Phase Engineering of Nanostructural Metallic Materials: Classification, Structures, and Applications.

Metallic materials are usually composed of single phase or multiple phases, which refers to homogeneous regions with distinct types of the atom arrangement. The recent studies on nanostructured metallic materials provide a variety of promising approaches to engineer the phases at the nanoscale. Tailoring phase size, phase distribution, and introducing new structures via phase transformation contribute to the precise modification in deformation behaviors and electronic structures of nanostructural metallic materials. Therefore, phase engineering of nanostructured metallic materials is expected to pave an innovative way to develop materials with advanced mechanical and functional properties. In this review, we present a comprehensive overview of the engineering of heterogeneous nanophases and the fundamental understanding of nanophase formation for nanostructured metallic materials, including supra-nano-dual-phase materials, nanoprecipitation- and nanotwin-strengthened materials. We first review the thermodynamics and kinetics principles for the formation of the supra-nano-dual-phase structure, followed by a discussion on the deformation mechanism for structural metallic materials as well as the optimization in the electronic structure for electrocatalysis. Then, we demonstrate the origin, classification, and mechanical and functional properties of the metallic materials with the structural characteristics of dense nanoprecipitations or nanotwins. Finally, we summarize some potential research challenges in this field and provide a short perspective on the scientific implications of phase engineering for the design of next-generation advanced metallic materials.

Statins as a risk factor for diabetic retinopathy: a Mendelian randomization and cross-sectional observational study.

BACKGROUND: Diabetic retinopathy (DR) is the foremost cause of vision loss among the global working-age population, and statins are among the most frequently prescribed drugs for lipid management in patients with DR. The exact relationship between statins and DR has not been determined. This study sought to validate the causal association between statins usage and diabetic retinopathy. METHODS: The summary-data-based Mendelian randomization (SMR) method and inverse-variance-weighted Mendelian randomization (IVW-MR) were used to identify the causal relationship between statins and DR via the use of expression quantitative trait loci (eQTL) data for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) (31,684 blood samples), low density lipoprotein cholesterol-related GWAS data (sample size: 440,546), and DR-related GWAS data (14,584 cases and 176,010 controls). Additionally, a cross-sectional observational study based on the data from the National Health and Nutrition Examination Survey (NHANES) was conducted to supplement the association between DR and statins (sample size: 106,911). The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) was employed to evaluate the results. RESULTS: Based on the results of the MR analysis, HMGCR inhibitors were causally connected with a noticeably greater incidence of DR (IVW: OR = 0.54, 95% CI [0.42, 0.69], p = 0.000002; SMR: OR = 0.66, 95% CI [0.52, 0.84], p = 0.00073). Subgroup analysis revealed that the results were not affected by the severity of DR. The sensitivity analysis revealed the stability and reliability of the MR analysis results. The results from the cross-sectional study based on NHANES also support the association between not taking statins and a decreased risk of DR (OR = 0.54, 95% CI [0.37, 0.79], p = 0.001). CONCLUSIONS: This study revealed that a significant increase in DR risk was causally related to statins use, providing novel insights into the role of statins in DR. However, further investigations are needed to verify these findings.

In vivo axial load-share ratio measurement using a novel hexapod system for safe external fixator removal.

