Technological progress and coupling renewables enable substantial environmental and economic benefits from coal-to-olefins.

China's growing demand for bulk chemicals and concerns regarding energy security are scaling up coal-to-olefins (CTO) production. Three generations of independent dimethyl ether/methanol-to-olefins technologies have been successively launched with greatly improved production efficiencies. However, to date, widespread concerns regarding the intensive environmental impacts and potential economic risks have not been addressed in the context of this industrialization. Here we show that, through the technological progress from the first to the third generation, life cycle energy consumption, water consumption, and carbon emissions can be reduced to 119.5 GJ/t, 27.6 t/t, and 9.1 t CO2-eq/t, respectively, and human health damage, ecosystem quality damage, and resource scarcity impacts can be decreased by 40.5 %, 50.1 %, and 16.4 %, respectively. This is accompanied by an excellent performance in terms of production cost, net present value, and internal return rate at 792.5 USD/t, 173.4 USD/t, and 19.4 %, respectively. Substantial environmental and economic benefits can be gained by coupling renewables in the form of using green hydrogen from solar and wind power to synthesize methanol. Particularly, life cycle carbon emissions and resource scarcity impacts are reduced by 23.4 % and 22.4 %, respectively, exceeding the reduction in technological progress. However, coupling renewables increases the life cycle energy consumption to 154.5 GJ/t, counteracting the benefits of technological progress. Our results highlight the importance of technological progress and coupled renewables for enhancing the sustainability of the CTO industry.

Cost-Effectiveness Analysis of Fixed-Dose Tiotropium/Olodaterol versus Tiotropium for COPD Patients in China.

Purpose: Tiotropium/olodaterol (TIO/OLO) fixed-dose combination (FDC) can improve lung function and quality of life for patients with chronic obstructive pulmonary disease (COPD), and is not inferior to other LAMA/LABAs. The aim of this study was to assess the cost-effectiveness of TIO/OLO FDC in patients with moderate to very severe COPD in China. Methods: A Markov model was developed to estimate the cost-effectiveness of TIO/OLO FDC versus TIO in the treatment of COPD from Chinese health system perspective. Four health states were based on 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021), which included moderate (GOLD II, 50% ≤ FEV1 ≤ 80% of predicted), severe (GOLD III, 30% ≤ FEV1 ≤ 50% of predicted) and very severe (GOLD IV, FEV1 > 30% of predicted) COPD and death. The model simulated in cycles yearly. The indicators of total costs, number of COPD exacerbations, life years (LYs) and quality-adjusted life-years (QALYs) were used as the model output. Costs and outcomes were discounted at a 5% annual rate. A cost-effectiveness analysis was conducted over a 10-year time horizon. The threshold of incremental total cost per unit effectiveness gained (ICER) was 1.5 times of GDP per capita. Uncertainty was assessed by one-way and probabilistic sensitivity analysis. Results: TIO/OLO was 0.007 QALYs more than TIO but 0.012 LYs lower, which increased the total cost by $2268.17 per patient, but the total exacerbations number was less. Incremental cost effectiveness analysis had shown that the ICER exceeded the willingness to pay threshold. Results were robust under most parameter variation, except the parameters of total drug cost of TIO/OLO FDC in univariate sensitivity analyses. Conclusion: Although TIO/OLO FDC could reduce the exacerbation risk, it was not cost-effective, and needed to be repriced.

Evaluation of Human Settlement Environment and Identification of Development Barriers Based on the Ecological Niche Theory: A Case Study of Northern Shaanxi, China.

The quality of human settlement environment (HSE) is related to people's well-being. Since the implementation of the Western Development Strategy and the Grain to Green Program, the HSE in northern Shaanxi has undergone a major transformation. In order to explore the evolution pattern and seek a coordinated development strategy for all systems in the whole region, this paper, from the perspective of "production-living-ecological", evaluates the HSE niche breadth of northern Shaanxi based on the ecological niche theory, analyzes its spatial differentiation characteristics, and identifies the development barrier factors, with the help of ArcGIS spatial analysis tools and the barrier degree model. It is found that: from 2000 to 2020, (1) the niche breadth of HSE in northern Shaanxi is high in the north and low in the south, showing obvious spatial unevenness; (2) the development of transportation promotes the improvement of HSE, but also intensifies the spatial unevenness, and the uncoordinated development rate of transportation and production and living systems has seriously restricted the further development of HSE; (3) the niche breadth of the ecosystem for each county is much lower than that of the production and living systems, and the ecological environment becomes the short board of the improvement of HSE in northern Shaanxi. Based on the patterns and problems found in the study, this paper proposes a strategy to improve the HSE of northern Shaanxi by prioritizing the balanced development of production, living systems, and transportation, strictly implementing the concept of ecological priority, dynamically adjusting the hierarchy of policies, vigorously optimizing the industrial layout, and focusing on the joint improvement of the human settlement environment in the whole region. This study expands the theories and evaluation methods of HSE to a certain extent, and the results have guiding values for promoting the sustainable development of HSE in northern Shaanxi and even the whole Loess Plateau region.

