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Mechanistic models of hepatic clearance have been evaluated for more than 50 years, with the first author of this mini-review serving as a co-author of the first paper proposing such a model. However, published quality experimental data are only consistent with the first of these models, designated as the well-stirred model, despite the universal recognition that this model is physiologically unrepresentative of what occurs with respect to liver metabolism and transport. Within the last 3 years, our laboratory has recognized that it is possible to derive clearance equations employing the concepts of Kirchhoff's Laws from physics, independent of the differential equation approach that has been utilized to derive reaction rates in chemistry. Here we review our published studies showing that the equation previously believed to be the well-stirred model, when hepatic basolateral transporters are not clinically relevant, is in fact the general equation for hepatic clearance when only systemic drug concentrations are measured, explaining why all experimental data fit this equation. To demonstrate that the equations deriving the mechanistic models of hepatic elimination for the past 50 years are not valid, we show that when calculating Kpuu, the ratio of unbound drug concentration in the liver to the unbound concentration of drug in the systemic circulation, for the well-stirred, parallel tube and dispersion models, Kpuu surprisingly can never exceed 1 and is a function of FH, the hepatic bioavailability following oral dosing. We believe that knowledgeable drug metabolism scientist and clinical pharmacologist will agree that this outcome is nonsensical. [ABSTRACT FROM AUTHOR]

Due to the design, manufacturing, and assembly processes, joint clearance inevitably occurs in mechanisms. To reduce the undesirable effects of this phenomenon, in this work a practical control method to decrease these effects is presented. This control method ensures permanent joint contact and follows the desired path based on the actuators in the system. As a result, because the controller seeks to achieve two control demands using one actuator, these mechanisms are known as an under-actuated system. For this purpose, an improved second-order sliding-mode controller (IS-SMC) is proposed. This choice is based on its robustness and its ability to meet control demands in a finite time, as well as its high accuracy for sub-excitation systems. In this research, the control method is applied to the crank-slider and the four-bar mechanisms. For this purpose, at first, the equations of these mechanisms have been expressed in an ideal form, and then the nonlinear equations have been extracted with the imperfect joint. The Lankarani-Nikravesh and the Ambrosio models have been used for modeling the clearance and friction force in the joint, respectively. In addition, verification of controller is implemented in Adams software. [ABSTRACT FROM AUTHOR]

In order to study the effect of design parameters on the contact performance of cycloid reducer, a new contact collision force model applicable to various restitution coefficients is proposed. Firstly, based on the L-N nonlinear contact theory and improved Winkler model, a contact force model with contact depth index and damping was proposed. Secondly, Hertzian contact theory was used to clarify the contact area, precise position and relative contact speed between the output pin and the cycloidal wheel in the presence of a clearance. By using the improved contact force model and simulation analysis, the effects of structural design parameters and working condition parameters on contact force were discussed. Finally, with the goal of reducing the contact force and volume of the reducer, the NSGA-II multi-objective genetic algorithm was used to construct an optimization model for the structural parameters of the reducer. The results show that the optimized structural parameters can effectively reduce the contact force of the output mechanism. [ABSTRACT FROM AUTHOR]

D-Alanine, a rare enantiomer of alanine, can potentially alleviate the worsening of viral infections and maintain circadian rhythm. This study aimed to analyze the kinetics of D-Alanine upon oral intake. Five healthy volunteers were administered D-Alanine as a single oral dose at 11,236 or 33,708 µmoL (1–3 g). Upon intake of the lower dose, the plasma level of D-Alanine reached its peak concentration of 588.4 ± 40.9 µM with a peak time of 0.60 ± 0.06 h. The compartment model estimated the clearance of D-Alanine at 12.5 ± 0.3 L/h, or 208 ± 5 mL/min, distribution volume of 8.3 ± 0.7 L and half-life of 0.46 ± 0.04 h, suggesting a rapid clearance of D-Alanine. The peak concentration and area under the curve increased proportionally upon intake of the higher dose, while the clearance, distribution volume and half-life did not. The urinary ratio of D-Alanine per sum of D- and L-Alanine reached its peak of nearly 100%, followed by a slow decline. The peak time of the urinary ratio was 1.15 ± 0.15 h, showing a time lag of blood to urine excretion. Fractional excretion, a ratio of the clearance of a substance per a standard molecule in kidney, of D-Alanine increased from 14.0 ± 5.8% to 64.5 ± 10.3%; the latter corresponded to the urinary clearance of D-Alanine as about 77 mL/min for an adult, with a peak time of 1.90 ± 0.56 h. D-Alanine was quickly absorbed and appeared in blood, followed by urinary excretion. This kinetic analysis increases our fundamental knowledge of the oral intake of D-Alanine for the chronic dosing. Trial number: #UMIN000050865. Date of registration: 2023/6/30. [ABSTRACT FROM AUTHOR]

Background: Misfolding and aggregation of amyloid β (Aβ), along with neurofibrillary tangles consisting of aggregated Tau species, are pathological hallmarks of Alzheimer’s disease (AD) onset and progression. In this study, we hypothesized the clearance of Aβ aggregates from the brain and body into the gut. Methods: To investigate this, we used surface-based fluorescence intensity distribution analysis (sFIDA) to determine the Aβ aggregate concentrations in feces from 26 AD patients and 31 healthy controls (HC). Results: Aβ aggregates were detectable in human feces and their concentrations were elevated in AD patients compared to HC (specificity 90.3%, sensitivity 53.8%). Conclusion: Thus, fecal Aβ aggregates constitute a non-invasive biomarker candidate for diagnosing AD. Whether digestion-resistant Aβ aggregates in feces are secreted via the liver and bile or directly from the enteric neuronal system remains to be elucidated. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49–1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93–1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52–1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78–1.34)] compared to the survivors [0.57 (0.48–0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis. [ABSTRACT FROM AUTHOR]

