Search Results (131)

Background: Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal antimicrobial exposure has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness have not previously been described. Methods: Pharmacokinetic, clinical and demographic data were collected from critically ill adults receiving intravenous clarithromycin. Drug concentrations were measured using high-performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling was added, and periods of renal replacement therapy were excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic–pharmacodynamic (PKPD) target attainment. Results: The analysis included 121 samples taken from 19 participants. A two-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates of clearance and volume of distribution were lower than previously reported, with high interindividual variability. Simulations suggested reasonable pharmacokinetic–pharmacodynamic (PKPD) target attainment with current dosing regimens for most organisms that clarithromycin is used to treat with known clinical breakpoints. Conclusions: To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin in humans. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population. Full article

With increasing demands for energy efficiency and environmental sustainability in pump stations, the development of digital and intelligent pump systems has become crucial. In this study, we focus on three speed ratios of pumps and propose a classification algorithm for pump performance curve fitting using the polyfit function based on the least squares principle. Software programs were developed to model and analyze pump performance curves. Additionally, the impact of seal ring clearance on pump performance and energy consumption was analyzed for pumps with specific speeds of 96.2, 185.5, and 493.3. External characteristic tests were conducted to evaluate these effects. When the clearance value of the sealing ring increases, the head and efficiency of the submersible sewage pump gradually decrease, while the shaft power of the pump presents different variation trends with an increase in the specific speed of the pump. When the specific speed is low–medium, the shaft power of the pump gradually increases. However, when the specific speed is relatively high (n_s > 300), the shaft power initially decreases, then increases, and finally decreases again. For intelligent monitoring, key variables and auxiliary power parameters were identified and mathematical models (Q-P and Q-H) were established as the basis for a soft measurement system. The results show that the Q-H, Q-P, and Q-η curves are generally fitted with polynomial curves of the third~fourth order. The maximum polynomial degree without inflection points is 3, while the maximum number of inflection points is 4, the two inflection points are fitted by segmentation. The pump monitoring system can integrates with an industrial cloud platform, enabling real-time parameter display, control, alarm of functions, recording and analyzing the historical data and operation trends. This research is significant for safe operation monitoring and energy conservation in pump systems. Full article

Background/Objectives: Physiologically based pharmacokinetic (PBPK) modeling is an important tool in biologic drug development. However, a standardized modeling strategy is currently missing. A cross-industry collaboration developed PBPK models for seven case studies, including monoclonal antibodies, antibody–drug conjugates, and bispecific T-cell engagers, to identify key parameters and establish a workflow to simulate biologic drugs in monkeys and in humans. Methods: PBPK models were developed in the monkey with limited data, including the molecular weight, the binding affinity to FcRn, and the additional systemic clearance of IgG, which is 20% of the total clearance. The binding affinity was only available for human FcRn and corrected for the known species-dependent differences in IgG binding. The strategy of monkey simulations was evaluated with an additional 14 studies published in the literature. Three different scenarios were simulated in humans afterwards: without, with allometrically scaled, and with optimized additional systemic clearance. Results: The plasma peak concentration and the area under the curve were predicted within 50% of the observed data for all studied case examples in the monkey, which demonstrates that sparse input parameters are sufficient for successful predictions in the monkey. Simulations in humans demonstrated the need for additional systemic clearance, because drug exposure was highly overpredicted without an additional systemic clearance term. Allometric scaling improved the predictions, but optimization led to the best fit, which is currently a limitation in the translation from animals to humans. Conclusions: This work highlights the importance of understanding the general mechanisms of drug uptake in different tissue types and cells in both target-dependent and -independent processes. Full article

