Search

Outline of the source, purification, synthesis process, physical and chemical properties, intervention to disease and improvement of activity of nattokinase.

Unstable foot-and-mouth disease virus particles were armored with nano-sized crystalline ZIF-8 by an elaborately manipulated biomineralization reaction and showed improved immune responses.

Ferritin nanoparticles with self-assembling properties have been widely explored as vaccine carrier by displaying foreign antigens through genetic fusion strategy. In the present work, an apoferritin (AFt) nanoparticle was tested as influenza vaccine carrier by chemically conjugating a matrix protein 2 ectodomain (M2e) antigen peptide or/and the full-length hemagglutinin (HA) antigen on the outer surface of the AFt, with heterobifunctional sSMCC or SM(PEG)24 containing PEG chain as linkers. To each AFt nanoparticle, about 30-32 M2e or 1.8 HA antigen could be coupled. The AFt-(PEG)24-M2e, in which the M2e was coupled through SM(PEG)24 containing PEG chain, conferred higher protective efficacy in immunized mice than AFt-M2e did, but was less effective than AFt-(PEG)24-HA. When both M2e and HA were coupled, the synthesized dual-antigen vaccine candidate AFt-(PEG)24-M2e/HA elicited high level of M2e and HA antigen-specific antibodies and conferred 100% protection against lethal infection of homologous PR8 H1N1 virus strain and 70% protection against a heterologous A/FM/1/47 (FM1, H1N1) strain, which was more effective than the M2e or HA single antigen vaccine candidates. The potential cross-protective effect of the dual-antigen vaccine was further demonstrated by significant specific hemagglutination inhibition (HAI) titers in serum of the immunized mice against three other heterologous viral strains including A/Singapore/GP1908/2015 (IVR-180) H1N1, A/Anhui/1/2005 H5N1, and A/Hong Kong H3N2.

SARS-CoV-2 has demonstrated extraordinary ability to evade antibody immunity by antigenic drift. Small molecule drugs may provide effective therapy while being part of a solution to circumvent SARS-CoV-2 immune escape. In this study we report an α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), RAY1216. Enzyme inhibition kinetic analysis established that RAY1216 is a slow-tight inhibitor with aKi of 8.6 nM; RAY1216 has a drug-target residence time of 104 min compared to 9 min of PF-07321332 (nirmatrelvir), the antiviral component in Paxlovid, suggesting that RAY1216 is approximately 12 times slower to dissociate from the protease-inhibitor complex compared to PF-07321332. Crystal structure of SARS-CoV-2 Mpro:RAY1216 complex demonstrates that RAY1216 is covalently attached to the catalytic Cys145 through the α-ketoamide warhead; more extensive interactions are identified between bound RAY1216 and Mproactive site compared to PF-07321332, consistent with a more stable acyl-enzyme inhibition complex for RAY1216. In cell culture and human ACE2 transgenic mouse models, RAY1216 demonstrates comparable antiviral activities towards different SARS-CoV-2 virus variants compared to PF-07321332. Improvement in pharmacokinetics has been observed for RAY1216 over PF-07321332 in various animal models, which may allow RAY1216 to be used without ritonavir. RAY1216 is currently undergoing phase III clinical trials (https://clinicaltrials.gov/ct2/show/NCT05620160) to test real-world therapeutic efficacy against COVID-19.