[Objective] Clearance between motion pairs is commonly observed in mechanisms due to manufacturing errors in components, assembly requirements, and wear of the mechanisms. When the mechanism operates at high speeds with large loads and small cross-sectional areas, components are susceptible to elastic deformation. This elastic deformation, combined with the clearance in motion pairs, significantly restricts the motion accuracy of the entire mechanism, leading to chaotic behavior and ultimately reducing its stability and reliability. Therefore, it is essential to investigate the influence of the coupling effect between the clearance of the motion pair and the flexible component on the motion state of the mechanism. [Methods] This paper proposes a chaos identification method for a rigid-flexible coupling experimental teaching platform with revolute clearance joints. First, a revolute clearance joint model was established based on the three-state model of "contact-separation-collision." In addition, a flexible beam element model was created using the absolute node coordinate method. Following this, a dynamic model of the rigid-flexible coupling six-link experimental platform with revolute clearance joints was established using the Lagrange multiplier method. Finally, both qualitative and quantitative identifications of chaotic phenomena in the six-link experimental platform were conducted using phase diagrams, Poincaré maps, and maximum Lyapunov exponents. The nonlinear characteristics of the rigid experimental platform with clearance and the rigid-flexible coupling experimental platform with clearance were compared and analyzed. Additionally, the effects of different clearance values, driving speeds, and friction coefficients on the nonlinear characteristics of the experimental teaching platform were studied. [Results] The results obtained using methods such as phase diagrams, Poincaré maps, and maximum Lyapunov exponents indicate that compared with the rigid experimental teaching platform mechanism with revolute clearance, the vibration frequency of the rigid-flexible coupling experimental teaching platform mechanism with revolute clearance is higher, leading to reduced stability and more pronounced chaotic phenomena. The chaotic behavior at the clearance of the revolute pair intensifies with an increase in clearance size and driving speed, whereas it weakens as the friction coefficient increases. [Conclusions] The coupling effect between the clearance of the motion pair and the flexibility of the component reduces the stability of the mechanism, leading to the emergence of chaos. The chaos identification method based on the experimental teaching of rigid-flexible coupling with revolute clearance proposed in this article can effectively distinguish the motion states of the mechanism. This method provides a systematic and comprehensive theoretical foundation for the study of nonlinear dynamics in high-precision, high-performance multilink mechanisms. This not only enhances students' ability to analyze and practice the nonlinear characteristics of mechanisms but also increases the diversity, intuitiveness, and engagement of the teaching process, ultimately improving the quality of education. [ABSTRACT FROM AUTHOR]

Secondary flow path is one of the crucial aspects during the design of centrifugal blood pumps. Small clearance size increases stress level and blood damage, while large clearance size can improve blood washout and reduce stress level. Nonetheless, large clearance also leads to strong secondary flows, causing further blood damage. Maglev blood pumps rely on magnetic force to achieve rotor suspension and allow more design freedom of clearance size. This study aims to characterize turbulent flow field and secondary flow as well as its effects on the primary flow and pump performance, in two representative commercial maglev blood pumps of CH-VAD and HeartMate III, which feature distinct designs of secondary flow path. The narrow and long secondary flow path of CH-VAD resulted in low secondary flow rates and low disturbance to the primary flow. The flow loss and blood damage potential of the CH-VAD mainly occurred at the secondary flow path, as well as the blade clearances. By contrast, the wide clearances in HeartMate III induced significant disturbance to the primary flow, resulting in large incidence angle, strong secondary flows and high flow loss. At higher flow rates, the incidence angle was even larger, causing larger separation, leading to a significant decrease of efficiency and steeper performance curve compared with CH-VAD. This study shows that maglev bearings do not guarantee good blood compatibility, and more attention should be paid to the influence of secondary flows on pump performance when designing centrifugal blood pumps. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body's natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis. [ABSTRACT FROM AUTHOR]

Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host‐protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement‐targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance. [ABSTRACT FROM AUTHOR]

A pump-turbine may generate high-amplitude hydraulic excitations during operation, wherein the flow-induced response of the spiral case and concrete is a key factor affecting the stable and safe operation of the unit. The preloading spiral case can enhance the combined bearing capacity of the entire structure, yet there is still limited research on the impact of the preloading pressure on the hydrodynamic response. In this study, the pressure fluctuation characteristics and dynamic behaviors of preloading a steel spiral case and concrete under different preloading pressures at rated operating conditions are analyzed based on fluid–structure interaction theory and contact model. The results show that the dominant frequency of pressure fluctuations in the spiral case is 15 f n , which is influenced by the rotor–stator interaction with a runner rotation of short and long blades. Under preloading pressures of 0.5, 0.7, and 1 times the maximum static head, higher preloading pressures reduce the contact regions, leading to uneven deformation and stress distributions with a near-positive linear correlation. The maximum deformation of the PSSC can reach 2.6 mm, and the stress is within the allowable range. The preloading pressure has little effect on the dominant frequency of the dynamic behaviors in the spiral case (15 f n ), but both the maximum and amplitudes of deformation and stress increase with higher preloading pressure. The high-amplitude regions of deformation and stress along the axial direction are located near the nose vane, with maximum values of 0.003 mm and 0.082 MPa, respectively. The contact of concrete is at risk of stress concentrations and cracking under high preloading pressure. The results can provide references for optimizing the structural design and the selection of preloading pressure, which improves operation reliability. [ABSTRACT FROM AUTHOR]