Background: This study aimed to develop a population pharmacokinetic (PK) model that characterized the plasma concentration–time profiles of the total and unbound pamiparib, a PARP inhibitor, in glioblastoma patients and identified patient factors influencing the PK. Methods: The total and unbound pamiparib plasma concentration data were obtained from 41 glioblastoma patients receiving 60 mg of pamiparib twice daily. Nonlinear mixed-effects modeling was performed using Monolix (2024R1) to simultaneously fit the total and unbound drug plasma concentration data. The covariate model was developed by covariate screening using generalized additive modeling followed by stepwise covariate modeling. Model simulations were performed following oral doses of 10–60 mg BID. Results: The total and unbound pamiparib plasma concentration–time profiles were best described by a one-compartment model with first-order absorption and elimination. Creatinine clearance and age were the significant covariates on the apparent volume of distribution (V/F) and apparent clearance (CL/F), respectively, explaining ~22% and ~5% of IIV of V/F and CL/F. Population estimates of the absorption rate constant (Ka), V/F, CL/F, and unbound fraction for the total drug were 1.58 h⁻¹, 44 L, 2.59 L/h, and 0.041. Model simulations suggested that doses as low as 20 mg BID may be adequate for therapeutic effects in a general patient population, assuming that a target engagement ratio (i.e., unbound C_ss,min/IC50) of 5 or above is sufficient for full target engagement. Conclusions: The total and unbound pamiparib plasma PK are well characterized by a linear one-compartment model, with creatinine clearance as the significant covariate on V/F. Model simulations support further clinical investigation into dose reduction to optimize the benefit-to-risk ratio of pamiparib, particularly in combination therapies. Full article

Elastic rings are extensively utilized in aero-engine rotor systems owing to their compact size and ease of assembly, where they play a critical role in vibration suppression during engine operation. The dynamic behavior of elastic rings is governed by their structural parameters, with stiffness being a pivotal factor influencing the rotor system’s performance. This study employs finite element methods to investigate the effects of elastic ring structural parameters, particularly the geometric features of bosses and internal/external assembly clearances, on stiffness nonlinearity, with a focus on its mechanisms and contributing factors. The results reveal that stiffness nonlinearity emerges when the whirling radius exceeds a critical threshold. Specifically, increasing the boss width, reducing the boss height, or augmenting the number of bosses all attenuate stiffness nonlinearity under identical whirling radii. Furthermore, external clearances exhibit a stronger capability to suppress stiffness nonlinearity compared to internal clearances. Engineering insights suggest that maintaining a small clearance fit during assembly effectively mitigates stiffness nonlinearity, thereby enhancing the rotor’s dynamic performance. This study elucidates the stiffness nonlinearity behavior of elastic rings in practical applications and provides actionable guidance for their design and operational optimization in rotor systems. Full article

Background: Respiratory syncytial virus (RSV) is a common respiratory virus that can cause serious illness in infants and the elderly. Vaccines for RSV have recently been introduced and have been shown to reduce the severity of the disease. However, there has been limited examination of how viral dynamics differ between vaccinated and unvaccinated individuals. Methods: Here, we use data from the MVA-BN-RSV Phase II vaccine study to quantify the dynamical differences between vaccinated and unvaccinated patients challenged with RSV. We use an ordinary differential equation model of within host viral dynamics to fit viral load data. Results: We find statistically significant differences in viral clearance rate and basic reproduction number. We also find that vaccinated patients experience a higher response variance than the placebo group. Conclusions: While the differences in viral clearance and basic reproduction number are promising, the high variability in response to the vaccine could leave many vaccinated patients without adequate protection. Full article

The landing gear of an aircraft plays a crucial role in ensuring the safe takeoff and landing of the aircraft. Several defects in landing gear press molding may occur, including cross-section distortion, wall thickness thinning, and the springback phenomenon. These defects can significantly impact the quality of the molded product. This study employs a combination of finite element simulation and ML models to predict the springback angle of 7075 high-strength aluminum alloy pipes. The ABAQUS 2021 software was used to simulate the deformation behavior in the bending process based on the large deformation elastoplasticity theory. By utilizing the entropy method and analysis of variance (ANOVA), the significant factors affecting the forming quality were determined in the following order: pipe diameter > mandrel and pipe clearance > material properties > wall thickness > speed. The training set was augmented to improve the model generalization ability to build a multi-stage prediction model based on Lasso regression. The results show that the R² score of the ridge model reaches 0.9669, which is significantly better than other common machine learning methods. Finally, the model was applied to a real experimental dataset example through a transfer learning technique, showing obvious improvement compared with the control group. This study effectively predicts the springback angle of large-diameter thin-walled pipes and significantly improves the molding quality of bent fittings. Full article