Introduction To compare the cost-effectiveness of vedolizumab with that of conventional therapy in patients with moderate-to-severe active Crohn’s disease (CD) in China. Methods A decision tree and Markov model were built to predict the lifetime cost and health outcomes in the induction phase and maintenance phase of vedolizumab treatment and conventional therapy (a combination of corticosteroids, immunosuppressants, and aminosalicylates) in adult patients with moderate-to-severe active CD from the perspective of China’s healthcare system. Clinical efficacy and health utility were derived from the GEMINI 2 and GEMINI 3 trials and published literature. Costs were mainly obtained from clinical physician surveys in China and are presented in 2020 US dollars. Health outcomes (quality-adjusted life years, QALYs) and costs were discounted at an annual rate of 5%. The incremental cost per QALY gained was used to compare the cost-effectiveness of the two treatments. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the model. Results The model predicted more QALYs (9.92 vs 9.00 QALYs) and lower incurred costs ($288,284 vs $309,680) in vedolizumab than in conventional therapy in a mixed population (anti-TNF-naïve and anti-TNF-failure populations) over a lifetime horizon in the base-case analysis. Similar results were observed in the anti-TNF-naïve and anti-TNF-failure subgroups of patients with CD. One-way sensitivity analysis results suggested that health state cost was the most influential factor in the model. The PSA results supported the dominance of vedolizumab in the base-case analysis. Conclusion Vedolizumab appears to be a cost-effective strategy option in the treatment of adult patients with moderate-to-severe active CD in China in both anti-TNF-naïve and anti-TNF-failure populations. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01806-7.

The paper explores the performance of face-threatening speech acts by Chinese and Japanese in BELF emails, focusing on the genre structure and the linguistic realizations of mitigation. Based on a corpus of 469 emails, the study identifies a five-move structure, i.e., openings + reasoning supportive moves (RSMs) + head acts + mitigating supportive moves (MSMs) + closings, for performing FTAs in business emails and finds that the major difference between Chinese and Japanese move structures lies in that Chinese tend to use more MSMs than Japanese. Both Chinese and Japanese exhibit a preference for the “RSMs + head acts” sequential pattern. In terms of the mitigating devices in MSMs, Chinese demonstrate a preference for the expression of gratitude as a mitigating strategy while Japanese prefer to use tag questions and apologies. The findings of the research can be explained from the perspectives of mode of thinking, language education and cultural identities. The study aims to shed some light on BELF communication by raising our awareness of certain taken-for-granted patterns in email interactions between two seemingly similar cultures to avoid possible communicative breakdown. In addition, the paper offers some pedagogical implications for business English teaching.

Maintaining structural integrity and enhancing stability of inactivated foot-and-mouth disease virus (iFMDV) antigen in adjuvants is crucial to ensure the vaccine potency. Unfortunately, formulation with most reported adjuvants leads to the accelerated dissociation of iFMDV into inactive pentamers. Here, an ionic liquid, i.e., choline and niacin ([Cho][Nic]), which was found to stabilize iFMDV against the acid- and thermo- induced dissociation in buffer solution, was applied to construct a novel oil-in-ionic liquid (o/IL) nanoemulsion adjuvant composed of [Cho][Nic], squalene, and Tween 80. The o/IL nanoemulsion formulated with iFMDV has a monodisperse diameter of 135.8 ± 40.4 nm. The thermostability and long-term stability of iFMDV were remarkably enhanced in o/IL nanoemulsion compared with that in the o/w emulsion without [Cho][Nic] and in the commercial Montanide ISA 206 adjuvant. The o/IL nanoemulsion exerted its adjuvant effects by improving the humoral immune responses. Immunization of o/IL nanoemulsion adjuvanted iFMDV induced specific IgG titers similar to that adjuvanted by Montanide ISA 206 and about 4-fold higher than the un-adjuvanted iFMDV, also promoted the activation of B lymphocytes and the secretion of interleukin-4 in the mice model. This [Cho][Nic]-based o/IL nanoemulsion can serve as a promising adjuvant platform for the foot-and-mouth disease vaccine.

