Ferric particle-assisted LDI-MS platform for metabolic fingerprinting of diabetic retinopathy.

OBJECTIVES: To explore the metabolic fingerprints of diabetic retinopathy (DR) in individuals with type 2 diabetes using a newly-developed laser desorption/ionization mass spectrometry (LDI-MS) platform assisted by ferric particles. METHODS: Metabolic fingerprinting was performed using a ferric particle-assisted LDI-MS platform. A nested population-based case-control study was performed on 216 DR cases and 216 control individuals with type 2 diabetes. RESULTS: DR cases and control individuals with type 2 diabetes were comparable for a list of clinical factors. The newly-developed LDI-MS platform allowed us to draw the blueprint of plasma metabolic fingerprints from participants with and without DR. The neural network afforded diagnostic performance with an average area under curve value of 0.928 for discovery cohort and 0.905 for validation cohort (95 % confidence interval: 0.902-0.954 and 0.845-0.965, respectively). Tandem MS and Fourier transform ion cyclotron resonance MS with ultrahigh resolution identified seven specific metabolites that were significantly associated with DR in fully adjusted models. Of these metabolites, dihydrobiopterin, phosphoserine, N-arachidonoylglycine, and 3-methylhistamine levels in plasma were first reported to show the associations. CONCLUSIONS: This work advances the design of metabolic analysis for DR and holds the potential to promise as an efficient tool for clinical management of DR.

Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Cross-Coupling Reaction for the Stereoselective Synthesis of Multisubstituted Olefins.

The aryl-to-vinyl nickel 1,4-migration (1,4-Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4-Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.

PoxCbh, a novel CENPB-type HTH domain protein, regulates cellulase and xylanase gene expression in Penicillium oxalicum.

The essential transcription factor PoxCxrA is required for cellulase and xylanase gene expression in the filamentous fungus Penicillium oxalicum that is potentially applied in biotechnological industry as a result of the existence of the integrated cellulolytic and xylolytic system. However, the regulatory mechanism of cellulase and xylanase gene expression specifically associated with PoxCxrA regulation in fungi is poorly understood. In this study, the novel regulator PoxCbh (POX06865), containing a centromere protein B-type helix-turn-helix domain, was identified through screening for the PoxCxrA regulon under Avicel induction and genetic analysis. The mutant ∆PoxCbh showed significant reduction in cellulase and xylanase production, ranging from 28.4% to 59.8%. Furthermore, PoxCbh was found to directly regulate the expression of important cellulase and xylanase genes, as well as the known regulatory genes PoxNsdD and POX02484, and its expression was directly controlled by PoxCxrA. The PoxCbh-binding DNA sequence in the promoter region of the cellobiohydrolase 1 gene cbh1 was identified. These results expand our understanding of the diverse roles of centromere protein B-like protein, the regulatory network of cellulase and xylanase gene expression, and regulatory mechanisms in fungi.

Ultrafast exciton delocalization and localization dynamics of a perylene bisimide quadruple π-stack: a nonadiabatic dynamics simulation.