BACKGROUND: External fixation is widely used in the treatment of traumatic fractures; however, orthopedic surgeons encounter challenges in deciding the optimal time for fixator removal. The axial load-share ratio (LS) of the fixator is a quantitative index to evaluate the stiffness of callus healing. This paper introduces an innovative method for measuring the LS and assesses the method's feasibility and efficacy. Based on a novel hexapod LS-measurement system, the proposed method is to improve the convenience and precision of measuring LS in vivo, hence facilitating the safe removal of external fixators. METHODS: A novel hexapod system is introduced, including its composition, theoretical model, and method for LS measurement. We conducted a retrospective study on 82 patients with tibial fractures treated by the Taylor Spatial Frame in our hospital from September 2018 to June 2020, of which 35 took LS measurements with our novel method (Group I), and 47 were with the traditional method (Group II). The external fixator was removed when the measurement outcome (LS < 10%) was consistent with the surgeon's diagnosis based on the clinical and radiological assessment (bone union achieved). RESULTS: No significant difference was found in the fracture healing time (mean 25.3 weeks vs. 24.9 weeks, P > 0.05), frame-wearing duration (mean 25.5 weeks vs. 25.8 weeks, P > 0.05), or LS measurement frequency (mean 1.1 times vs. 1.2 times, P > 0.05). The measurement system installation time in Group I was significantly shorter compared to Group II (mean 14.8 min vs. 81.3 min, P < 0.001). The LS value of the first measurement in Group I was lower than that of Group II (mean 5.1% vs. 6.9%, P = 0.011). In Group I, the refracture rate was 0, but in Group II it was 4.3% (2/47, P > 0.05). CONCLUSION: The novel hexapod LS-measurement system and involved method demonstrated enhanced convenience and precision in measuring the LS of the external fixator in vivo. The LS measurement indicates the callus stiffness of fracture healing, and is applicable to evaluate the safety of removing the fixator. Consequently, it is highly recommended for widespread adoption in clinical practice.

Factors affecting outdoor physical activity in extreme temperatures in a sub-tropical Chinese urban population: an exploratory telephone survey.

BACKGROUND: Physical activity (PA) can be affected by extreme temperatures, however fewer studies have identified factors impacting this relationship. This study sought to identify factors associated with changes of outdoor PA during extreme cold/heat events in a sub-tropical Chinese urban population, including factors of sociodemographic, health conditions, temperature-related awareness and attitude, and protective behaviours. METHODS: Two telephone surveys were conducted a week after extreme cold/heat events in 2016 and 2017 among a cohort of Hong Kong residents over age 15. Data was collected on self-reported changes in outdoor PA level during the periods of extreme temperatures, health status, comorbidities, sociodemographic, and temperature-related awareness, and behavioural variables. We conducted multivariable logistic regression analyses to assess predictors of change in outdoor PA over the two extreme temperature events. RESULTS AND CONCLUSION: Among 435 participants (42.8% response rate), over a third of the participants reported decreased outdoor PA level in extreme temperature events, while 10% reported an increase in extreme heat. Self-reported cardiovascular diseases were associated with decreased PA level in extreme cold, while hypertension was associated with unchanged/increased PA level in extreme heat. These results suggest physical activity to be an important consideration in the understanding of climate change-and-health pathways and meriting further research.

GBAP1 polymorphisms (rs140081212, rs1057941 and rs2990220) contribute to reduced risk of gastric cancer.

Aim: This study was designed to evaluate the contribution of GBAP1 variants to gastric cancer (GC) risk in a Chinese Han population. Methods: The genotypes of GBAP1 polymorphisms were detected using the Agena MassARRAY platform. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. Results: GBAP1 rs140081212 (OR = 0.51, p = 4.50 × 10-07), rs1057941 (OR = 0.48, p = 1.19 × 10-08) and rs2990220 (OR = 0.46, p = 7.34 × 10-09) contribute to reduced GC risk, especially gastric adenocarcinoma. Interestingly, the contribution of GBAP1 variants to GC susceptibility was associated with age, sex, BMI, smoking and drinking. Conclusion: This research suggested that GBAP1 polymorphisms might provide a protective effect against GC occurrence in a Chinese Han population.

Marker- three dimensional measurement versus traditional radiographic measurement in the treatment of tibial fracture using Taylor spatial frame.