Effective antigen delivery and immune stimulation in nasal mucosa determine the success of mucosal immunity. Here, an oil-in-ionic liquid (o/IL) nanoemulsion formulated with choline and niacin IL ([Cho][Nic]), squalene, and Tween 80 surfactant is explored as a vaccine delivery system for intranasal mucosal immunization. Compared to the o/w emulsion counterpart without the ILs, the o/IL manoemulsion showed a reduced and more uniform size of approximately 168 nm and significantly improved stability. Studies in mice model showed that when was used as an intranasal vaccine delivery system for influenza split-virus antigens, the antigens in the o/IL nanoemulsion induced strong mucosal immune responses with secretory IgA titers 25- and 5.8-fold higher than those of naked and commercial MF59-adjuvanted antigens, respectively. The o/IL nanoemulsion system also induced stronger systemic humoral responses. The excellent mucosal adjuvant effects of the o/IL nanoemulsion mainly benefited from the prolonged retention of antigens in the nasal cavity, enhanced antigen permeation into the submucosa, and the consequently promoted proliferation of CD11b cells and CD4

Objective: To evaluate the cost effectiveness of vedolizumab vs. infliximab in the treatment of anti-tumor necrosis factor-alpha (TNF-α)-naïve patients with moderate-to-severe active ulcerative colitis (UC) in China.Methods: The costs and effectiveness of vedolizumab and infliximab in the treatment of anti-TNF-α naïve patients with moderate-to-severe active UC were compared using a hybrid decision tree model and a Markov model. From the perspective of the Chinese healthcare system, this study simulated the lifetime health benefits [quality-adjusted life-years (QALYs)] and costs (USD) for patients with UC from the induction phase to the maintenance phase, with an annual discount rate of 5%. The clinical efficacy and transition probability data were based on a previously published network meta-analysis. The health utility, surgical risk, biologic drug discontinuation rate, and mortality were derived from previous literature and the Chinese statistical yearbook. The cost data were based on China's drug purchase and biding platform and the results of a survey sent to clinicians in 18 tertiary hospitals. One-way and probabilistic sensitivity analyses (PSAs) were performed to validate the robustness of the models' assumptions and specific parameter estimates.Results: The results of the base-case analyses showed that compared with infliximab, vedolizumab led to a gain of 0.25 QALYs (9.56 vs. 9.31 QALYs) and was less expensive by $7,349 ($180,138 vs. 187,487), indicating that the use of vedolizumab was a dominant strategy. The results of one-way sensitivity analyses suggested that the annual discount rate and health-state costs had the greatest impact, but the results were otherwise consistent with those of the base-case analyses. The PSAs suggested that vedolizumab had a 98.6% probability of being effective at a threshold of 3 times the gross domestic product (GDP) per capita in China in 2020.Conclusion: Compared with infliximab, vedolizumab appears to be a more cost-effective option in the treatment of anti-TNF-α naïve adult patients with moderate-to-severe, active UC in China.

To assess the cost-effectiveness of alectinib versus crizotinib as first-line treatments for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients from the perspective of China’s healthcare system. A Markov model was developed to assess the clinical outcomes and costs of alectinib and crizotinib, which included five health states: progression-free (PF) without central nervous system (CNS) progression, PF with CNS progression, post-progression (PP) without CNS progression, PP with CNS progression, and death. Clinical data for transition probabilities were obtained from the ALEX trial at the updated data cutoff. Healthcare resource utilization and costs were derived from clinical expert opinions and published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the results. Scenario analyses were conducted including using clinical data from the ALESIA trial in Asian patients, using utilities from the ALEX trial, and choosing different parametric survival models. In base case analysis, alectinib yielded an additional 1.04 quality-adjusted life years (QALYs) with incremental costs of $54,827, resulting in an incremental cost-effectiveness ratio (ICER) of $52,869/QALY. In scenario analysis, the ICER was $56,787/QALY using clinical data from the ALESIA trial. In probabilistic sensitivity analysis, the probabilities of alectinib being cost-effective were 0.4% and 43.7% when the willingness-to-pay (WTP) thresholds were $28,109/QALY and $50,000/QALY, respectively. Alectinib could prolong the mean time of PF and delay the time to CNS progression. However, because of its high drug cost, alectinib was unlikely to be cost-effective for untreated ALK-positive NSCLC patients in China.