Unraveling the photogenerated exciton dynamics of π-stacked molecular aggregates is of great importance for both fundamental studies and industrial applications. Among various π-stacked molecular aggregates, perylene tetracarboxylic acid bisimide (PBI) based aggregates are regarded as one of the prototypes due to their inherent high fluorescence quantum yield and excellent photostability and flexibility in controlling intermolecular forces via chemical modifications. However, the exciton dynamics of these PBI based aggregates remain elusive up to now. In this work, we have first employed LR-TDDFT-based nonadiabatic dynamics simulations and static electronic structure calculations to investigate the ultrafast exciton dynamics of a newly synthesized perylene bisimide quadruple (PBQ) π-stack. Upon photoexcitation, the S6 to S10 states are the most likely populated excited states, which can be regarded as a combination of local excited (LE) excitons and charge transfer (CT) excitons of those four PBI chromophores. Then, the excited PBQ π-stack relaxes ultrafast to the lowest lying excited S1 state within 500 fs, which is accompanied by the complicated exciton conversion as well as exciton localization/delocalization dynamics. In short, the initially populated hybrid LE and CT excitons convert to the LE excitons of B/C and A/D, in which the LE excitons of B/C contribute the most (∼0.44) while the LE excitons of A/D also have minor contributions (0.21), indicating the formation of the localized excimer state. We use the notations A/B/C/D here to represent the four PBI fragments of PBQ π-stacks along the direction perpendicular to the PBI molecular plane. Additionally, using a recently defined root mean square deviation (RMSD) of electron and hole spatial distributions along three Cartesian coordinates, we could investigate the exciton localization/delocalization dynamics in a quantitative way. Our simulation results indicate that the photoinduced electrons and holes of the PBQ π-stack exhibit an ultrafast localization(∼10 fs)-delocalization(∼60 fs)-localization(∼200 fs) dynamics, during which both LE and CT excitons play crucial roles. Our present work is not only consistent with previous experimental studies, but also provides more detailed insights into the relevant processes, which might be useful for the future design of PBI based optoelectronic devices with improved performances.

Correlation between the accumulation of skin glycosylation end products and the development of type 2 diabetic peripheral neuropathy.

BACKGROUND: The accumulation of advanced glycation end products (AGEs) occurring in skin tissues can be measured by AGE Reader. Here, we assessed the correlation between AGEs values and the development of type 2 diabetic peripheral neuropathy (DPN). METHODS: The basic clinical information of 560 patients with T2DM was collected through an electronic system. AGEs and diabetic complication risk score was measured by AGE Reader, a non-invasive optical signal detector. All of the participants were classified into 4 groups based on Dyck criteria: grade 0 (non-DPN group), grade 1 (early stage group), grade 2 (middle stage group) and grade 3 (advanced group). Pearson correlation analysis and Spearman correlation analysis were used to evaluate the correlation between AGEs and other indexes. The sensitivity and specificity of glycosylated products were evaluated by ROC curve. RESULTS: With the increase of DPN severity, the accumulative AGEs showed an increasing trend. Significant differences (P = 0.000) of AGEs were found among grades 0, 1, 2, and 3 of DPN, and significant differences (P = 0.000) of AGEs were found between grades 1 and 3. There were significant differences in DPN risk score between grades 0, 1, 2, and 3, between grades 1, 2, and 3, and between grades 2 and 3 (P < 0.01 or P < 0.05). AGEs were positively correlated with age, blood uric acid, disease course, systolic blood pressure, the risk scores of the four major complications of diabetes, renal function indicators (serum creatinine, Cystatin C, homocysteine, the ratio of urinary albumin and creatinine, urinary microalbumin, α-microglobulin, urinary transferrin, urinary immunoglobulin), inflammatory indicators (white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, C-reactive protein), and TCSS score. However, it was negatively correlated with BMI,fasting insulin, insulin 1-3 h postprandial, lymphocyte count, HOMA insulin resistance index and estimated glomerular filtration rate. The area under the AGEs cumulant and neuropathy risk score curve was 0.769 and 0.743, respectively. The confidence intervals were (71.2-82.6%) and (68.8-79.9%), respectively. The maximum Youden's index of AGEs cumulant was 0.440, and the corresponding AGEs cumulant value was 77.65. The corresponding sensitivity and specificity were 0.731 and 0.709, respectively. Furthermore, the maximum Youden's index of neuropathy risk score was 0.385, and the corresponding neuropathy risk score was 66.25. The corresponding sensitivity and the specificity were 0.676 and 0.709, respectively. CONCLUSION: The cumulative amount of skin AGEs can be used as the diagnostic index and the prediction and evaluation index of DPN severity. Moreover, the diabetic peripheral neuropathy risk score can predict the risk of DPN in patients with T2DM.

Experimental and Computational Studies of Palladium-Catalyzed Spirocyclization via a Narasaka-Heck/C(sp3 or sp2)-H Activation Cascade Reaction.