Target modules (TMs), intermediate molecules required for UniCAR T-cell therapy, are promising molecules for immunotheranostic approaches. In the current work, we developed TMs containing a monomeric or dimeric form of the antagonist bombesin peptide (BBN2) and assessed their potential for diagnostic imaging using positron emission tomography (PET) as well as immunotherapy in combination with UniCAR T-cells to target and image GRPR expression in prostate cancer. Synthesized monomeric and dimeric BBN2 TMs retained binding to GRPR in vitro. Both BBN2 TMs specifically activated and redirected UniCAR T-cells to eradicate PC3 and LNCaP cancer cells with high efficiency and in a comparable manner. UniCAR T-cells retained a non-exhausted memory phenotype favorable to their persistence and fitness. The ⁶⁸Ga-labeled BBN2 TMs showed proof-of-target towards GRPR in PC3 and LNCaP xenografts with similar uptake profiles for both BBN2 TMs in dynamic PET experiments. Clearance occurred exclusively through renal elimination. A tremendously increased in vivo metabolic stability of the BBN2 TMs was observed compared to their counterparts without E5B9. Both monomeric and dimeric BBN2 TMs represent novel and promising immunotheranostic tools for application in prostate cancer with exceptionally high in vivo metabolic stability. Full article

This study aims to investigate the dynamic behavior of water-lubricated stern bearings during service. A transient rotor dynamics numerical model is developed to research the effects of operating conditions and critical structural parameters on the variation patterns of the dynamic characteristic coefficients and journal orbit of WLBs. The main stiffness and damping formulas for dimensionless bearings are fitted based on numerical results. Additionally, the accuracy of the model calculations is experimentally verified on a water-lubricated bearing test rig. The results demonstrate that the variation trends of the main stiffness and main damping coefficients in the horizontal and vertical directions of the bearings are proportional to the external load and inversely proportional to the rotational speed. Under eccentric excitation, the dynamic characteristic coefficients of the bearings change periodically with time as an approximately sinusoidal function. With the increase in the bearing length-to-diameter ratio or the decrease in the radial clearance-to-radius ratio, the main stiffness and the main damping coefficients in the horizontal direction increase, while the main stiffness coefficient in the vertical direction decreases. This study provides theoretical support for modeling the transient transverse vibration of a propulsion shaft system. Full article

Background/Objectives: Foam rolling is a new and emergent recovery tool in sports. The aim of this study seeks to compare the acute effects of foam rolling and passive rest on recovery markers in CrossFit athletes following a high-intensity workout. Methods: A quasi-experimental crossover study design was completed with 14 amateur CrossFit athletes. Participants completed the FRAN CrossFit WOD and then completed a recovery protocol including either a foam roller or passive rest. Heart rate, blood lactate, and perceived exertion were collected at three time points (pre-workout, post-WOD, and post-recovery). Results: The foam rolling group had no significant differences from the passive rest group on recovery markers. Blood lactate increased significantly post-WOD in both groups, yet there was no significant difference in blood lactate post-recovery. Perceived exertion and heart rate had a similar pattern to blood lactate. Conclusions: High-intensity training causes significant physiological changes; however, foam rolling offers no additional benefit over passive rest for lactate clearance, heart rate recovery, and perceived exertion. CrossFit athletes can choose their preferred method of recovery based on personal preference, as foam rolling neither enhances nor hinders recovery. Full article