The ultrasonic transmission monitoring in risers is a promising method for the early detection of gas kick in deepwater drilling. It is difficult to obtain satisfactory results using only theoretical calculation because the ultrasonic wave propagation in the multiphase flow in risers is very complicated. In addition, the key parameters such as bubble shape and void fraction of two-phase flow are hard to be accurately controlled and measured. In view of the above-mentioned facts, this paper aims to analyze the principle and physical model of ultrasonic monitoring of gas kick in risers, and to establish a numerical simulation model based on COMSOL platform. Through an analysis of the numerical simulation results, it was found that the time domain diagram of the received signals contains longitudinal wave, transverse wave, surface wave and coda wave. The cross-correlation function was used to quantitatively analyze the waveform of the received signals under different void fraction conditions. It also suggested that the direct wave was insensitive to the void fraction while the coda wave was sensitive to the void fraction, which was verified through frequency domain analysis. By establishing the experimental system, the attenuation coefficient was used to verify the numerical simulation results. After comparing and analyzing data, this paper argued that the numerical simulation method established in the project can be used as an effective supplement to experiments, and it can be used to calculate and analyze the ultrasonic propagation and attenuation under conditions, such as different bubble sizes and densities, and bubble non-uniform distribution, which can not be accurately and quantitatively measured or controlled in the experiments.

BACKGROUND: Proton pump inhibitors (PPIs) have been recommended as standard of care for reflux esophagitis (RE). Vonoprazan (VPZ), a novel potassium-competitive acid blocker (P-CAB), has been approved in China after demonstrating clinical benefit in RE. However, there are not any published literature reported the cost-effectiveness of VPZ compared with PPI in Chinese healthcare setting. Thus, this study aimed to estimate the cost-effectiveness of VPZ compared with PPIs for the treatment of RE patients in China and take advantage of this result to inform healthcare decision-making. METHODS: A Markov model was developed to predict the effectiveness and costs of VPZ for 4 weeks and PPI group for 8 weeks in RE treatment over a 5-year time horizon from a healthcare system perspective. Four health states within healing and maintenance phases were defined in the model: mucosa healed, mucosa unhealed, relapse, and death. Transition probabilities including healing rate and relapse rate were derived from a single-arm meta-analysis and mortality were obtained from Chinese life table. Drug costs and other medical expenses were retrieved from China tendering prices and local clinical expert estimation. Utility parameters were derived from published literature. Both health outcomes and costs were discounted at a rate of 5% annually. Quality-adjusted life years (QALYs), direct medical costs and incremental cost-effectiveness ratios were evaluated. Uncertainty was assessed by one-way and probabilistic sensitivity analysis (PSA). RESULTS: The healing rate for VPZ and PPI were 90% (95% CI: 82–97%) and 74% (95% CI: 71–76%) at week 4 respectively and were 94% (95% CI: 88–99%) and 87% (95% CI: 85–88%) at week 8 respectively. Treatment with VPZ resulted in 4.35 QALYs at a total cost of USD 1,354 over 5 years. Compared with the PPI group, treating RE with VPZ was associated with 0.02 QALYs gained and a cost saving of USD 943. Thus, VPZ should be considered as the dominant treatment option. The model results were deemed robust in sensitivity analyses. CONCLUSIONS: VPZ generates incremental QALYs at a lower cost compared with PPI, thus could be considered as an optional choice in the treatment of patients with RE.

Borehole ballooning is a special phenomenon observed during drilling operations in the formation with a narrow safe density window. This phenomenon is easy to be confused with well kick. This study...