The first synthesis of highly strained spirocyclobutane-pyrrolines via a palladium-catalyzed tandem Narasaka-Heck/C(sp3 or sp2)-H activation reaction is reported here. The key step in this transformation is the activation of a δ-C-H bond via an in situ generated σ-alkyl-Pd(II) species to form a five-membered spiro-palladacycle intermediate. The concerted metalation-deprotonation (CMD) process, rate-determining step, and energy barrier of the entire reaction were explored by density functional theory (DFT) calculations. Moreover, a series of control experiments was conducted to probe the rate-determining step and reversibility of the C(sp3)-H activation step.

In Vivo Delivery of siRNAs Targeting EGFR and BRD4 Expression by Peptide-Modified Redox Responsive PEG-PEI Nanoparticles for the Treatment of Triple-Negative Breast Cancer.

The study aims to investigate the in vivo distribution, antitumor effect, and safety of cell membrane-penetrating peptide-modified disulfide bond copolymer nanoparticles loaded with small-interfering RNA (siRNA) targeting epidermal growth factor receptor (EGFR) and bromodomain-containing protein 4 (BRD4) in triple-negative breast cancer (TNBC). Polyethylene glycol disulfide bond-linked polyethylenimine (PEG-SS-PEI) was modified with peptides GALA and CREKA and used as vectors to prepare siRNA nanoparticles. The GALA- and CREKA-modified PEG-SS-PEI nanoparticles (GC-NPs) were prepared by mixing siEGFR and siBRD4 (1:1) with GALA-PEG-SS-PEI and CREKA-PEG-SS-PEI (1:1) in an aqueous solution at an N/P ratio of 30:1. Nanoparticles loaded with scrambled siRNA were prepared with the same method. The gene silencing effect on EGFR and BRD4 in vitro was evaluated by Western blotting analysis. TNBC xenograft models were established by subcutaneous injection of MDA-MB-231 cells into female nude mice. At 1, 3, 6, 12, and 24 h after administration of five formulations of Cy5-siRNA (133 µg/10 g) via the tail vein, the mice were observed and imaged for a biodistribution study using an in vivo imaging system. In the pharmacodynamics experiment, tumor-bearing mice were treated with respective siRNA preparations at a dose of 133 µg/10 g for 18 days, and the body weight and tumor size were recorded every other day. The protein expression levels of EGFR, p-EGFR, PI3K, p-PI3K, Akt, p-Akt, BRD4, and c-Myc were determined using Western blotting analysis. Hematological and serum biochemical parameters, organ indices, and HE staining results for the heart, liver, spleen, lung, and kidney were analyzed to evaluate the safety of the nanoparticles. GC-NPs loaded with siEGFR and siBRD4 significantly inhibited the expression of EGFR and BRD4 in vitro. The strongest fluorescence signals were observed in the GC-NP group, especially in tumors, indicating the excellent tumor-targeted delivery of GC-NPs we constructed. Tumor growth was significantly inhibited in the GC-NP-treated group, and the expression of EGFR, p-EGFR, PI3K, p-PI3K, Akt, p-Akt, BRD4, and c-Myc in the tumors decreased by 71%, 68%, 61%, 68%, 48%, 58%, 59%, and 74% compared to the control group, respectively. There was no significant change in hematological parameters, biochemical indices, or tissue morphology in GC-NP-treated mice. SiRNA cotargeting EGFR and BRD4 delivered by GALA- and CREKA-modified PEG-SS-PEI had favorable antitumor effects in vivo toward TNBC with tumor-targeting efficacy and good biocompatibility.

Complex renal calculi treated with traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy.

To analyze the effect of traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy and lithotripsy in the treatment of complex kidney stones. Totally 100 patients with complicated kidney stones admitted to our hospital from January 2019 to January 2021 were selected and randomly divided into a control group and an experimental group, with 50 cases in each group. The control group was treated with laparoscopic ureterectomy for stone removal, the experimental group was treated with traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy for stone removal. The therapeutic effects of the two groups were compared. The total effective rate of treatment in the control group was 76% and that of the experimental group was 96%. The stone clearing time, time to pain resolution and time to hematuria disappearance time in the experimental group were significantly shorter as compared with the control group. After treatment, the levels of serum creatinine and blood urea nitrogen in the experimental group were significantly lower than those in the control group. Traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy and lithotripsy for treatment of complex kidney stones ameliorates the treatment efficacy, shortens the time of stone removal, mitigates the clinical symptoms of patients, and helps restore renal function, which is worthy of clinical promotion and application.