Mechanism systems are important components of dynamic mechanical systems. The time-varying reliability assessment of mechanism systems is of great significance for the safety and fault diagnosis of mechanical products. In this paper, a time-varying reliability evaluation method for mechanisms under the fatigue failure mode is proposed, which takes into account the joint effects of clearance, local structural stiffness, random load and random strength degradation. The proposed mechanism reliability models are established by nonlinear dynamic analysis considering failure factors and establishing random stress history characterization matrices. Additionally, the models are validated by the Monte Carlo simulation method. The results show that the mechanism clearance, local stiffness, and initial strength dispersion have a significant effect on the time-varying reliability of the mechanisms. Furthermore, both local stiffness and initial strength dispersion have a greater influence on the effect of clearance on the time-varying reliability of the mechanisms. The proposed reliability models can quantitatively analyze the dynamic effects of failure factors on the reliability of the mechanisms, which can be used for the stochastic remaining life evaluation and fault diagnosis of the mechanism systems. [ABSTRACT FROM AUTHOR]

The flow and mass transport through different membrane types from different hemodialyzers are investigated in a co-current direction to emphasize the effect of solute diffusion through the dialyzer membranes. The numerical model consists of the blood flowing in a hollow fiber surrounded by a dialysate flow, where the mass transport and fluid flow were simultaneously calculated. The high flux dialyzers considered in the present study are FINEFLUX FIX-210S eco, ELISIO-210HR, and PEPA FDY-21B, which differ mainly in characteristics of the membrane structure and surface. Urea and maltodextrin solutions are used as model solutes to consider the effect of molecular size difference. The numerically predicted outlet concentrations closely align with experimental values, where the variation between predicted and measured values remain below 10% across all dialyzer types for urea solutions, and specifically below 8% for maltodextrin solution. Among the various dialyzers tested, FINEFLUX membrane could provide the highest maltodextrin clearance (83.09 ml/min) and overall mass transfer area coefficient (KoA) (119.56 ml/min) potentially due to its fast-diffusion characteristic. In this co-current flow study, the results suggest that urea transport is primarily influenced by flow control with minimal impact from boundary layers, while maltodextrin transport is predominantly governed by diffusion control.Article Highlights: The mass transport simulation of different hemodialysis membranes (in co-current flow) closely aligns with the experimental results. FINEFLUX membrane could provide the highest maltodextrin clearance due to its fast-diffusion characteristic. Urea clearance is controlled by dialysate flow; maltodextrin clearance is limited by membrane diffusion. [ABSTRACT FROM AUTHOR]

Currently, some parts made from workpieces in the form of sheets or strips are obtained by applying piercing processes. In the research whose results are presented in the article, square-shaped holes were made to evaluate the piercing accuracy of the surfaces generated by piercing in sheets of three different metal materials (carbon steel 1.033, aluminum alloy AlMg3, and stainless steel X5CrNi18-10) with different thicknesses. Apart from the nature of the material, the thickness of the sheet, the size of the clearance between the puncher and the die, and the average speed of the puncher were considered as input factors in the piercing process. The output parameters tracked were the size of the side of the square-shaped hole and the height of the burr generated by the cut. The experimental results were mathematically processed using special software, obtaining empirical mathematical models that highlight the influence of the input factors considered on the deviation of the side size of the square-shaped hole and the burr height. The analysis of the results showed that the intended size of the square hole side exerts the strongest influence on the piercing accuracy. The factor with the most significant influence on the height of the burr is the clearance between the puncher and the die. [ABSTRACT FROM AUTHOR]

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20–35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0–24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0–24 following a VAN LD of 20 mg/kg. Methods: This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0–24. Therapeutic AUC0–24 was defined as 400–600 mg/l*h. Results: Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0–24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0–24, patients with subtherapeutic AUC0–24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0–24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0–24. Conclusions: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations. [ABSTRACT FROM AUTHOR]

The study investigated how variations in pressure ratio affect the leakage flow of a brush seal for both contact and clearance structures, in which the clearance is measured as the distance between the bristles tip and the rotor surface. This investigation utilized the Reynolds-Averaged-Navier–Stokes (RANS) equations alongside a two-dimensional axisymmetric anisotropic porous medium model. To verify the model's accuracy and dependability, the obtained results were compared with previous numerical results and experimental observations, showing a satisfactory level of agreement. The results indicate that the predominant pressure drop occurs downstream of the bristle pack with the clearance model exhibiting a higher leakage rate compared to the contact model. Leakage increases proportionally with the pressure ratio, while axial velocity gradually rises and radial velocity experiences a significant increase. In conclusion, the leakage in the brush seal contact structure is significantly lower than in the clearance structure, resulting in the best performance. [ABSTRACT FROM AUTHOR]