In deepwater drilling, the subsea wellhead is in a complicated stress state and carries the risk of instability. The mechanical stability of subsea wellhead has gradually become one of the key factors in the design and construction of deepwater drilling. In this paper, through the analysis of stress and deformation of subsea wellhead system in deepwater drilling, the characteristic parameters that characterize the mechanical stability of subsea wellhead were determined. On this basis, the influence of different factors on characteristic parameters was analyzed based on dimensionless processing and sensitivity analysis. Factors that were more sensitive and had greater impact on the wellhead mechanical stability of the instance well were screened. Aiming at the problem of greater uncertainty of resistance coefficient, the risk assessment method of subsea wellhead instability considering of uncertain factors was established. Using this method, the wellhead instability risks could be quantitatively evaluated in the drilling process, construction parameters and monitoring values of environmental loads which meet the wellhead safety requirements that could also be proposed. Example shows that: according to the selected parameters such as center value of drag coefficient $$\mu = 0.8$$ , fluctuation coefficient of drag coefficient $$\sigma = 0.05$$ , safety limit of subsea wellhead displacement $$S_{\mathrm{wm}} = 0.37\,\hbox {m}$$ , and safety limit of subsea wellhead deflection angle $$\theta _{\mathrm{wm}} = 3.1{^{\circ }}$$ , there was 24% probability of occurrence of wellhead instability for the target well. Meanwhile, the platform drift $$S_{\mathrm{w}}$$ should be

Nowadays, the oil and gas exploration and development have been developed into the deep and complex formations. More and more abnormal pressure is encountered, which gives a great challenge to the safe and efficient drilling. Accurate description of pore pressure is of great significance to avoid drilling risk. The complexity of petroleum geology, the incompleteness of the logging or seismic data, the precision of the mathematical model and other issues can all lead to uncertainty in pore pressure prediction. The uncertainty of pore pressure is one of the fundamental causes for drilling risk. In order to address these challenges, a new quantitative description method for uncertainty of pore pressure was established. Firstly the sources of the pore pressure prediction uncertainty were analyzed. Then the uncertainties of Eaton index and normal compaction trend were, respectively, described. Finally the uncertainty interval of pore pressure was established based on Monte–Carlo simulation and normal information diffusion theory. The pore pressure prediction result obtained in this paper was not a single value, but an interval with probability distribution characteristic. The results of example showed that the measured values of pore pressure were all in pore pressure interval with confidence of 90%. Case study validated the feasibility and effectiveness of the proposed method.

Virus-like particles (VLPs) holding internal cavity with diameter from tens up to one hundred nanometers are attractive platform for drug delivery. Nevertheless, the packing of drugs in the nanocage mainly relies on complicated disassembly-reassembly process. In this study, hepatitis B core protein (HBc) VLPs which can withstand temperature up to 90 °C was employed as carrier to load a lipophilic near infrared dye IR780. It was found that an attaching-dis-atching-diffusing process was involved for the entering of IR780 in the cavity of HBc. The first two steps were associated with the electrostatic interactions between oppositely charged HBc and IR780, which was critically manipulated by ionic strength and HBc/IR780 mass ratio at which they were mixed; while the diffusion of IR780 across the shell of HBc showed a temperature-dependent manner that can be triggered by thermal induced pore-opening of the HBc capsid. At optimized condition, about 1055 IR780 molecules were encapsulated in each HBc by simply mixing them for 10 min at 60 °C. Compared with free IR780, the HBc-IR780 particles showed significantly improved aqueous and photostability, as well as enhanced photothermal and photodynamic performance for cancer therapy. This study provides a novel drug loading strategy and nanomemedicine for cancer phototherapies.

It is one of the important technical difficulties to improve the cementing sealing capacity of the carbon dioxide (CO2) injection well for ensuring the long-term effective of the CO2 geological storage. The two experiments with and without protective layer were conducted under the conditions of 10 MPa confining pressure and 70 °C environmental temperature. The casing pressure gradually increased from 10 MPa, and the channeling detection pressure was 10 MPa. According to the physical properties of the materials and the environment conditions applied in the experiments, two 2D finite element models of casing-cement-formation system for these two experiments were built respectively, and the failure modes of the cement sheaths in the experiments were analyzed. As shown in the experiments, the maximum casing pressure that the cement sheath in the experiment with protective layer can bear is 19.4 MPa higher than that of another experiment. According to the finite element analysis, the maximum Von-Mises stress of the cement sheaths had all not reached the yield strength of 15.2 MPa before failed, thus no plastic deformation or micro-annulus had occurred. During the casing pressure in these two experiments increasing from 40 MPa to 50 MPa and from 20 MPa to 30 MPa respectively, the cement sheaths begin to produce tensile failure. If ignoring the actual failures of the cement sheaths and continuously increasing the casing pressure in the finite element analysis, the cement sheathes in the two models will produce plastic deformation when the casing pressure reaching 93 MPa and 57 MPa respectively. Therefore, this preventive measure is effective to protect the cementing sealing integrity of CO2 injection well.