Silver Trifluoromethanesulfonate-Catalyzed Annulation of Propargylic Alcohols with 3-Methyleneisoindolin-1-one.

A silver-catalyzed formal [3 + 3] annulation of 3-methyleneisoindolin-1-one with alkynol for the synthesis of 1,5-dihydroindolizin-3(2H)-one derivatives is disclosed. The protocol allows practical synthesis of N-heterocyclic scaffolds with a broad scope of functional groups and could be efficiently scaled up to gram scale, which incarnates a potential application of this methodology. In addition, a range of chlorine anion substitution of alkenes can be constructed by adjusting the structure of the alkynol substrates with the use of TMSCl.

Economic evaluation of dapagliflozin versus metformin in Chinese patients whose diabetes is inadequately controlled with diet and exercise.

BACKGROUND: To investigate the long-term economic outcome of dapagliflozin versus metformin in Chinese patients with type 2 diabetes mellitus (T2DM) whose diet and exercise have not provided sufficient glycemic control. METHODS: An economic analysis of dapagliflozin versus metformin was conducted by using the Chinese Outcomes Model for T2DM with a time horizon of lifetime, which was developed and validated based on the Chinese population. The efficacy data of lowering HbA1c of dapagliflozin and metformin was derived from a network meta-analysis. Other clinical, cost and utility inputs were obtained from published sources. Lifetime discounted quality-adjusted life-years, cost, and incremental cost-effectiveness ratio were measured. The uncertainty was facilitated by one-way and probabilistic sensitivity analyses. RESULTS: The comparison of metformin and dapagliflozin in Chinese patients with insufficient glycemic control by diet and exercise showed that dapagliflozin was more costly and produced fewer health benefits in our simulated cohort. The sensitivity analyses indicated that the results were robust. CONCLUSIONS: Dapagliflozin is not likely to be cost-effective compared with metformin for Chinese patients with T2DM inadequately controlled with diet and exercise.

Regulatory Efficacy of the Polyunsaturated Fatty Acids from Microalgae Spirulina platensis on Lipid Metabolism and Gut Microbiota in High-Fat Diet Rats.

Ultra-high performance liquid chromatography coupled with photo-diode array detector and electrospray ionization-mass spectrometry was employed to analyze the major fatty acids in Spirulina platensis 95% ethanol extract (SPL95). The effects of SPL95 on hepatoprotection were evaluated, including liver tissue histopathology, liver, and serum biochemical analysis. The active principle of SPL95 revealed a hypolipidemic effect, as indicated by down-regulating the mRNA and protein levels of sterol regulatory element-binding transcription factor-1c, 3-hydroxy-3-methyl glutaryl coenzyme A reductase, acetyl CoA carboxylase pathway, and upregulating adenosine 5'-monophosphate-activated protein kinase-α in liver. SPL95 enriched the beneficial bacteria, including Prevotella, Alloprevotella, Porphyromonadaceae, Barnesiella, and Paraprevotella. Treatment with SPL95 led to a decrease in microbes, such as Turicibacter, Romboutsia, Phascolarctobacterium, Olsenella, and Clostridium XVIII, which were positively correlated with serum triglyceride, total cholesterol, and low-density-lipoprotein cholesterol levels, but negatively correlated with the serum high-density-lipoprotein cholesterol levels. These results provide evidence that the fatty acid from SPL95 may be used as a novel adjuvant therapy and functional food to regulate gut microbiota in obese and diabetic individuals.

Synthesis of Organophosphorus Compounds through Copper-Catalyzed Annulation Involving C-O and C-P Bond Formations.