Bennett linkage has broad application prospects in civil engineering, aerospace engineering, mechanical engineering, etc. The existence of clearance in the revolute joints makes the journal collide with the bearing and thus affects the dynamic responses of the Bennett linkage. Based on the finite particle method, an effective approach is proposed for the dynamics analysis of the deployment process of the Bennett linkage with revolute clearance joints. Firstly, a simplified computational model of the Bennett linkage is proposed to consider the size effects and contacts. The corresponding beam element, torsion spring element, and face-to-face contact element are derived. Subsequently, the detection method of the axial and radial contact states of revolute clearance joints is presented, and the calculation model of the contact force is depicted. Finally, dynamics analysis of a typical Bennett linkage with clearance joints is carried out. The results of the simplified model are consistent with the higher-fidelity model, demonstrating the effectiveness of the proposed method. The Bennett linkage with clearance joints is observed to exhibit more oscillations than that with ideal joints during deployment, and its energy is dissipated due to the existence of clearance. The increase of the number of the revolute clearance joints leads to more dynamic effects of the mechanism. The increase of clearance size causes more oscillations in the mechanism. The increase of the friction coefficient in revolute clearance joints reduces the oscillations of the mechanism. The growth of the damping coefficient results in more energy dissipation and weakens the additional dynamic response caused by clearance. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate age, adjunctive antiseizure medication (ASM), and specific ASMs on lacosamide (LCM) weight normalized dose-to-concentration ratio (DCR) and US Food and Drug Administration (FDA) dosing guidelines in pediatric patients. METHODS Patients 1 mo to ≤18 years with a LCM serum concentration between October 2009 and June 2017 were considered. Demographics, LCM DCR, and adjunctive ASM were recorded. LCM DCR/hr was used as a surrogate for clearance. Data were stratified by age (1 mo-< 2 yr; ≥ 2–6 yr; ≥ 6–12 yr; and ≥12–≤18 yr), FDA dosing weights, and ASM potential to interaction with LCM. RESULTS There were 646 sera (380 patients) with median dose 8.36 mg/kg/day (IQR, 5.92–11.16). 50.2% of doses were within FDA-weight guidelines; however, 40.4% exceeded recommendations. Most (81.3%) LCM concentrations were between 2 and 12 mg/L. A difference existed in DCR between ages, with those <2 years having the highest DCR (p < 0.001). Moving across age groups, the DCR decreases by 30.7%, 50.5%, and 63.4%. There was a weak (r2 = 0.073) but significant (p < 0.001) negative correlation between DCR and age. 84.8% received adjunctive ASM consisting of at least one of 31 different ASMs. DCR was higher with adjunctive ASMs compared with monotherapy [0.061 (0.039–0.095) vs 0.043 (0.030–0.062)], respectively (p < 0.001) and was greatest with inducers. Phenobarbital increased DCR by 2.6-fold, topiramate by 72.1%, and clobazam by 32.6%. Inhibitors had no effect. CONCLUSIONS The correlation between age and DCR was weak, accounting for 6% of variability. Strong inducers significantly increased DCR. Synergy may exist when multiple inducers are given. Weak inhibitors did not affect DCR. Those ≥6 to 11 kg, ≥30 to 50 kg, and those given strong inducers may require larger initial LCM doses. Serum concentrations should be used to individualize dosing, especially in those receiving strong inducers. [ABSTRACT FROM AUTHOR]

The coupling effects of flexible joints and clearance on the dynamics of a robotic system were investigated. A numerical analysis was undertaken to reveal the coupling effects between flexible joints and clearance. The nonlinear spring-damping model and Coulomb model were applied to characterize the contact characteristics of the clearance, and a model for the flexible joint was formulated using the equivalent spring theory. An accurate robot model was established based on the clearance and joint flexibility characterization. The dynamic equation of a robot was obtained according to the Newton-Euler method. A comparative analysis was performed to assess the impacts of both the joint action of clearance and flexible joints and varying joint clearance values on the performance of the robot. The results showed that the coupling effects of flexible joints and clearance had a negative impact on the system dynamic performance. The amplitudes of the dynamic responses caused by the clearance are weakened by the flexible joint, but it leads to the lag of the system response. This study served as the theoretical foundation for exploring precise control techniques in robotics research. [ABSTRACT FROM AUTHOR]

Background: The aim of this experimental study was to elucidate whether different distances between central venous catheter tips can affect drug clearance during continuous renal replacement therapy (CRRT). Central venous catheters (CVCs) are widely used in intensive care patients for drug infusion. If a patient receives CRRT, a second central dialysis catheter (CDC) is required. Where to insert CVCs is directed by guidelines, but recommendations regarding how to place multiple catheters are scarce. There are indications that a drug infused in a CVC with the tip close to the tip of the CDC, could be directly aspirated into the dialysis machine, with a risk of increased clearance. However, studies on whether clearance is affected by different CVC and CDC tip positions, when the two catheters are in the same vessel, are few. Methods: In this model with 18 piglets, gentamicin (GM) and vancomycin (VM) were infused through a CVC during CRRT. The CVC tip was placed in different positions in relation to the CDC tip from caudal, i.e., proximal to the heart, to cranial, i.e., distal to the heart. Serum and dialysate concentrations were sampled after approximately 30 min of CRRT at four different positions: when the CVC tip was 2 cm caudally (+ 2), at the same level (0), and at 2 (− 2) and 4 (− 4) cm cranially of the tip of the CDC. Clearance was calculated. A mixed linear model was performed, and level of significance was set to p < 0.05. Results: Clearance of GM had median values at + 2 cm, 0 cm, − 2 cm and − 4 cm of 17.3 (5.2), 18.6 (7.4), 20.0 (16.2) and 26.2 (12.2) ml/min, respectively (p = 0.04). Clearance of VM had median values at + 2 cm, 0 cm, − 2 cm and − 4 cm of 16.2 (4.5), 14.7 (4.9), 19.0 (10.2) and 21.2 (11.4) ml/min, respectively (p = 0.02). Conclusions: The distance between CVC and CDC tips can affect drug clearance during CRRT. A cranial versus a caudal tip position of the CVC in relation to the tip of the CDC led to the highest clearance. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), characterized by low immunogenicity, high biocompatibility and targeting specificity along with excellent blood-brain barrier permeability, are increasingly recognized as promising drug delivery vehicles for treating a variety of diseases, such as cancer, inflammation and viral infection. However, recent findings demonstrate that the intracellular delivery efficiency of EVs fall short of expectations due to phagocytic clearance mediated by the host mononuclear phagocyte system through Fcg receptors, complement receptors as well as non-opsonic phagocytic receptors. In this text, we investigate a range of bacterial virulence proteins that antagonize host phagocytic machinery, aiming to explore their potential in engineering EVs to counteract phagocytosis. Special emphasis is placed on IdeS secreted by Group A Streptococcus and ImpA secreted by Pseudomonas aeruginosa, as they not only counteract phagocytosis but also bind to highly upregulated surface biomarkers aVb3 on cancer cells or cleave the tumor growth and metastasis-promoting factor CD44, respectively. This suggests that bacterial anti-phagocytic proteins, after decorated onto EVs using preloading or post-loading strategies, can not only improve EV-based drug delivery efficiency by evading host phagocytosis and thus achieve better therapeutic outcomes but also further enable an innovative synergistic EVbased cancer therapy approach by integrating both phagocytosis antagonism and cancer targeting or deactivation. [ABSTRACT FROM AUTHOR]