Background: For many decades, gemcitabine + cisplatin has been a preferred and accepted treatment option for patients with urothelial cancer (UC). In patients ineligible for standard-dose cisplatin, split-dose cisplatin is a promising alternative. This study aimed to provide insights into the use of split-dose cisplatin and factors influencing treatment choice. Methods: Between January and March 2024, an international cross-sectional survey was carried out, which involved oncologists and urologists treating patients with locally advanced/metastatic UC (la/mUC) in Australia, Brazil, Canada, France, Germany, India, Italy, Spain, the UK, and the USA. Demographics, practice patterns, and clinical parameters influencing treatment choice were collected. Results: Of the 791 respondents, most were male (73%), the mean age was 43 years, and the mean time spent in clinical practice was 13 years. In total, 85% reported using split-dose cisplatin in UC, ranging from 97% in Canada to 67% in Brazil. The preferred schedule in la/mUC was gemcitabine + cisplatin 35 mg/m² on days 1 and 8 of 21-day cycles (57%). Most respondents (64%) were comfortable prescribing split-dose cisplatin to otherwise fit patients with a creatinine clearance ≥40 mL/min. Standard- and split-dose cisplatin were preferred regimens for otherwise fit patients with creatinine clearance of 45–60 mL/min. Conclusions: This large international survey demonstrates the extensive use of split-dose cisplatin in patients with la/mUC. Responses indicate that split-dose cisplatin is administered to patients in clinical practice with a wider range of creatinine clearance, performance status, and comorbidities than suggested for standard-dose cisplatin. Results highlight the need to evaluate split-dose cisplatin prospectively and establish consensus guidelines for its use, especially in patients unfit for standard-dose cisplatin. Full article

As drilling depth increases, the demand for a multi-layer wellbore structure grows. However, with the upper wellbore diameter fixed, reducing the casing-to-wellbore clearance becomes necessary to increase the number of casing strings. This poses a significant challenge to maintaining adequate casing-to-wellbore clearance. However, in actual drilling operations, the casing-to-wellbore clearance cannot be continuously reduced. Equivalent circulating density (ECD) during running casing becomes a critical factor to consider. When the casing-to-wellbore clearance is too small, excessive surge pressures can occur, increasing the risk of lost circulation. In this study, a surge pressure calculation model was developed for the casing running process to analyze the variation in ECD under 10,000 m well conditions in China. Focusing on key formations with narrow density windows, the effects of different casing-to-wellbore clearances on ECD were evaluated. The analysis determined that under the constraints of fracture pressure, the minimum allowable casing-to-wellbore clearance for this casing string is 27 mm. Subsequently, using response surface methodology, a fitting formula was derived to describe the relationship between the selected variables—drilling fluid density, casing running speed, and casing-to-wellbore clearance—and the ECD during casing operations. This provides a theoretical basis for the optimal matching of casing-to-wellbore clearance. Full article

Increasing evidence suggests that dalbavancin is an effective long-term treatment for ventricular assist device (VAD) infections, with various prolonged dosing regimens currently in use. This retrospective study aimed to assess dalbavancin pharmacokinetics in VAD patients and identify optimal, feasible dosing regimens for long-term suppressive outpatient therapy. Data from Heidelberg University Hospital’s VAD register were analyzed using non-linear mixed-effects modeling for pharmacokinetic analysis and dosing simulations (Lixoft^®). The probability of target attainment (PTA) and cumulative fraction of response (CFR) were calculated for different protein-binding scenarios considering the minimum inhibitory concentration (MIC) distribution of Staphylococcus aureus. Using data from 13 patients with 38 blood samples, a two-compartment model best described the dalbavancin pharmacokinetics, with a typical value for clearance of 0.050 L/h, central volume of distribution of 6.5 L, and peripheral volume of 15.4 L. No covariates significantly improved the model fit. The observed protein binding varied between 96 and 98%. Dosing simulations demonstrated that 1500 mg every 3 weeks ensured the target attainment for stasis at MIC values of 0.125 mg/L (PTA ≥ 90%) up to a protein binding of 99%. Considering the CRF, longer dosing intervals up to 5 weeks might be possible. Depending on individual MICs and protein binding, a dalbavancin regimen of 1500 mg every 3 to 5 weeks therefore appears to be a valuable option for outpatient therapy of VAD infections. Therapeutic drug monitoring should be considered to manage inter-individual variability and to support clinicians in long-term treatments of subacute and chronic infections. Full article