A novel copper(II) trifluoromethanesulfonate-catalyzed, high-efficiency, and atom-economical synthesis of valuable organophosphorus compounds via cascade annulation of propargylic alcohols with diphenylphosphine oxide is described. This protocol, which has a good functional-group compatibility and insensitivity to an ambient atmosphere, provides a simple and direct pathway to the products, organophosphorus compounds, in good yields under mild conditions. The method could be efficiently scaled up to gram scale, thus highlighting a potential application of this methodology.

Two new tenvermectins from a genetically engineered strain Streptomyces avermitilis MHJ1011.

Two new tenvermectins, tenvermectins C (1) and D (2), were isolated from Streptomyces avermitilis MHJ1011. Their structures were determined by extensive spectroscopic analysis and by comparison with a related known compound, tenvermectin A. Compounds 1 and 2 exhibited potent nematocidal and acaricidal activities against Bursaphelenchus xylophilus and Tetranychus cinnabarinus.

Three new 16-membered macrolide compounds from a genetically engineered strain S. avermitilis MHJ1011.

Three new 16-membered macrolide compounds, 13α-O-α-l-oleandrosyl milbemycin ß3 (1), 13α-O-α-l-oleandrosyl-25-ethyl milbemycin ß3 (2), 13α-O-α-l-oleandrosyl-25-isopropyl milbemycin ß3 (3), were isolated from the genetically engineered strains Streptomyces avermitilis MHJ1011. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Both compounds 1-3 displayed impressive acaricidal activity against larval mites with the IC50 values of 0.0327, 0.0276 and 0.0235mg/L, respectively, which are higher than those of 13α-hydroxy milbemycin ß3 and 13α-hydroxy-25-ethyl milbemycin ß3.

Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer's Disease.

PURPOSE: H102, a novel ß-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD). METHODS: The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia. RESULTS: The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa. CONCLUSIONS: The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.

Equivariant Line Graph Neural Network for Protein-Ligand Binding Affinity Prediction.

Binding affinity prediction of three-dimensional (3D) protein-ligand complexes is critical for drug repositioning and virtual drug screening. Existing approaches usually transform a 3D protein-ligand complex to a two-dimensional (2D) graph, and then use graph neural networks (GNNs) to predict its binding affinity. However, the node and edge features of the 2D graph are extracted based on invariant local coordinate systems of the 3D complex. As a result, these approaches can not fully learn the global information of the complex, such as the physical symmetry and the topological information of bonds. To address these issues, we propose a novel Equivariant Line Graph Network (ELGN) for binding affinity prediction of 3D protein-ligand complexes. The proposed ELGN firstly adds a super node to the 3D complex, and then builds a line graph based on the 3D complex. After that, ELGN uses a new E(3)-equivariant network layer to pass the messages between nodes and edges based on the global coordinate system of the 3D complex. Experimental results on two real datasets demonstrate the effectiveness of ELGN over several state-of-the-art baselines.

Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

Isolation, expression, and characterization of a hydroperoxide lyase gene from cucumber.

A full-length cDNA coding for hydroperoxide lyase (CsHPL) was isolated from cucumber fruits of No. 26 (Southern China type) and No.14-1 (Northern China type), which differed significantly in fruit flavor. The deduced amino acid sequences of CsHPL from both lines show the same and significant similarity to known plant HPLs and contain typical conserved domains of HPLs. The recombinant CsHPL was confirmed to have 9/13-HPL enzymatic activity. Gene expression levels of CsHPL were measured in different organs, especially in fruits of different development stages of both lines. The HPL activities of fruit were identified basing on the catalytic action of crude enzyme extracts incubating with 13-HPOD (13-hydroperoxy-(9Z,12E)-octadecadienoic acid) and 13-HPOD + 9-HPOD (9-hydroperoxy-(10E,12Z)-octadecadienoic acid), and volatile reaction products were analyzed by GC-MS (gas chromatography-mass spectrometry). CsHPL gene expression in No. 26 fruit occurred earlier than that of total HPL enzyme activity and 13-HPL enzyme activity, and that in No. 14-1 fruit was consistent with total HPL enzyme activity and 9-HPL enzyme activity. 13-HPL enzyme activities decreased significantly and the 9-HPL enzyme activities increased significantly with fruit ripening in both lines, which accounted for the higher content of C6 aldehydes at 0-6 day post-anthesis (dpa) and higher content of C9 aldehydes at 9-12 dpa.