BACKGROUND: The Taylor Spatial Frame (TSF) has been widely used for tibial fracture. However, traditional radiographic measurement method is complicated and the reduction accuracy is affected by various factors. The purpose of this study was to propose a new marker- three dimensional (3D) measurement method and determine the differences of reduction outcomes, if any, between marker-3D measurement method and traditional radiographic measurement in the TSF treatment. METHODS: Forty-one patients with tibial fracture treated by TSF in our institution were retrospectively analyzed from January 2016 to June 2019, including 21 patients in the marker-3D measurement group (experimental group) and 20 patients in the traditional radiographic measurement group (control group). In the experimental group, 3D reconstruction with 6 markers installed on the TSF was performed to determine the electronic prescription. In the control group, the anteroposterior (AP) and lateral radiographs were performed for the traditional parameter measurements. The effectiveness was evaluated by the residual displacement deformity (RDD) and residual angle deformity (RAD) in the coronal and sagittal plane, according to the AP and lateral X-rays after reduction. RESULTS: All patients achieved functional reduction. The residual RDD in AP view was 0.5 (0, 1.72) mm in experimental group and 1.74 (0.43, 3.67) mm in control group. The residual RAD in AP view was 0 (0, 1.25) ° in experimental group and 1.25 (0.62, 1.95) °in control group. As for the lateral view, the RDD was 0 (0, 1.22) mm in experimental group and 2.02 (0, 3.74) mm in control group, the RAD was 0 (0, 0) ° in experimental group and 1.42 (0, 1.93) ° in control group. Significant differences in all above comparisons were observed between the two groups (AP view RDD: P = 0.024, RAD: P = 0.020; Lateral view RDD: P = 0.016, RAD: P = 0.004). CONCLUSIONS: The present study introduced a marker-3D measurement method to complement the current TSF treatment. This method avoids the manual measurement error and improves the accuracy of fracture reduction, providing potential advantages of bone healing and function rehabilitation.

Effect of HIF1α on the TRPC6 channel of glomerular podocytes under chronic hypoxia.

BACKGROUND: Chronic hypoxia plays an important role in the initiation and progression of chronic renal disease. The pathogenic role of chronic hypoxia in tubulointerstitial injury has been investigated widely, but little is known about acute hypoxia implications in glomerular damage. In this study, we investigated the effect of chronic hypoxia on transient receptor potential cation channel 6 (TRPC6) and the underlying mechanism in cultured human podocytes. METHODS: Fluo-3 was used as a calcium indicator of the OAG-induced receptor operated calcium entry (ROCE) and basal [Ca2+]i levels were monitored using laser scanning confocal microscope after exposure of cells to chronic hypoxia. 2-aminoethoxydiphenylborane (2-APB), a pharmacological blocker of TRPCs channels, was used to determine the role of TRPC6 in podocytes under chronic hypoxia. The mRNA expression and protein levels of TRPC6 were determined using Real-time RT-PCR and Western Blotting under normoxic and chronic hypoxic conditions. Actin arrangement was analyzed by confocal microscopy using phalloidin staining of F-actin in podocytes. RESULTS: Cytosolic free Ca2+ was increased by hypoxia or the treatment of TRPC6 agonist OAG under normoxic conditions. The increase of intracellular Ca2+ induced by hypoxia was time- and dose-dependent, which can be inhibited by 2-APB, demonstrating that the changes of intracellular Ca2+ induced by OAG depend on the activation of TRPC6. Further study showed that the TRPC6 expression levels were significantly increased by hypoxia, which were inhibited by the HIF1α inhibitor in podocytes. Similarly, the increase of intracellular Ca2+ induced by hypoxia was decreased when the podocytes were incubated with HIF1α inhibitor. We also found that F-actin was ruptured by hypoxia in podocytes, showing cytoskeleton reorganization. CONCLUSIONS: TRPC6 mRNA and protein expression levels were significantly increased in podocytes under hypoxia, which may result in the increase of intracellular Ca2+. This alternation of TRPC6 may be relevant to the modulation of HIF1α. Hypoxia in podocytes can result in cytoskeleton reorganization, which further leads to podocytes injury and disfunction.

Narrative review of non-pharmaceutical behavioural measures for the prevention of COVID-19 (SARS-CoV-2) based on the Health-EDRM framework.