Hydraulic spool valves may clamp under the action of sensitive particles when working in hydraulic oils that contain solid particles, which will then bring about a devastating detriment to the machines. According to the failure statistics of hydraulic systems organized by ISO, more than 80% of the operational failures of hydraulic systems are caused by fluid contamination, and particulate contamination is the most important factor causing spool valve stagnation. In this paper, we considered various factors, including the material, size, and concentration of particles and the spool postures, and built a systematic spool clamping mechanical model. A device was designed to measure the spool valve friction under the action of particles. The influence of particle material, concentration, and size on the friction force of spool valves was investigated. By experiments, we measured the spool clamping force under the action of each single factor and then fitted the datum quantity of spool clamping force and the empirical equation of pulsating quantity. The study results demonstrate three types of non-ideal postures of spools in a valve hole, which are off-center, tilting, and off-center with tilting. Those three postures can engender clamping risk zones with different ranges inside the clearance between spool valves, increasing the risk of spool clamping. The kind of particles is found to have a certain but limited impact on the spool clamping force. Usually, particles with a higher elastic modulus can trigger a larger spool clamping force, which is in line with the theoretical equation. Within a certain range, the probability density distribution of particle size tallies with the normal distribution function, where the “sensitive particles” take up 0.7–1 of the clearance between spool valves. A higher particle volume fraction in oils means a greater number of sensitive particles and a larger spool clamping force. For the particles of a similar size with the clearance between spool valves, when their volume concentration tops over the “sensitive concentration”, namely 5%, the risk of spool clamping rises in a drastic manner. This study provides a theoretical reference and an empirical equation for the mechanism of spool clamping under the action of particles, as well as a definite quantitative indicator for the prediction and estimation of spool clamping which is of positive significance for the study of the predictive maintenance of hydraulic equipment. Full article

This study addresses the issue of unsatisfactory smoothness in the movement of integrated internal and external cross roller bearings post-assembly, which compromises the movement flexibility of the finished bearing and fails to meet index requirements. Focusing on a specific type of precision cross roller bearing, this paper establishes a finite element explicit dynamic simulation model that takes into account the plugging position and matching relationship. A transient dynamic simulation of the roller blockage process was conducted, yielding insights into the contact pressure and deformation experienced by the roller and plug during this blockage. The results indicate that when both the taper pin are positioned centrally, and the plug matching clearance, plug sag and protruding amount, and plug rotation offset degrees are all set to 0 μm, the contact pressure between the roller and raceway, as well as the roller deformation displacement, are minimized. The plugging position and fit were subsequently validated through testing, which also measured the impact of these parameters on the roundness of the raceway surface and the bearing’s friction torque. The test findings corroborate that when the taper and pin are centrally aligned, and the stopper clearance is 5 μm, with the plug sag, protrusion, and offset all at 0 μm, the roundness of the raceway surface and the bearing’s friction torque reach their lowest values, thereby optimizing the stability of bearing motion. By comparing the simulation and experimental results, it is concluded that during bearing assembly, it is crucial to maintain the taper pin in a central position, control the plug matching clearance to approximately 5 μm, and ensure the plug sag, protrusion, and rotation offset amount are both at 0 μm. This approach guarantees optimal contact conditions and motion stability during operation. The findings of this research offer valuable design guidance for the selection of appropriate plugging positions and fits in precision cross roller bearings. Full article