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1.
J Med Chem ; 67(5): 3437-3447, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38363074

RESUMO

Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 µM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Humanos , Animais , Camundongos , Tripanossomíase Africana/tratamento farmacológico , Trypanosoma brucei rhodesiense , Trypanosoma brucei gambiense , Tripanossomicidas/toxicidade , Tripanossomicidas/uso terapêutico
2.
Crit Care ; 28(1): 26, 2024 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-38245768

RESUMO

BACKGROUND AND AIMS: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN. METHODS: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion. RESULTS: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L. CONCLUSIONS: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L. TRIAL REGISTRATION: ISRCTN12233792, registered on November 24, 2017.


Assuntos
Estado Terminal , Nutrição Enteral , Humanos , Estado Terminal/terapia , Ingestão de Energia , Nutrição Enteral/métodos , Unidades de Terapia Intensiva , Estado Nutricional , Nutrição Parenteral/métodos , Proteínas , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Cancer Chemother Pharmacol ; 93(4): 307-317, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37955741

RESUMO

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement. Fifty-eight participants received treatment. Total exposure to fedratinib was similar after oral administration of intact capsules or when dispersed in a nutritional supplement (area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration geometric mean ratio [AUC0-t GMR] [90% CI], 1.007 [0.929-1.092]). Total exposure to fedratinib was slightly reduced following nasogastric administration (AUC0-t GMR 0.850 [0.802-0.901]) and as a divided dose (AUC0-t GMR 0.836 [0.789-0.886]). No new safety signals were identified for fedratinib, and most participants found the taste and palatability acceptable when dispersed in a nutritional supplement. Overall, results suggest no clinically meaningful differences in total exposure to fedratinib between the tested oral administration methods. These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).


Assuntos
Disponibilidade Biológica , Adulto , Humanos , Estudos Cross-Over , Administração Oral , Área Sob a Curva
4.
J Colloid Interface Sci ; 652(Pt A): 1006-1015, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37639923

RESUMO

Designing Pt-skin on the catalyst surface is critical to developing efficient and stable electrocatalysts toward oxygen reduction reaction (ORR) in proton exchange membrane fuel cells. In this paper, an acidic reductant is proposed to synchronously manipulate in-situ growth of Pt-skin on the surface of alloyed Pt-Cu nanospheres (PtCuNSs) by a facile one-pot synthesis in an aqueous solution. Ascorbic acid can create a Pt-skin of three atomic layers to make the typical PtCu-alloy@Pt-skin core/shell nanostructure rather than the uniform alloys generated by using alkaline reductants. Surfactant as soft-template can make the alloyed PtCuNSs with a three-dimensional porous network structure. Multiple characterizations of XRD, XPS and XAFS are used to confirm Pt-alloying with Cu and formation of core/shell structure of such a catalyst. This PtCuNSs/C exhibits a half-wave potential of 0.913 V (vs. RHE), with mass activity and specific activity about 3.5 and 6.4 times higher than those of Pt/C, respectively. Fuel cell tests verify the excellent activity of PtCuNSs/C catalyst with a maximum power density of about 1.2 W cm-2. Moreover, this catalyst shows excellent stability, achieving a long-term operation of 40,000 cycles. Furthermore, theoretical calculations reveal the enhancement effect of characteristic PtCu-alloy@Pt-skin nanostructure on both catalytic ORR activity and stability.

5.
Lancet ; 402(10402): 641-654, 2023 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-37295445

RESUMO

BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.


Assuntos
Leucemia Linfocítica Crônica de Células B , Idoso , Feminino , Humanos , Masculino , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Indução de Remissão , Sulfonamidas/uso terapêutico
6.
Opt Lett ; 48(13): 3591-3594, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37390188

RESUMO

Various approaches to implementing optical analog differentiation have been studied extensively and applied in edge-based image processing. Here, we report a topological optical differentiation scheme based on complex amplitude filtering, i.e., amplitude and spiral phase modulation in Fourier space. The isotropic and anisotropic multiple-order differentiation operations are demonstrated both theoretically and experimentally. Meanwhile, we also achieve multiline edge detection corresponding to the differential order for the amplitude and phase objects. This proof-of-principle work could open up new avenues for engineering a nanophotonic differentiator and realizing a more compact image-processing system.