INTRODUCTION: Non-pharmaceutical measures to facilitate a response to the COVID-19 pandemic, a disease caused by novel coronavirus SARS-CoV-2, are urgently needed. Using the World Health Organization (WHO) health emergency and disaster risk management (health-EDRM) framework, behavioural measures for droplet-borne communicable diseases and their enabling and limiting factors at various implementation levels were evaluated. SOURCES OF DATA: Keyword search was conducted in PubMed, Google Scholar, Embase, Medline, Science Direct, WHO and CDC online publication databases. Using the Oxford Centre for Evidence-Based Medicine review criteria, 10 bottom-up, non-pharmaceutical prevention measures from 104 English-language articles, which published between January 2000 and May 2020, were identified and examined. AREAS OF AGREEMENT: Evidence-guided behavioural measures against transmission of COVID-19 in global at-risk communities were identified, including regular handwashing, wearing face masks and avoiding crowds and gatherings. AREAS OF CONCERN: Strong evidence-based systematic behavioural studies for COVID-19 prevention are lacking. GROWING POINTS: Very limited research publications are available for non-pharmaceutical measures to facilitate pandemic response. AREAS TIMELY FOR RESEARCH: Research with strong implementation feasibility that targets resource-poor settings with low baseline health-EDRM capacity is urgently needed.

MiR-224 Executes a Tumor Accelerative Role during Hepatocellular Carcinoma Malignancy by Targeting Cytoplasmic Polyadenylation Element-Binding Protein 3.

PURPOSE: The purpose of our study was to probe the mechanism of how miR-224/cytoplasmic polyadenylation element-binding protein 3 (CPEB3) axis is concerned with hepatocellular carcinoma (HCC). METHODS: The expressions and prognostic values of miR-224 and CPEB3 in HCC patients were analyzed based on the data acquired from the TCGA and GEO databases. qRT-PCR was conducted to test the mRNA expression levels of miR-224 and CPEB3. The expression level of miR-224 in SMMC-7721/HuH-7 cells was up-/downregulated by miR-224 mimic/inhibitor to explore its influence on HCC cell proliferation and motility by utilizing CCK8 and transwell assays, respectively. Luciferase activity assay was applied for verifying the target of miR-224. The relationship between miR-224 and CPEB3 was analyzed utilizing Pearson's correlation coefficient. The protein level of CPEB3 was tested by Western blotting. Rescue assay was performed to determine whether CPEB3 involved in the process of HCC cell phenotype changes caused by miR-224 alteration. RESULTS: MiR-224 was highly expressed and CPEB3 was lowly expressed in HCC tissues. Besides, the high expression of miR-224 and low expression of CPEB3 were correlated with worse prognosis in HCC patients. Up-/downregulation of miR-224 accelerated/restrained SMMC-7721/HuH-7 cell proliferation and motility. CPEB3 was predicted and proofed as a target gene of miR-224. We discovered that CPEB3 was negatively modulated by miR-224. We also found a sharply negative correlation between CPEB3 and miR-224. Using rescue assay, we showed that overexpression of CPEB3 suppressed the proliferation and motility of SMMC-7721 cells with overexpressed miR-224, while knockdown of CPEB3 facilitated the proliferation and motility of HuH-7 cells with downregulated miR-224. CONCLUSION: Our data provided evidences that miR-224 is implicated in HCC cell proliferation and motility via targeting CPEB3. The relationship between miR-224 and CPEB3 might be a novel finding, and miR-224/CPEB3 axis might be markers for providing therapeutic and prognostic information in HCC.

Health impact of climate change in cities of middle-income countries: the case of China.

