanism that can be targeted in pulmonary hypertension intervention.

BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3.METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720.FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection.FUNDING: Merck & Co, Inc.

Background There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. Methods Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1–6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [

Summary This paper focuses on the research of a new method to enhance oil recovery in fault-block reservoirs at high water cut stage. Through three-dimensional water flooding experimental analysis and Nuclear Magnetic Resonance (NMR) analysis, the distribution of remaining oil at high water cut stage in fault block reservoir is clarified from macro and micro aspect. Although the development of reservoirs has stepped into the ultra-high water cut stage, there still has a great potential for development with two kinds of remaining oil. One is located on the top of tectonic structures which is hardly swept by water flooding and the fault barrier increases the recovery difficulty of this kind. The other is the highly dispersive residual oil between wells. The paper investigates the whole vertical structural position and presents a new development mode named bidirectional displacement to extract those two kinds of remaining oil: the top structure is for gas injection while the bottom is for water injection, thereby bidirectionally (upper and lower) compensating formation energy for oil displacement in the middle of the structure. In the higher position, we adjust working system by injecting gas from old wells and then force the gas to migrate to the top to displace oil. During this process, a newly formed artificial gas cap is matched with reservoir scale and displaces oil by gas cap expansion energy when the reservoir pressure declines. At the bottom, we convert oil wells with high water cut into water injection wells with wide well spacing and large displacement to form the artificial edge water flood that can re-aggregate the dispersed remaining oil, achieving efficient development of remaining oil in fault-block reservoirs with bidirectional displacement. In this paper, a typical geological model of fault-block reservoirs is built by numerical simulation, and the factors that influence the development effect are discussed by orthogonal experimental design. We obtain the influence of various development and geological factors on bidirectional displacement, optimize the working system at different developmental stages, establish a corresponding matching relationship between production and injection wells for stable development and form the screening criteria for bidirectional displacement.

Localized heating during slip avalanches is relevant to the understanding of the transition from shear banding to cracking in bulk metallic glasses (BMGs). Here we focus on the released elastic energies (incorporating the influence of machine stiffness) and avalanche durations for regularly appearing large avalanches to study the maximum temperature increases of a Zr-based BMG compressed at three strain rates of 3 × 10−5, 3 × 10−4, and 3 × 10−3 s−1. The maximum released elastic energies during slip avalanches decrease with the increase of strain rates. The durations of the avalanches are on the scale of tens of milliseconds for each strain rate. As strain rate increases, the maximum temperature rises due to shear-band slips are decreased from 2.6, 2.3 to 1.9 K. Moderate heating during the large slip avalanches for three strain rate implies that thermal softening has only a small effect on the shear-banding instability.

Intrinsic monolayer graphene has no band gap between its conduction and valence bands, which limits its application in many aspects as a semiconductor. Antidot lattices by constructing periodic holes on graphene have been proved to be an intriguing strategy to introduce a band gap into graphene. Here we used the e-beam lithography (EBL) combined with the oxygen reactive ion etching (RIE) to fabricate tunable antidot lattices with different and uniform regularly spaced holes on graphene. In this way, tunable periodic graphene nanostructures with the dimensions ranging from ∼20 nm to several hundreds of nanometers can be fabricated by controlling exposure dose and etching time.

AIMS Application of autochthonous strain Kocuria rosea KDF3 and its protease KP3 as adjuncts for acceleration of Kedong sufu ripening. METHODS AND RESULTS Kedong sufu was manufactured using autochthonous cultures (batch A), K. rosea KDF3 plus autochthonous cultures (batch B) and protease KP3 plus autochthonous cultures (batch C). The effects of certain key factors on the quality of sufu were analysed during a 150-day ripening period. The physicochemical properties of sufu samples from batches B and C after 120 days of ripening met the national standard requirements and samples from batch A after 150 days of ripening. The sensory evaluations of sufu samples from batches B and C after 120 days of ripening and from batch A after 150 days of ripening showed no significant differences (P > 0·05). Furthermore, the mechanism underlying the shorter ripening time and typical sensory quality of sufu prepared with K. rosea KDF3 or protease KP3 was partly revealed by profiles of peptides and free amino acids. The maturation times of Kedong sufu were shortened by 30 days, and the desired characteristics were obtained by adding K. rosea KDF3 or its protease KP3. CONCLUSIONS Kocuria rosea KDF3 or its protease KP3 can hasten sufu maturation. They could be used as adjuncts or additives for accelerating the ripening of Kedong sufu. SIGNIFICANCE AND IMPACT OF THE STUDY This study is the first report of using autochthonous strain K. rosea KDF3 or its protease KP3 as adjuncts for accelerating Kedong sufu ripening. The results are useful for characterizing the ripening of Kedong sufu, and they lay the foundation for pilot plant tests and full-scale plant tests.

Big Q system of enterprise is a complex management system, which includes several sub-systems, and it suggests that the concept of “Big Q” should be formed in response to the needs of the growing situation through analyzing evolution in quality concept in this paper. Then, the intension and characteristics of big Q synergetic concept are proposed by analyzing the characteristics of the big Q system. Based on these studies, the relationship between the synergetic model of big Q and environment is explored, and the synergetic mechanism of the Big Q system is dissected by means of mathematical analysis. To be effective, the big quality system must be studied deeply. By applying the theory of self-organizing to study the big quality system, we can generalize features, characteristics and operation rules of the big quality system. So we can manage the big quality system scientifically and effectively to obtain an optimal function of the system.

The superelasticity of a β Ti alloy, Ti–7.5Nb–4Mo–2Sn (in atom percent) was evaluated by using loading and unloading cyclic tensile tests under different thermomechanical conditions, and the effects of the plastic deformation, temperature, strain rate and cyclic loading on the superelasticity of the alloy were studied. It is found that, with the applied strain increasing, the stress inducing the reverse martensitic transformation σ α″−β and the strain recovery rate η decreases. The increase of deformation temperature promotes σ β−α″ , σ α″−β and Δ σ , and the temperature dependency of the stresses obeys the Clausius–Clapeyron relation. σ β−α″ , σ α″−β and Δ σ are independent on the strain rate when it is lower than 8.35×10 −4 s −1 . However, when the strain rate is higher than 8.35×10 −4 s −1 , σ β−α″ and Δ σ increase, but σ α″−β decreased with increasing the strain rate. By cyclic loading and unloading to the maximum strain of 6% at 25 °C under the strain rate of 1.67×10 −4 s −1 , the alloy exhibits a improved superelasticity after seventh cycles due to the training effect.

The effect of ternary alloying elements (X=Ta, Fe, Zr, Mo, Sn and Si) on the microstructure, the mechanical properties and the superelasticity of Ti–-22Nb–X alloys were investigated. The 1% addition of a ternary alloying element (X=Ta, Fe, Zr, Mo, Sn and Si) has a slight influence on the microstructure of the Ti–22Nb alloy. All the alloys after solution-treatment at 1073 K for 1.8 ks contain β and α″ phases. The elements of Sn, Si, Fe and Ta with a high number of valence electrons or a small atomic size have a strong solid–solution strengthening effect to the β phases in the alloys and the alloys with high M d ¯ and low B o ¯ exhibit low elastic moduli. All the alloying elements improve the superelasticity of Ti–22Nb–X alloys. The elements, Fe, Mo, Sn and Si, which are with a high number of valence electrons and a small atomic size, strongly increase σSIM of the Ti–22Nb alloy.