Drug repurposing strategy II: from approved drugs to agri-fungicide leads.

Epidemic diseases of crops caused by fungi deeply affected the course of human history and processed a major restriction on social and economic development. However, with the enormous misuse of existing antimicrobial drugs, an increasing number of fungi have developed serious resistance to them, making the diseases caused by pathogenic fungi even more challenging to control. Drug repurposing is an attractive alternative, it requires less time and investment in the drug development process than traditional R&D strategies. In this work, we screened 600 existing commercially available drugs, some of which had previously unknown activity against pathogenic fungi. From the primary screen at a fixed concentration of 100 µg/mL, 120, 162, 167, 85, 102, and 82 drugs were found to be effective against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, Phytophthora capsici, Fusarium graminearum and Fusarium oxysporum, respectively. They were divided into nine groups lead compounds, including quinoline alkaloids, benzimidazoles/carbamate esters, azoles, isothiazoles, pyrimidines, pyridines, piperidines/piperazines, ionic liquids and miscellaneous group, and simple structure-activity relationship analysis was carried out. Comparison with fungicides to identify the most promising drugs or lead structures for the development of new antifungal agents in agriculture.

Prevalence of hypertension in Shenzhen, China: a population-based, cross-sectional study.

OBJECTIVE: Hypertension (HTN) is an important public health issue worldwide, associated with the rapid economic development and urbanisation over the last decades. This is especially the case in Shenzhen, which has benefited greatly from the reform and opening-up policies. However, there is limited information on the epidemiology of HTN in this region. This study was designed to investigate the prevalence, awareness, treatment and control of HTN and the associated factors among adult residents in Shenzhen, China. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Through the multistage stratified random sampling method, a representative sample of 10 043 urban population aged ≥18 years were selected. Three consecutive blood pressure (BP) readings were measured after resting for a 5 min seat by trained staff and HTN was defined as mean systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg and/or self-reported current use of antihypertensive drugs. Participants were interviewed using a structured questionnaire. Anthropometric details, BP, blood and urine samples were also collected. PRIMARY OUTCOME MEASURE: Prevalence of HTN. RESULTS: Overall, the weighted prevalence of HTN among residents in Shenzhen was 19.2% (95% CI 18.5 to 20.0). Among patients with HTN, 55.0% (95% CI 52.9 to 57.1) were aware of their condition and 44.9% (95% CI 42.8 to 47.1) were taking antihypertensive medications, but only 21.7% (95% CI 20.0 to 23.5) achieved BP control. Among those who knew their HTN, 81.7% (95% CI 79.3 to 83.8) were under treatment and 48.3% (95% CI 45.1 to 51.5) were controlled among those with treated HTN. Male, older age, lower educational level, overweight and obesity, family history of HTN, tobacco smoking, alcohol intake, diabetes mellitus, dyslipidaemia and high uric acid were associated with HTN. CONCLUSIONS: HTN is a major public health concern in Shenzhen, which has low awareness, treatment and control rates, and is associated with several risk factors. Effective multifaceted implementation strategies are highly needed to combat the emerging burden of HTN.

Cost-Effectiveness of Umeclidinium/Vilanterol versus Salmeterol/Fluticasone in Elderly Patients with Chronic Obstructive Pulmonary Diseases in China.