BACKGROUND: This review examines the human health impact of climate change in China. Through reviewing available research findings under four major climate change phenomena, namely extreme temperature, altered rainfall pattern, rise of sea level and extreme weather events, relevant implications for other middle-income population with similar contexts will be synthesized. SOURCES OF DATA: Sources of data included bilingual peer-reviewed articles published between 2000 and 2018 in PubMed, Google Scholar and China Academic Journals Full-text Database. AREAS OF AGREEMENT: The impact of temperature on mortality outcomes was the most extensively studied, with the strongest cause-specific mortality risks between temperature and cardiovascular and respiratory mortality. The geographical focuses of the studies indicated variations in health risks and impacts of different climate change phenomena across the country. AREAS OF CONTROVERSY: While rainfall-related studies predominantly focus on its impact on infectious and vector-borne diseases, consistent associations were not often found. GROWING POINTS: Mental health outcomes of climate change had been gaining increasing attention, particularly in the context of extreme weather events. The number of projection studies on the long-term impact had been growing. AREAS TIMELY FOR DEVELOPING RESEARCH: The lack of studies on the health implications of rising sea levels and on comorbidity and injury outcomes warrants immediate attention. Evidence is needed to understand health impacts on vulnerable populations living in growing urbanized cities and urban enclaves, in particular migrant workers. Location-specific climate-health outcome thresholds (such as temperature-mortality threshold) will be needed to support evidence-based clinical management plans and health impact mitigation strategies to protect vulnerable communities.

Antero-lateral minimally invasive plate osteosynthesis (MIPO) with the radial nerve exploration for extra-articular distal-third diaphyseal fractures of the humerus.

INTRODUCTION: Traditional open reduction and internal fixation (ORIF) of extra-articular distal humerus fractures has a risk of iatrogenic radial nerve injury, extensive soft tissue stripping, and long incision scar. We performed an antero-lateral minimally invasive plate osteosynthesis (MIPO) technique with the radial nerve exploration for distal-third diaphyseal fractures of the humerus and evaluated clinical and radiographic outcomes through this respective study. METHODS: From April 2010 to June 2016, 28 cases of extra-articular distal-third diaphyseal fractures were treated with an antero-lateral MIPO procedure. Patient demographics, Disabilities of the Arm, Shoulder and Hand (DASH) Score, Mayo Elbow Performance (MEP) Score, elbow range of motion, scars and post-operative complications were recorded and analyzed. RESULTS: All fractures were united with a mean time of 3.5 months. One patient exhibited delayed union (3.6%). The mean DASH Score was 6.6, and all patients had excellent or good MEP Score values. The average scar length was 6.8 cm, and the shortest was 4.5 cm. CONCLUSIONS: The MIPO technique via an antero-lateral approach for extra-articular distal-third diaphyseal fractures of the humerus results in satisfactory clinical outcomes. LEVEL OF EVIDENCE: Level IV, case series, treatment study.

Liquid-Liquid Phase Transition in Nanoconfined Silicon Carbide.

We report theoretical evidence of a liquid-liquid phase transition (LLPT) in liquid silicon carbide under nanoslit confinement. The LLPT is characterized by layering transitions induced by confinement and pressure, accompanying the rapid change in density. During the layering transition, the proportional distribution of tetracoordinated and pentacoordinated structures exhibits remarkable change. The tricoordinated structures lead to the microphase separation between silicon (with the dominant tricoordinated, tetracoordinated, and pentacoordinated structures) and carbon (with the dominant tricoordinated structures) in the layer close to the walls. A strong layer separation between silicon atoms and carbon atoms is induced by strong wall-liquid forces. Importantly, the pressure confinement phase diagram with negative slopes for LLPT lines indicates that, under high pressure, the LLPT is mainly confinement-induced, but under low pressure, it becomes dominantly pressure-induced.

Numerical investigation and optimal design of capillary barrier cover with passive gas collection pipes on the performance at limiting landfill gas emissions.