This paper presents the leakage characteristics of stepped labyrinth seals, considering the impact of rotation in the circumferential direction. Two types of casing, honeycomb and solid lands, were applied to the labyrinth seal, and a numerical study was performed with a wide operating range of the rotational speed, pressure ratio and clearance. The effect of the rotational speed on the sealing performance was analyzed for each clearance size through a parametric study. Regardless of the casing type, the flow function decreased as the rotational speed increased, and the smaller the clearance was, the more the leakage performance was affected by the rotation effect. In particular, it was confirmed that the honeycomb seal had a stronger tendency to decrease the flow function due to the rotation than the solid seal. The honeycomb seal allowed a larger leakage flow in comparison to the solid seal, and the rotational speed played an important role when the clearance was small or moderate. However, when the clearance became large, the leakage flow of the two seal types became almost the same, and the rotational effect became marginal. [ABSTRACT FROM AUTHOR]

Background: Sepsis is an infection-related systemic inflammatory response that often leads to elevated lactate levels. Monitoring lactate levels during severe sepsis is vital for influencing clinical outcomes. The aim of this study was to assess the association between plasma lactate levels and mortality in children with severe sepsis or septic shock. Methods: The current prospective study was conducted in the PICU of University Children's Hospital. The International Paediatric Sepsis Consensus Conference criteria for Definitions of Sepsis and Organ Failure in 2005 were used to diagnose patients with sepsis. We measured plasma lactate levels upon admission (Lac H0) and 6 h later (Lac H6). The static indices included the absolute lactate values (Lac H0 and Lac H6), while the dynamic indices included the delta-lactate level (ΔLac) and the 6-hour lactate clearance. The 6-hour lactate clearance was calculated using the following formula: [(Lac H0–Lac H6)100/Lac H0]. ΔLac was calculated as the difference between the Lac H0 and Lac H6 levels. Patient survival or death after a PICU stay was the primary outcome. Results: A total of 46 patients were included in this study: 25 had septic shock, and 21 had severe sepsis. The mortality rate was 54.3%. The Lac H0 did not significantly differ between survivors and nonsurvivors. In contrast, the survivors had significantly lower Lac H6 levels, higher ΔLac levels, and higher 6-hour lactate clearance rates than nonsurvivors. Lactate clearance rates below 10%, 20%, and 30% were significantly associated with mortality. The best cut-off values for the lactate clearance rate and Lac H6 for the prediction of mortality in the PICU were < 10% and ≥ 4 mmol/L, respectively. Patients with higher Lac H6 levels and lower lactate clearance rates had significantly higher PICU mortality based on Kaplan–Meier survival curve analysis. Conclusions: This study highlights the significance of lactate level trends over time for the prediction of mortality in the PICU in patients with severe sepsis or septic shock. Elevated lactate levels and decreased lactate clearance six hours after hospitalisation are associated with a higher mortality rate. [ABSTRACT FROM AUTHOR]