Assuntos
Engenharia , Processamento de Imagem Assistida por Computador
7.
Opt Express ; 31(6): 9416-9427, 2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-37157513

RESUMO

Optical lattices with spatially regular structures have recently attracted considerable attention across physics and optics communities. In particular, due to the increasing emergence of new structured light fields, diverse lattices with rich topology are being generated via multi-beam interference. Here, we report a specific ring lattice with radial lobe structures generated via superposition of two ring Airy vortex beams (RAVBs). We show that the lattice morphology evolves upon propagation in free space, switching from a bright-ring lattice to dark-ring lattice and even to fascinating multilayer texture. This underlying physical mechanism is related to the variation of the unique intermodal phase between the RAVBs as well as topological energy flow with symmetry breaking. Our finds provide an approach for engineering customized ring lattices to inspire a wide variety of new applications.

8.
iScience ; 26(5): 106730, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37216112

RESUMO

Innovation of catalyst structure is extremely important to develop the high-performance electrocatalysts for oxygen-reduction reaction (ORR). Herein, nitrogen-doped carbon semi-tube (N-CST) is used as a functional support for stabilizing the microwave-reduced Pt nanoparticles with an average size of ∼2.8 nm to synthesize the semi-tubular Pt/N-CST catalyst. The contribution of interfacial Pt-N bond between N-CST support and Pt nanoparticles with electrons transfer from N-CST support to Pt nanoparticles is found by electron paramagnetic resonance (EPR) and X-ray absorption fine structure (XAFS) spectroscopy. This bridged Pt-N coordination can simultaneously help ORR electrocatalysis and promote electrochemical stability. As a result, the innovative Pt/N-CST catalyst exhibits excellent catalytic performance, realizing ORR activity and electrochemical stability superior to the commercial Pt/C catalyst. Furthermore, density functional theoretical (DFT) calculations suggest that the interfacial Pt-N-C site with unique affinity of O∗ + OH∗ can provide new active routes for the enhanced electrocatalytic ORR capacity.

9.
Materials (Basel) ; 16(9)2023 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-37176368

RESUMO

Fiber metal laminates have been widely used as the primary materials in aircraft panels, and have excellent specific strength. Bending deformation is the most common loading mode of such components. An accurate theoretical predictive model for the bending process for the carbon reinforced aluminum laminates is of great significance for predicting the actual stress response. In this paper, based on the metal-plastic bending theory and the modified classical fiber laminate theory, a modified bending theory model of carbon-fiber-reinforced aluminum laminates was established. The plastic deformation of the thin metal layer in laminates and the interaction between fiber and metal interfaces were considered in this model. The bending strength was predicted analytically. The FMLs were made from 5052 aluminum sheets, with carbon fibers as the reinforcement, and were bonded and cured by locally manufacturers. The accuracy of the theory was verified by three-point bending experiments, and the prediction error was 8.4%. The results show that the fiber metal laminates consisting of three layers of aluminum and two layers of fiber had the best bending properties. The theoretical model could accurately predict the bending deformation behaviors of fiber metal laminates, and has significant value for the theoretical analysis and performance testing of laminates.

10.
Polymers (Basel) ; 15(9)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37177244

RESUMO

The surface microstructure formed by physical or chemical modification is essential for the desired joint strength. However, defects in the bonding interface and adhesive can be found. Such defects decrease shear strength and durability. In this study, ultrasonic vibration was applied to liquid adhesive on the sandblasted aluminum alloy plates. With ultrasonic treatment, the joints obtained the compact bonding interfaces and lower porosity of the adhesive layer. The treatment improved the shear strength by 9.1%. After two weeks of hydrothermal aging, the shear strength of joints only sandblasted decreased drastically by 48.9%, while it was 14% for the joints with ultrasonic vibration. The cavitation effect in the adhesive was detected by the aluminum foil erosion method. The result showed that a great number of micro-jets generated by the cavitation effect have intensive impact on the bonding interface which provide the adhesive with powerful force to fill the micro-grooves. Another finding in this work is that bubbles were gathered in the adhesive away from the vibration area. This mechanism was successfully used to reduce the porosity of the adhesive layer of joints.