Relying solely on soil properties may not fully ensure the performance of capillary barrier covers at limiting landfill gas (LFG) emissions. This study proposed to install passive gas collection pipes in the coarse-grained soil layers of capillary barrier covers to enhance their performance at limiting LFG emissions. First, the LFG generation rate of municipal solid waste and its influencing factors were analyzed based on empirical formulas. This information provided necessary bottom boundary conditions for the analyses of LFG transport through capillary barrier covers with passive gas collection pipes (CBCPPs). Then, numerical simulations were conducted to investigate the LFG transport properties through CBCPPs and reveal relevant influencing factors. Finally, practical suggestions were proposed to optimize the design of CBCPPs. The results indicated that the maximum whole-site LFG generation rate occurred at the end of landfilling operation. The gas collection efficiency (E) of CBCPPs was mainly controlled by the ratio of the intrinsic permeability between the coarse- and fine-grained soil (K2/K1) and the laying spacing between gas collection pipes (D). E increased as K2/K1 increased but decreased as D increased. An empirical expression for estimating E based on K2/K1 and D was proposed. In practice, CBCPPs were supposed to be constructed once the landfilling operation finished. It is best to select the fine- and coarse-grained soils with K2/K1 exceeding 10,000 to construct CBCPPs.

Elemental partitioning-mediated crystalline-to-amorphous phase transformation under quasi-static deformation.

The transformation induced plasticity phenomenon occurs when one phase transforms to another one during plastic deformation, which is usually diffusionless. Here we present elemental partitioning-mediated crystalline-to-amorphous phase transformation during quasi-static plastic deformation, in an alloy in form of a Cr-Ni-Co (crystalline)/Zr-Ti-Nb-Hf-Ni-Co (amorphous) nanolaminated composite, where the constitute elements of the two phases have large negative mixing enthalpy. Upon plastic deformation, atomic intermixing occurs between adjacent amorphous and crystalline phases due to extensive rearrangement of atoms at the interfaces. The large negative mixing enthalpy among the constituent elements promotes amorphous phase transformation of the original crystalline phase, which shows different composition and short-range-order structure compared with the other amorphous phase. The reduced size of the crystalline phase shortens mean-free-path of dislocations, facilitating strain hardening. The enthalpy-guided alloy design based on crystalline-to-amorphous phase transformation opens up an avenue for the development of crystal-glass composite alloys with ultrahigh strength and large plasticity.

Silicon nanowire array/Cu2O crystalline core-shell nanosystem for solar-driven photocatalytic water splitting.

P-type Cu2O nanocrystals were deposited on n-type silicon nanowire arrays (Si NWs) to form core-shell heterojunction arrays structure via a simple electroless deposition technique. Scanning electron microscopy, transmission electron microscope and x-ray diffraction were utilized to characterize the morphology and structure of the core-shell nanosystem. The reflectivity of the obtained core-shell structure measured by UV/vis spectrometry showed a comparatively low reflectivity in the visible-light region, which implied good optical absorption performance. The water splitting performance of the obtained Si NWs, planar Si/Cu2O structure and Si NW/Cu2O core-shell nanosystem were studied. Owing to the large specific surface area, heterojunctions formed between Cu2O nanocrystallites and Si NWs and the light trapping effect of the NW array structure, the photocatalytic performance of the Si NW/Cu2O core-shell nanosystem increased markedly compared with that of pure silicon NWs and a planar Si/Cu2O structure, which means excellent hydrogen production capacity under irradiation with simulated sunlight. In addition, the photocatalytic performance of the core-shell nanosystem was improved obviously after platinum nanoparticles were electrodeposited on it.

Curvature effects on the bifunctional oxygen catalytic performance of single atom metal-N-C.