Background Primary membranous nephropathy (pMN) is one of the most common types of glomerulonephritis, with a third of patients progressing to renal insufficiency. Various prognostic factors have been reported, of which urinary protein and renal function are the most critical parameters. Fractional excretion of total protein (FETP) indicates protein leakage that accounts for creatinine kinetics and serum protein levels. In this study, we investigated the association between FETP and renal prognosis in pMN. Methods We retrospectively identified 150 patients with pMN. FETP was calculated as follows: (serum creatinine × urine protein)/(serum protein × urine creatinine) %. We divided the patients into three groups according to FETP values and compared the clinicopathological findings. The primary outcome was an estimated glomerular filtration rate (eGFR) decrease of ≥30% from the baseline level. Results FETP was associated with urinary protein and renal function, Ehrenreich and Churg stage, and global glomerulosclerosis. The primary outcome was observed in 38 patients (25.3%), and the frequency of the primary outcome was higher in the high FETP group (P  = .001). FETP is higher than protein–creatinine ratio (PCR) in the area under the curve. In the multivariate analysis adjusted for age, eGFR, PCR and treatment, FETP was significantly associated with primary outcome (adjusted hazard ratio, 8.19; P  = .019). Conclusions FETP is a valuable indicator that can reflect the pathophysiology and is more useful than PCR as a predictor of renal prognosis in patients with Japanese pMN. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis C (CHC) infection is a potentially life‐threatening condition characterized by various complications, including end‐stage liver disease and cirrhosis. The mortality rate associated with CHC has been increasing due to the presence of comorbidities and the use of chronic medications. Therefore, the objective of this study was to investigate the impact of these comorbidities and chronic medications on the treatment plan for CHC. Methods: To achieve this objective, a cross‐sectional retrospective study was conducted at a tertiary hospital in Jeddah, Saudi Arabia. The study population included patients aged 12 years and above who were diagnosed with CHC between 2016 and 2021. Patients below the age of 12 were excluded from the study. A total of 170 patients with CHC were included in the analysis. The study aimed to evaluate the relationship between CHC complications and the treatment approach. Results: The mean age of the study participants was 66.78 years, with a higher proportion of female patients. The findings revealed a significant association between hypertension (p = 0.042) and cirrhosis (p = 0.007) with changes in the treatment plan for CHC. Moreover, the presence of diabetes mellitus (p = 0.045), renal diseases (p < 0.001), and hypothyroidism (p = 0.004) were significantly associated with HCV clearance after the initiation of therapy. Additionally, the use of proton pump inhibitors (p = 0.033) and levothyroxine (p = 0.025) was found to be associated with a higher rate of CHC clearance. Conclusion: In conclusion, this study highlights the prevalence of comorbid conditions and the use of chronic medications among patients with CHC. The findings emphasize the importance of considering the effects of comorbidities and chronic medications when developing treatment plans for CHC infections. By taking these factors into account, healthcare professionals can optimize the management of CHC and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020–2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1–2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope =.85), with no significant change in the 2nd trimester (slope =.11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period. [ABSTRACT FROM AUTHOR]

In order to develop a standardized nomenclature for the mechanisms and materials utilized during extracorporeal blood purification, a consensus expert conference was convened in November 2022. Standardized nomenclature serves as a common language for reporting research findings, new device development, and education. It is also critically important to support patient safety, allow comparisons between techniques, materials, and devices, and be essential for defining and naming innovative technologies and classifying devices for regulatory approval. The multidisciplinary conference developed detailed descriptions of the performance characteristics of devices (membranes, filters, and sorbents), solute and fluid transport mechanisms, flow parameters, and methods of treatment evaluation. In addition, nomenclature for adsorptive blood purification techniques was proposed. This report summarizes these activities and highlights the need for standardization of nomenclature in the future to harmonize research, education, and innovation in extracorporeal blood purification therapies. [ABSTRACT FROM AUTHOR]

Background and Purpose: Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF–TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF–TNFi complexes is lacking. We hypothesized a role for Fc‐mediated clearance of TNF–TNFi immune complexes. Therefore, we investigated circulating TNF–TNFi complexes upon treatment with certolizumab—lacking Fc tails—in comparison with adalimumab, golimumab, infliximab and etanercept. Experimental Approach: Drug‐tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow‐up of 1 year. Effects on in vitro TNF production and Fc‐mediated uptake of TNF–TNFi complexes were investigated for all five TNFi. Key Results: Circulating TNF concentrations were >20‐fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml−1. Internalization of TNF–TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. Conclusions and Implications: Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target‐mediated drug disposition of TNFi. [ABSTRACT FROM AUTHOR]

Vancomycin is a widely used glycopeptide antibiotic with the need for therapeutic drug monitoring to avoid renal toxicity. We report a case of severe vancomycin-associated anuric acute kidney injury managed with successful drug-removal by hemodialysis (HD) using different types of dialyzers. Medium cut-off (MCO) and high-flux dialyzers were effective in drug removal. Higher vancomycin elimination rate and lower plasma half-life were achieved with MCO dialyzer despite low-flow vascular access and intolerance to ultrafiltration. MCO dialyzers may be reasonable for drug removal in patients with intolerance of ultrafiltration, low-flow vascular access or impracticality of hemodiafiltration. Future studies should explore the use of MCO dialyzers in comparison with high-flux HD and hemodiafiltration in both the acute and chronic setting. [ABSTRACT FROM AUTHOR]

Background and aim: Vancomycin, a glycopeptide antimicrobial drug. PPK has problems such as difficulty in accurately reflecting inter-individual differences, and the PPK model may not be accurate enough to predict individual pharmacokinetic parameters. Therefore, the aim of this study is to investigate whether the application of machine learning combined with the PPK method can improve the prediction of vancomycin CL in adult Chinese patients. Methods: In the first step, a vancomycin CL prediction model for Chinese adult patients is given by PPK and Hamilton Monte Carlo sampling is used to obtain the reference CL of 1,000 patients; the second step is to obtain the final prediction model by machine learning using an appropriate model for the predictive factor and the reference CL; and the third step is to randomly select, in the simulated data, a total of 250 patients for prediction effect evaluation. Results: XGBoost model is selected as final machine learning model. More than four-fifths of the subjects' predictive values regarding vancomycin CL are improved by machine learning combined with PPK. Machine learning combined with PPK models is more stable in performance than the PPK method alone for predicting models. Conclusion: The first combination of PPK and machine learning for predictive modeling of vancomycin clearance in adult patients. It provides a reference for clinical pharmacists or clinicians to optimize the initial dosage given to ensure the effectiveness and safety of drug therapy for each patient. [ABSTRACT FROM AUTHOR]