11.
J Med Chem ; 66(11): 7374-7386, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37216489

RESUMO

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.


Assuntos
Antiprotozoários , Leishmania , Leishmaniose , Humanos , Animais , Camundongos , Leishmaniose/tratamento farmacológico , Leishmaniose/induzido quimicamente , Leishmaniose/parasitologia , Antiprotozoários/química , Benzamidas/farmacologia , Benzamidas/uso terapêutico
12.
Materials (Basel) ; 16(4)2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36837311

RESUMO

The rocket nozzle is one of the core components to ensure the safe flight of rockets. To overcome the problems of multi-step forming, the occurrence of defects, and severe plastic deformation in traditional technology, a novel forming method named tube upsetting-bulging (TUBG) is put forward. With the support of internal pressure, a tube is deformed with an upsetting and bulging process at the same time. The tube is thickened at the small end and thinned at the large end. A nozzle with sharply varying diameters can be obtained. A theoretical model of TUBG that considers wrinkles and rupture is built. The influence factors of internal pressure during TUBG are discussed. Experiments and simulation works are conducted to analyze the plastic deformation process of TUBG. Results show that mechanical properties and geometrical parameters have an obvious influence on critical internal pressure. The proposed theoretical model can be used to predict a forming zone without wrinkles, rupture, and severe strain values. A well-formed nozzle can be obtained using the predicted forming zone, which verifies the correctness of the theoretical analysis. It can be found that TUBG is a novel potential method to fabricate rocket nozzles with high efficiency and quality without defects.

13.
Materials (Basel) ; 16(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36676415

RESUMO

Problems of rapid degradation and poor biocompatibility (endothelialization and hemocompatibility) limit magnesium (Mg) alloy's further applications in vascular stents. To solve these problems, a novel composite coating was designed on Mg alloy via a two-step method. First, a Mg alloy sample was immersed in hydrofluoric acid. Then, a poly-l-lactic acid (PLLA) coating was made by ultrasonic atomization spraying with 5 and 10 layers (referred to as PLLA(5)-HF-Mg and PLLA(10)-HF-Mg). Characterizations were analyzed from the microstructure, element distribution, and wettability. The degradation behavior was tested with an electrochemical test and immersion test. Endothelialization was investigated using human umbilical vein endothelial cells (HUVECs). Hemocompatibility was examined with a platelet adhesion test. The results showed that the PLLA coating could not only cover the surface, but also could permeate through and cover the holes on the MgF2 layer, mechanically locked with the substrate. Thus, the composite coating had higher corrosion resistance. The PLLA/MgF2 coating, especially on PLLA(10)-HF-Mg, enhanced HUVECs' viability and growth. While incubated with platelets, the PLLA/MgF2 coating, especially on PLLA(10)-HF-Mg, had the lowest platelet adhesion number and activity. Taken together, the novel PLLA/MgF2 coating controls Mg alloy's degradation by spraying different layers of PLLA, resulting in better endothelialization and hemocompatibility, providing a promising candidate for cardiovascular stents.