Understanding the fundamental relationship between the structural information of electrocatalysts and their catalytic activities plays a key role in controlling many important electrochemical processes. Recently, single-atom catalysts (SACs) with the so-called MN4 structure, consisting of a central transition metal quadruply bound to four pyridine nitrogen atoms all situated in an extended carbon-based matrix, have attracted intensive scientific attention owing to their exceptional catalytic performance. In this work, we perform the first-principles density functional theory (DFT) calculations to explore the curvature effects of the carbon matrix surfaces on the catalytic activities for two fundamental electrochemical processes, namely, the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER). Our DFT results suggest that the curved surface structure can weaken the interaction between the metal atom and the N-doped carbon matrix, modify the electronic structure of the metal atom, and thus increase the adsorption strength of the reaction intermediates, resulting in enhanced OER and ORR catalytic activities of MN4 catalysts. More importantly, a prediction model is developed to evaluate the bifunctional catalytic activities of such catalysts based on their directly obtained parameters including the surface curvature of the catalysts, the number of d electrons of the metal element, and the electronegativity of the metal atom and its coordination atoms in MN4 catalysts. This prediction model not only provides some candidates, for example, FeN4, CoN4 and OsN4 for the ORR; CoN4, NiN4, RuN4, RhN4 and IrN4 for the OER; and CoN4, RuN4, IrN4 and OsN4 for the bifunctional ORR and OER, but also reasonably links the structure of catalysts with their catalytic performance, providing new possibilities for the quick design of high-performance catalysts.

A Novel Al-Cu Composite with Ultra-High Strength at 350 °C via Dual-Phase Particle Reinforced Submicron-Structure.

Thermal stability determines a material's ability to maintain its performance at desired service temperatures. This is especially important for aluminum (Al) alloys, which are widely used in the commercial sector. Herein, an ultra-strong and heat-resistant Al-Cu composite is fabricated with a structure of nano-AlN and submicron-Al2 O3 particles uniformly distributed in the matrix. At 350 °C, the (8.2AlN+1Al2 O3 )p /Al-0.9Cu composite achieves a high strength of 187 MPa along with a 4.6% ductility under tension. The high strength and good ductility benefit from strong pinning effect on dislocation motion and grain boundary sliding by uniform dispersion of nano-AlN particles, in conjunction with the precipitation of Guinier-Preston (GP) zones, enhancing strain hardening capacity during plastic deformation. This work can expand the selection of Al-Cu composites for potential applications at service temperatures as high as ≈350 °C.

Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli.

The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli. From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli. Seven compounds, including ivacaftor (25), butenafine (19), naftifine (27), pimozide (30), thioridazine (35), trifluoperazine (37), and meloxicam (26), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor (25) inhibited efflux dose dependently, had no effect on an E. coli strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 µg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.

Enrollment Success, Factors, and Prediction Models in Cancer Trials (2008-2019).

PURPOSE: To investigate the enrollment success rate of cancer clinical trials conducted in 2008-2019 and various factors lowering the enrollment success rate. METHODS: This is a cross-sectional study with clinical trial information from the largest registration database ClinicalTrials.gov. Enrollment success rate was defined as actual enrollment greater or equal to 85% of the estimated enrollment goal. The association between trial characteristics and enrollment success was evaluated using the multivariable logistic regression. RESULTS: A total of 4,004 trials in breast, lung, and colorectal cancers were included. The overall enrollment success rate was 49.1%. Compared with 2008-2010 (51.5%) and 2011-2013 (52.1%), the enrollment success rate is lower in 2014-2016 (46.5%) and 2017-2019 (36.4%). Regression analyses found trial activation year, phase I, phase I/phase II, and phase II (v phase III), sponsor agency of government (v industry), not requiring healthy volunteers, and estimated enrollment of 50-100, 100-200, 200, and >500 (v 0-50) were associated with a lower enrollment success rate (P < .05). However, trials with placebo comparator, ≥5 locations (v 1 location), and a higher number of secondary end points (eg, ≥5 v 0) were associated with a higher enrollment success rate (P < .05). The AUC for prediction of the final logistic regression models for all trials and specific trial groups ranged from 0.69 to 0.76. CONCLUSION: This large-scale study supports a lower enrollment success rate over years in cancer clinical trials. Identified factors for enrollment success can be used to develop and improve recruitment strategies for future cancer trials.