Online graduating student clearance systems are important platforms that greatly reduce the tedious processes involved in getting graduating students cleared for certification. These platforms are hardly available in most colleges of education and other tertiary institutions in Nigeria. The existing trends in the student clearance method is that the processes are done by moving from one office to another and having records on paper. Most existing clearance tasks are done manually. This scenario creates a system that is unreliable and confusing to keep the correct track of the records and can be very overwhelming and stressful to say the least. At the conclusion of the academic session, a clearance form is issued to students. Students apply for the clearance form to their respective department if the students need to exit the college. The consequences of this type of clearance system is that, at most times, most of the personnel required for the signing of the graduating students form are often not accessible and this creates serious challenges to the students. Also, in most cases, some of the papers issued to the students go missing in the course of their study and they are asked to pay for dues that have been originally paid. This research presents an automated and robust clearance system that generates students' clearance per session and final clearance to graduating students. Developing an online customs clearance system called a Robust Web-based Clearance System is the major contribution of this research. The system was developed using Java as a programming language. The system was hosted using Xampp as a local server. The system was tested and validated by management and students. The results from the test showed a high level of acceptability of the developed system. [ABSTRACT FROM AUTHOR]

Background Understanding the natural history of human papillomavirus (HPV) infections is essential to cervical cancer prevention planning. We estimated HPV type-specific infection detection and clearance in young women. Methods The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study is a prospective cohort of 502 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at 6 clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness. Results By 24 months, we detected incident infections in 40.4% (CI, 33.4%–48.4%) of women. Incident subgenus 1 (43.4; CI, 33.6–56.4), 2 (47.1; CI, 39.9–55.5), and 3 (46.6; CI, 37.7–57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections. Conclusions Our analyses provide type-specific infection natural history estimates for cervical cancer prevention planning. HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections persist longer than their low oncogenic risk subgenera 1 and 3 counterparts. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.01) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD. [ABSTRACT FROM AUTHOR]

Copyright of Kosmetische Medizin + Ästhetische Chirurgie is the property of gmc-Gesundheitsmedien & Congress GmbH and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Vulvar lichen sclerosus (VLS) is characterized by progressive anatomical changes which become increasingly severe and irreversible. The objective of this study was to investigate if a "window of opportunity" exists in VLS, i.e., to assess if an early treatment may prevent disease progression and facilitate clearance of symptoms and/or signs. Methods: This retrospective, cohort study included VLS patients treated for the first time with a topical corticosteroid, namely with mometasone furoate 0.1% ointment, for 12 weeks (2016–2021). Scoring of subjective symptoms (global subjective score, GSS, and dyspareunia) and clinical features (global objective score [GOS] and sclerosis-scarring-atrophy) was performed at baseline (T0) and at the control visit (T1). We assessed if the achievement of clearance in GSS, GOS, sclerosis-scarring-atrophy, or dyspareunia depended on the time elapsed between VLS onset and treatment initiation. Results: Among the 168 patients (59.2 ± 13.2 years) included, the median time between VLS onset and first treatment was 14.0 months. At T1, 48.8% of patients achieved clearance of GSS, 28% of GOS and 11.9% of both GSS and GOS, 57.9% of dyspareunia, and 19.2% of sclerosis-scarring-atrophy. The logistic regression model showed that each 10-month increase in treatment initiation adversely affected the clearance of GSS while starting treatment within 6 months of disease onset was significantly associated with clearance of GOS and sclerosis-scarring-atrophy. Conclusion: Early treatment is crucial in determining a complete healing of VLS-related symptoms and signs, especially of tissue sclerosis-scarring-atrophy, which appear poorly responsive, or even unresponsive, after the earliest stages of the disease. Thus our findings provide evidence for a "window of opportunity" in VLS treatment. [ABSTRACT FROM AUTHOR]

Introduction: Continuous renal replacement therapies (CRRTs) require constant monitoring and periodic treatment readjustments, being applied to highly complex patients, with rapidly changing clinical needs. To promote precision medicine in the field of renal replacement therapy and encourage dynamic prescription, the Acute Dialysis Quality Initiative (ADQI) recommends periodically measuring the solutes extracorporeal clearance with the aim of assessing the current treatment delivery and the gap from the therapeutic prescription (often intended as effluent dose). To perform this procedure, it is therefore necessary to obtain blood and effluent samples from the extracorporeal circuit to measure the concentrations of a target solute (usually represented by urea) in prefilter, postfilter, and effluent lines. However, samples must be collected simultaneously from the extracorporeal circuit ports, with the same suction flow at an unknown rate. Methods: The proposed study takes the first step toward identifying the technical factors that should be considered in determining the optimal suction rate to collect samples from the extracorporeal circuit to measure the extracorporeal clearance for a specific solute. Results: The results obtained identify the low suction rate (i.e., 1 mL/min) as an ideal parameter for an adequate sampling method. Low velocities do not perturb the external circulation system and ensure stability prevailing pressures in the circuit. Higher velocities can be performed only with blood flows above 120 mL/min preferably in conditions of appropriate filtration fraction. Discussion/Conclusions: The specific value of aspiration flow rate must be proportioned to the prescription of CRRT treatments set by the clinician. [ABSTRACT FROM AUTHOR]

The article discusses the challenges and potential of studying extracellular vesicles (EVs) in understanding human and animal physiology. EVs are small particles released by cells into body fluids, and they can provide valuable insights into complex conditions such as hypertension. However, purifying, characterizing, and studying EVs have been difficult. To address these challenges, the International Society of Extracellular Vesicles (ISEV) has published guidelines called "Minimal Information for Studies of Extracellular Vesicles" (MISEV). The updated version, MISEV2023, provides essential information on current methods and emphasizes transparency and reproducibility in EV research. The article also highlights the importance of studying EVs in physiological regulation and introduces experimental models and tools to explore their role in health and diseases. Overall, the MISEV2023 guidelines offer a valuable resource for researchers to gain a better understanding of EVs and their significance in physiology. [Extracted from the article]