14.
Microsc Res Tech ; 86(2): 181-192, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36278826

RESUMO

The evaluation of oocyte viability in the laboratory is limited to the morphological assessment by naked eyes, but the realization that most normal-appearing oocytes may conceal abnormalities prompts the search for automated approaches that can detect the abnormalities imperceptible to naked eyes. In this study, we developed an image processing pipeline applicable to bright-field microscope images to quantify the causal relationship between the quantitative imaging features and the developmental potential of oocytes. We acquired 19 imaging features of approximately 700 oocytes and determined two imaging subtypes, namely viable and nonviable subtypes that correlated closely with a viability fluorescence indicator and cleavage rates. The causal relationship between these imaging features and oocyte viability was derived from a viability-oriented Bayesian network that was developed based on the Bayesian information criterion and Tabu search. Our experimental results revealed that entropy with mean Gray Level Co-Occurrence Matrix energy describing the uniformity and texture roughness of cytoplasm were salient features for the automated selection of promising oocytes that exhibited excellent developmental potential.


Assuntos
Oócitos , Teorema de Bayes , Citoplasma
15.
Polymers (Basel) ; 14(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36236158

RESUMO

To accurately evaluate the mechanical performance of three-dimensional (3D) braiding composites, it is essential to consider the braiding process and generate realistic representative volume element (RVE) structures. An efficient simulation methodology based on truss elements was used to simulate the 3D four-directional (3D4D) braiding process utilizing the finite element method (FEM) on the macroscale. The goal was to obtain the spatial trajectories of yarns and establish the relationship between the braiding parameters and the preform structure. Based on the initial yarn topology, the yarns were discretized as bundles of virtual sub-yarns. Then, a temperature drop simulation using hybrid elements was implemented to deform the yarn cross-section and obtain the interior, surface, and corner cells on the mesoscale. The simulation results show good agreement with the experiment. A parametric study was deployed to identify the effect of the model input parameters on the computation cost and accuracy. Furthermore, the approach applies to the other braiding processes, such as the cylindrical braiding composite.

16.
Ultrason Sonochem ; 89: 106126, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36007330

RESUMO

Poor adhesion of nickel surface limits its further application in the aerospace field. In this study, plasma modification was conducted on the surface of the nickel plate pretreated by sandblasting, and then ultrasonic vibration was applied during the adhesively bonding process of the CFRP(Carbon fibre-reinforced polymer)/Ni joints. The bonding strength of the joints was increased by 65%. The adherend surface and the bonding interface were analyzed from microstructure, element distribution and chemical bonding to study the strengthening mechanism. By the sandblasting, irregular pits were formed on the nickel surface, effectively increasing the surface roughness. The plasma modification could introduce active functional groups including hydroxyl, amino and carbonyl on the nickel surface, which improved the surface wettability macroscopically. However, at a microscopic level, the adhesive with high viscosity and poor fluidity did not form a compact interface with the nickel. The ultrasonic application could promote the filling of the adhesive in irregular micro-scale pits on the surface, thereby strengthening the mechanical anchoring effect. Furthermore, the ultrasonic application produced dynamic impingement at the interface, enhancing the contact between the adhesive and the nickel plate. The adhesive molecules could fully collide and react with the active functional groups introduced on the nickel surface to form more chemical bonds, thus effectively improving the bonding strength of the CFRP/Ni joints.


Assuntos
Adesivos , Níquel , Fibra de Carbono , Teste de Materiais , Níquel/química , Plásticos , Ondas Ultrassônicas
17.
Cancer Chemother Pharmacol ; 90(4): 325-334, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36001108

RESUMO

PURPOSE: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib. This study evaluated the effect of multiple doses of the dual CYP3A4 and CYP2C19 inhibitor, fluconazole, on the pharmacokinetics of a single dose of fedratinib. METHODS: In this non-randomized, fixed-sequence, open-label study, healthy adult participants first received a single oral dose of fedratinib 100 mg on day 1. Participants then received fluconazole 400 mg on day 10 and fluconazole 200 mg once daily on days 11-23, with a single oral dose of fedratinib 100 mg on day 18. Pharmacokinetic parameters were calculated for fedratinib administered with and without fluconazole. RESULTS: A total of 16 participants completed the study and were included in the pharmacokinetic population. Coadministration of fedratinib with fluconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) of fedratinib by 21% and 56%, respectively, compared with fedratinib alone. Single oral doses of fedratinib 100 mg administered with or without fluconazole were well tolerated. CONCLUSIONS: Systemic exposure after a single oral dose of fedratinib was increased by up to 56% when fedratinib was coadministered with fluconazole compared with fedratinib alone. TRIAL REGISTRY: CLINICALTRIALS.GOV: NCT04702464.