Purpose To assess the cost-effectiveness of osimertinib used as a second-line treatment after failure of epidermal growth factor receptor tyrosine kinase inhibitor therapy for advanced non–small cell lung cancer (NSCLC) in China. Methods From the perspective of China's health care system, a Markov model was used for estimating the costs and health outcomes of osimertinib and 4 platinum-based chemotherapies, including pemetrexed + platinum (PP), gemcitabine + platinum (GP), docetaxel + platinum (DP), and paclitaxel + platinum (TP). Two scenarios were considered, one in all confirmed patients with T790M-positive disease (scenario 1) and the other in all patients whose disease progressed after epidermal growth factor receptor tyrosine kinase inhibitor therapy, which consisted of patients with T790M-positive or T790M-negative NSCLC (scenario 2). Clinical data for transition probabilities and treatment effects were obtained from published clinical trials. Health care resource utilization and costs were derived from local administrative databases and published literature. Deterministic and probabilistic sensitivity analyses were conducted to assess the uncertainty of the results. Findings In the base-case analysis, compared with the 4 platinum-based chemotherapies, osimertinib yielded an additional 0.671 to 0.846 quality-adjusted life-year (QALY), with incremental costs of 15,943 to 20,299 USD in scenario 1, and an additional 0.376 to 0.808 QALY with incremental costs of 9710 to 15,407 USD in scenario 2. In the probabilistic sensitivity analysis, the probabilities that osimertinib would be cost-effective were 57.7% in scenario 1 and 58.4% in scenario 2 if the willingness-to-pay threshold were 30,000 USD/QALY, and probabilities would be more than 75 % in both scenarios if the willingness-to-pay threshold were 50,000 USD/QALY. Implications Osimertinib is likely to be cost-effective when used as a second-line treatment of advanced NSCLC in China based on the latest reimbursement price of osimertinib through National Reimbursement Drug List negotiation.

Deepwater oil and gas wells will generate annular pressure due to the redistribution of wellbore temperature in production stage when the hyper-thermal fluid is lifted from reservoir formation. Annular pressure threatens casing integrity and well safety. Related accidents have been reported in Mexico Gulf, South China Sea and some other deepwater oilfield. The analysis indicates that annular pressure buildup is so high that deepwater well is in the risk of casing collapse, so it is necessary to take some measures to mitigate annular pressure. Since subsea wellhead is unable to release pressure, appropriate completion measures must be considered. Good understanding of mechanism as well as accurate calculation is prerequisite for appropriate completion, so a model is built based on comprehensive consideration of multi-string interaction and heat transfer process to offer basic pressure data for well completion. According to Annular Pressure Build-up mechanism, pressure can be controlled by releasing expanded liquid out or getting extra space to accommodate liquid as well as slowing down increasing speed of annular liquid temperature. Some completion technologies can work as mitigation measures. These mitigation methods can be divided into two types: active and passive. Active methods function through increasing heat-transfer resistance or eliminating annulus, including full-height cementing, heat-insulated liquid, thermal-insulated pipes and reducing production rate. Passive methods mitigate pressure build-up by releasing some extra space to contain expanded fluid, including cement shortfall, rupture disc, compressible foam and highly compressible annular fluid. These measures differs at cost, operating difficulty, reliability and working mechanism. Among them, thermal-insulated Pipes, heat-insulated liquid, compressible foam, rupture disc, increase the annular liquid compressibility possess good applicability and have been applied in some wells or tested through experiments. Considering deepwater wells' structure, this paper analyzes the feasible measures and offer design methods.