Background: Fixed dose dual bronchodilators such as long-acting muscarinic antagonists (LAMAs) plus long-acting ß2-agonists (LABAs) are a new and important inhaled preparation for COPD treatment in China. Among these, umeclidinium/vilanterol (UMEC/VIL) is increasingly being used in China, especially among the elderly. Purpose: This study aimed to assess the cost-effectiveness of maintenance treatment with UMEC/VIL compared with salmeterol/fluticasone (FSC) as one of the main therapeutic drugs for moderate to very severe COPD in China. Methods: A Markov model was developed to estimate the costs and outcomes from a societal perspective in a 10-year time horizon. Patients with moderate-to-very severe COPD were treated with UMEC/VIL (62.5/25µg) or FSC (50/500ug). Data concerning clinical efficacy, costs, utilities, transition probability, exacerbation rate, and mortality were obtained from the published literature and official government datasets. The costs were presented in US dollars based on 2021 prices. The indicators of total costs, life years (LYs), quality-adjusted life-years (QALYs), and mortality were used as the model output. Costs and outcomes were discounted at a 5% annual rate. Incremental cost-effectiveness ratios were calculated considering the threshold recommended by WHO. One-way and probabilistic sensitivity analyses were conducted to assess the stability of results. Results: Compared with FSC, treatment with UMEC/VIL could save $1947.18, with a gain of 0.12 life-years and 0.05 QALYs. Further, 28.0% patients treated with UMEC/VIL and 29.2% patients treated with FSC were predicted to die after 10 years. Incremental cost effectiveness analysis showed that UMEC/VIL was dominant to FSC. Sensitivity analyses confirmed that the results were robust. Conclusion: UMEC/VIL is a cost-effective treatment option compared with FSC among patients with moderate-to-very severe COPD.

Population Pharmacokinetics Analysis and Dosing Simulations Of Meropenem in Critically Ill Patients with Pulmonary Infection.

PURPOSE: This study aimed to develop a population pharmacokinetic (PPK) model for meropenem to optimize dosing regimens for critically ill patients with pulmonary infection. PATIENTS AND METHODS: This prospective PPK study of meropenem was conducted on a pooled dataset of 236 blood samples obtained from 48 patients with pulmonary infection in the intensive care unit. Meropenem plasma concentrations were measured by a validated high-performance liquid chromatography-tandem mass spectrometry method, and the data were analyzed using NONMEM. The effect of covariates on meropenem pharmacokinetics was investigated. The probability of target attainment (PTA) to achieve the target of 100% fT>MIC at the proposed dosage regimens were investigated by Monte Carlo simulations. RESULTS: A two-compartment model adequately described the data with estimated glomerular filtration rate (eGFR) as a covariate significantly associated with the clearance (CL) from the central compartment. The typical value of CL was 7.48 L/h, with an eGFR adjustment factor of 0.0103 mL•1.73 m2/min, and the typical values of volume of the central compartment (V1), peripheral compartmental clearance (Q), and volume of the peripheral compartment (V2) were 15.9 L, 15.8 L/h, and 14.8 L, respectively. The goodness-of-fit plots, normalized prediction distribution error, and visual predictive checks showed good fitting and predictability of the final PPK model. When eGFR was >90 mL/min/1.73 m2, and there was a short duration of infusion (<60min), it was difficult for the probability target attainment (PTA) to reach >90% for MIC ≥ 2. Continuous infusion and frequent administration were necessary to achieve the target of 100% fT>MIC for critically ill patients with pulmonary infection. CONCLUSION: To achieve the optimal PTA, meropenem must be administered by frequent administration or continuously by an intravenous infusion. Our findings provide important information to optimize the meropenem regime in critically ill patients with pulmonary infection depending on eGFR values.

Pharmacokinetics of Linezolid Dose Adjustment for Creatinine Clearance in Critically Ill Patients: A Multicenter, Prospective, Open-Label, Observational Study.

PURPOSE: The aim of this study is to use a population pharmacokinetic (PK) approach to evaluate the optimal dosing strategy for linezolid (LNZ) in critically ill patients. METHODS: This multicenter, prospective, open-label, observational study was conducted in 152 patients, and 117 of them were included in the PK model, whereas the rest were in the validation group. The percentage of therapeutic target attainment (PTTA) comprising two pharmacodynamic indices and one toxicity index was used to evaluate dosing regimens based on Monte Carlo simulations stratified by low, normal, and high renal clearance for MICs of 0.25-4 mg/L. RESULTS: A single-compartment model with a covariate creatinine clearance (CrCL) was chosen as the final model. The PK parameter estimates were clearance of 5.60 L/h, with CrCL adjustment factor of 0.386, and a distribution volume of 43.4 L. For MIC ≤2 mg/L, the standard dosing regimen (600 mg q12h) for patients with severe renal impairment (CrCL, 40 mL/min) and standard dosing or 900 mg q12h for patients with normal renal functions (CrCL, 80 mL/min) could achieve PTTA ≥74%. The dose of 2400 mg per 24-h continuous infusion was ideal for augmented renal clearance (ARC) with MIC ≤1 mg/L. For MICs >2 mg/L, rare optimal dose regimens were found regardless of renal function. CONCLUSION: In critically ill patients, the standard dose of 600 mg q12h was sufficient for MIC ≤2 mg/L in patients without ARC. Moreover, a 2400 mg/day 24-h continuous infusion was recommended for ARC patients.