Assuntos
Fluconazol , Pirrolidinas , Adulto , Área Sob a Curva , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Fluconazol/farmacocinética , Voluntários Saudáveis , Humanos , Pirrolidinas/farmacocinética , Sulfonamidas/farmacocinética
18.
Micromachines (Basel) ; 13(7)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35888904

RESUMO

The early steps of embryogenesis are controlled exclusively by the quality of oocyte that linked closely to its mechanical properties. The mechanical properties of an oocyte were commonly characterized by assuming it was homogeneous such that the result deviated significantly from the true fact that it was composed of subcellular components. In this work, we accessed and characterized the subcellular components of the oocytes and developed a layered high-fidelity finite element model for describing the viscoelastic responses of an oocyte under loading. The zona pellucida (ZP) and cytoplasm were isolated from an oocyte using an in-house robotic micromanipulation platform and placed on AFM to separately characterizing their mechanical profiling by analyzing the creep behavior with the force clamping technique. The spring and damping parameters of a Kelvin-Voigt model were derived by fitting the creeping curve to the model, which were used to define the shear relaxation modulus and relaxation time of ZP or cytoplasm in the ZP and cytoplasm model. In the micropipette aspiration experiment, the model was accurate sufficiently to deliver the time-varying aspiration depth of the oocytes under the step negative pressure of a micropipette. In the micropipette microinjection experiment, the model accurately described the intracellular strain introduced by the penetration. The developed oocyte FEM model has implications for further investigating the viscoelastic responses of the oocytes under different loading settings.

19.
Polymers (Basel) ; 14(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35808668

RESUMO

Carbon fiber reinforced polymer (CFRP) blades are often exposed to wild and even harsh environments. The durability of the blade can be greatly improved by adhesively bonding a Ni erosion shield to the leading edge. In a traditional bonding process, the permeation of adhesive is poor at the interface, which gives an insufficient micromechanical interlocking. In this study, ultrasonic vibration was applied during the bonding process of sandblasted Ni plates and CFRP laminates. The values of shear strength were measured by tensile tests to verify the strengthening effect of applying ultrasonication. The cross-section of the bonded interface was characterized by scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS), and the surfaces with different treatments were explored by atomic force microscopy (AFM). The cross-sectional morphology and failure model of the samples were investigated. The strengthening mechanism was then studied by a molecular dynamics method. For the simulation of molecular dynamics, the CFRP/Ni bonding interface model was designed using the Materials Studio software package. The Perl scripts were used to simulate the ultrasonic vibration with different frequencies and amplitudes. The results showed that the ultrasonic process could improve the permeability and uniformity of the adhesive, enhancing the micromechanical interlocking effect.

20.
Polymers (Basel) ; 14(5)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35267727

RESUMO

Traditional thickness-prediction methods underestimate the actual dome thickness at polar openings, leading to the inaccurate prediction of the load-bearing capacity of composite hydrogen storage vessels. A method of thickness prediction for the dome section of composite hydrogen storage vessels was proposed, which involved fiber slippage and tow redistribution. This method considered the blocking effect of the port on sliding fiber tows and introduced the thickness correlation to predict the dome thickness at polar openings. The arc length corresponding to the parallel circle radius was calculated, and then, the actual radius values corresponding to the bandwidth were obtained by the interpolation method. The predicted thickness values were compared with the actual measured thickness. The maximum relative error of the predicted thickness was 4.19%, and the mean absolute percentage error was 2.04%. The results show that the present method had a higher prediction accuracy. Eventually, this prediction method was used to perform progressive damage analysis on vessels. By comparing with the results of the cubic spline function method, the analysis results of the present method approached the actual case. This showed that the present method improved the accuracy of the design.

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