Cost-effectiveness of ceftazidime/avibactam plus metronidazole versus meropenem as first-line empiric therapy for the treatment of complicated intra-abdominal infections: A study based on the in-vitro surveillance data in China.

BACKGROUND: With the increase in drug resistance rates of pathogens isolated from complicated intra-abdominal infections (cIAIs), ceftazidime/avibactam (CAZ-AVI) is increasingly used clinically. However, given the high drug cost and the fact that not yet covered by the health insurance payment, this study evaluated the cost-effectiveness of CAZ-AVI plus metronidazole versus meropenem as a first-line empiric treatment for cIAIs from the perspective of the Chinese healthcare system. METHODS: A decision analytic model with a one-year time horizon was constructed to assess the cost-effectiveness based on the entire disease course. Model inputs were mainly obtained from clinical studies, published literature, and publicly available databases. Primary outcomes were cost, quality-adjusted life years (QALYs), life years (Lys), and incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analysis were also performed. RESULTS: In the base cases, compared to meropenem, CAZ-AVI plus metronidazole had a shorter mean hospital length of stay (-0.77 days per patient) and longer life expectancy (+0.05 LYs and +0.06 QALYs). CAZ-AVI plus metronidazole had an ICER of $25517/QALY, which is well below the threshold of $31509 per QALY in China. The one-way sensitivity analysis showed that the change of the treatment duration of CAZ-AVI plus metronidazole was the parameter that most influenced the results of the ICER. In probabilistic sensitivity analysis, CAZ-AVI plus metronidazole was the optimal strategy in 75% of simulations at $31510/QALY threshold. CONCLUSIONS: CAZ-AVI plus metronidazole could be considered as a cost-effective option for the empiric treatment of patients with cIAIs in China, and this benefit will be more evident when the price of CAZ-AVI decreases by 23.8%.

Study on Proportioning Scheme of Coal System Rocky Similar Material Based on Orthogonal Test.

Similar materials play an important role in model testing. In order to meet the demand for similar materials in modeling tests, such as those on coal mining, coal system rocky similar materials were formulated using yellow sand as a coarse aggregate, heavy calcium carbonate as a fine aggregate, and cement and gypsum as binders. Based on the orthogonal experimental design method, four influencing factors, namely the aggregate-binder ratio, heavy calcium carbonate content, cement-gypsum ratio, and moisture content, were selected. Each factor was designed at five levels. Through weighing, uniaxial compression, Brazilian splitting, and variable-angle plate shear tests on 225 specimens under 25 different ratios, five physico-mechanical property indicators of the material, including density, compressive strength, tensile strength, cohesion, and internal friction angle, were obtained under different ratios. The test results indicate that the similar materials formulated with the above raw materials had a wide range of mechanical properties, which met the simulation needs of different types of coal rocks, such as main coking coal, anthracite, shale, etc., in the similar model test. Range analysis was adopted to analyze the sensitivities to each factor, which showed that the density and internal friction angle of similar materials are mainly controlled by the aggregate-binder ratio; the cement-gypsum ratio mainly controls the compressive strength, tensile strength, and cohesion of the material. Analysis of variance (ANOVA) was adopted to analyze the sensitivities to each factor, which showed that the aggregate-binder ratio had a highly significant effect on the density of the material, the cement-gypsum ratio had a highly significant effect on the compressive and tensile strength of the material, the cement-gypsum ratio had a significant effect on the cohesion and density of the material, and the moisture content had a significant effect on the compressive strength of the material. The remaining factors did not significantly affect the material parameters. The results of this study can provide some reference for the selection of coal system rocky similar materials in subsequent physical modeling tests.