Assessment of 17 clinically available renal biomarkers to predict acute kidney injury in critically ill patients.

BACKGROUND: Systematic estimation of renal biomarkers in the intensive care unit (ICU) patients is lacking. Seventeen biomarkers were assessed to predict acute kidney injury (AKI) after admission to ICU. MATERIALS AND METHODS: A prospective, observational study was conducted in the general ICU of Guangdong Provincial People's Hospital. Seventeen serum or urine biomarkers were studied for their abilities alone or in combination for predicting AKI and severe AKI. RESULTS: Of 1498 patients, 376 (25.1%) developed AKI. Serum cystatin C (CysC) showed the best performance for predicting both AKI (area under the receiver operator characteristic curve [AUC] = 0.785, mean square error [MSE] = 0.118) and severe AKI (AUC = 0.883, MSE = 0.06). Regarding biomarkers combinations, CysC plus N-acetyl-ß-d-glucosaminidase-to-creatinine ratio (NAG/Cr) was the best for predicting AKI (AUC = 0.856, MSE = 0.21). At the same time, CysC plus lactic acid (LAC) performed the best for predicting severe AKI (AUC = 0.907, MSE = 0.058). Regarding combinations of biomarkers and clinical markers, CysC plus Acute Physiology and Chronic Health Evaluation (APACHE) II score showed the best performance for predicting AKI (AUC = 0.868, MSE = 0.407). In contrast, CysC plus Multiple Organ Dysfunction Score (MODS) had the highest predictive ability for severe AKI (AUC = 0.912, MSE = 0.488). CONCLUSION: Apart from CysC, the combination of most clinically available biomarkers or clinical markers does not significantly improve the forecasting ability, and the cost-benefit ratio is not economical.

The cellular economy of the Saccharomyces cerevisiae zinc proteome.

Zinc is an essential cofactor for many proteins. A key mechanism of zinc homeostasis during deficiency is "zinc sparing" in which specific zinc-binding proteins are repressed to reduce the cellular requirement. In this report, we evaluated zinc sparing across the zinc proteome of Saccharomyces cerevisiae. The yeast zinc proteome of 582 known or potential zinc-binding proteins was identified using a bioinformatics analysis that combined global domain searches with local motif searches. Protein abundance was determined by mass spectrometry. In zinc-replete cells, we detected over 2500 proteins among which 229 were zinc proteins. Based on copy number estimates and binding stoichiometries, a replete cell contains ∼9 million zinc-binding sites on proteins. During zinc deficiency, many zinc proteins decreased in abundance and the zinc-binding requirement decreased to ∼5 million zinc atoms per cell. Many of these effects were due at least in part to changes in mRNA levels rather than simply protein degradation. Measurements of cellular zinc content showed that the level of zinc atoms per cell dropped from over 20 million in replete cells to only 1.7 million in deficient cells. These results confirmed the ability of replete cells to store excess zinc and suggested that the majority of zinc-binding sites on proteins in deficient cells are either unmetalated or mismetalated. Our analysis of two abundant zinc proteins, Fba1 aldolase and Met6 methionine synthetase, supported that hypothesis. Thus, we have discovered widespread zinc sparing mechanisms and obtained evidence of a high accumulation of zinc proteins that lack their cofactor during deficiency.

Biosynthetic energy cost for amino acids decreases in cancer evolution.

Rapidly proliferating cancer cells have much higher demand for proteinogenic amino acids than normal cells. The use of amino acids in human proteomes is largely affected by their bioavailability, which is constrained by the biosynthetic energy cost in living organisms. Conceptually distinct from gene-based analyses, we introduce the energy cost per amino acid (ECPA) to quantitatively characterize the use of 20 amino acids during protein synthesis in human cells. By analyzing gene expression data from The Cancer Genome Atlas, we find that cancer cells evolve to utilize amino acids more economically by optimizing gene expression profile and ECPA shows robust prognostic power across many cancer types. We further validate this pattern in an experimental evolution of xenograft tumors. Our ECPA analysis reveals a common principle during cancer evolution.