Copyright of Science Technology & Engineering is the property of Chinese Society of Technology Economics and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.2, 95%CI: 1.7-2.8; p<0.11) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD. [ABSTRACT FROM AUTHOR]

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three‐day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3 [ABSTRACT FROM AUTHOR]

Background/Aims: This study compares the peritoneal elimination of the low-molecular-weight-protein (LMWP) C-terminal agrin fragment (tCAF, size 22 kDa), a promising biomarker for kidney function, in continuous cycling peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD). Methods: 103 sets of serum, 24h-urine and dialysate samples were obtained in 15 CCPD (63 sets) and 11 CAPD (40 sets) patients. Total, renal and peritoneal substrate removals/clearances were measured/calculated for tCAF, creatinine, blood-urea-nitrogen (BUN), cystatin C and albumin and correlated with the peritoneal transport type. Results: Serum und urine concentrations of all biomarkers did not differ between both groups, urinary substrate removal was higher in CAPD patients for all biomarkers due to better residual renal function. Peritoneal substrate removal of tCAF and albumin were significantly higher in CAPD (tCAF: 35.3 vs. 19.3 µg/d, p<0.001; albumin: 4.3 vs. 3.7 g/d, p=0.001), whereas cystatin C and creatinine did not differ between CAPD and CCPD (cystatin: 7.7 vs. 6.1 mg/d, p=0.08, creatinine: 423.9 vs. 456.7 mg/d, p=0.241). BUN was better removed by CCPD (4846.6 vs. 3393.4 mg/d, p<0.001). CAPD patients with high-transporter characteristics had a higher peritoneal tCAF removal compared to high-average-transporters (49.8 vs. 28.4 µg/d, p<0.001), no differences could be detected in CCPD patients between these groups. CAPD patients using icodextrin twice/day had higher peritoneal clearance of tCAF compared to once daily (4.4 vs. 2.8 l/wk/1.73 m2 body-surface-area, p<0.001). Conclusions: CAPD was superior to CCPD concerning peritoneal tCAF removal. This finding was pronounced in high-transporters and CAPD patients using icodextrin twice daily. [ABSTRACT FROM AUTHOR]

Recent publications by Benet and coworkers, Korzekwa and Nagar, and Rowland et al. signal disagreement regarding the use of Kirchhoff's laws in combining pharmacokinetic parameters, especially clearances and rate constants. Here, it is pointed out that Kirchhoff's laws as applied to pharmacokinetics simply assert that concentrations are well defined and that molar or mass balances hold. The real issue is how to combine parameters for clearance processes in sequence, which may be reversible, irreversible, or even active in either or both directions. It is also demonstrated that Kirchhoff's laws cannot be used to resolve contradictory results observed in liver transport and clearance. Finally, a simple argument is provided relating nonlinear clearance to apparently anomalous bioavailability observations. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.01) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD. [ABSTRACT FROM AUTHOR]

The wear of motion pair is a common phenomenon in mechanisms and can significantly affect the dynamic behavior of mechanical systems, posing a huge challenge to the precise dynamic modeling and characteristic prediction of mechanisms. The main contribution of this paper is to propose a multi body system dynamic modeling method and dynamic accuracy reliability model for complex multi-link mechanisms considering irregular wear clearance. Firstly, an accurate dynamic model of a six-link mechanism considering irregular wear clearance is established. Secondly, a dynamic accuracy reliability model considering irregular wear clearance is established. Finally, the differences in dynamic response and nonlinear characteristics of the mechanism before and after wear are compared. The different effects of clearance values and driving speed on wear characteristics, dynamic response and nonlinear characteristics are analyzed in detail. The influences of different contact force models on the dynamic response of mechanism considering wear clearance are analyzed. And the dynamic accuracy reliability of the mechanism before and after wear are analyzed. The results show that wear can lead to irregular wear on the shaft and bearing surfaces, leading to an increase in the vibration frequency and peak value of dynamic response. This further reinforces the chaotic characteristics of the mechanism and reduces the kinematic accuracy and stability of the mechanism. [ABSTRACT FROM AUTHOR]

Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts. Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown. Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Climate change is significantly impacting the structure and functioning of marine communities through temperature rise and the repeated occurrence of temperature spikes and marine heat waves. The present study investigated the metabolic responses of the sponge Chondrilla nucula, an important component of benthic ecosystems in the Mediterranean Sea, to temperature. Organisms were exposed to six different temperatures ranging from 15 to 32 °C, and respiration and clearance rates were measured. The results revealed temperature-dependent effects on both traits. Higher temperatures correlated with increased respiration rates, peaking at 26 °C. In contrast, clearance rates declined beyond 26 °C, signifying reduced food intake not mirrored by respiration rates. This response at high temperatures implied a potential negative energy balance, suggesting vulnerability to chronic or repeated thermal stress. Consequently, this study predicted the susceptibility of C. nucula to climate change conditions, with potential repercussions for its metabolic performance, ecological role, and the associated ecosystem services it provides. As a result of climate change, the Mediterranean Sea has been exposed to an increase in the frequency and intensity of marine heat waves in the last decades, some of which caused mass mortality events of benthic invertebrates, including sponges. Sponges are an important component of benthic ecosystems and can be the dominant group in some rocky shallow-water areas in the Mediterranean Sea. In this study, we exposed the common shallow-water Mediterranean sponge Chondrilla nucula (Demospongiae: Chondrillidae) to six different temperatures for 24 h, ranging from temperatures experienced in the field during the year (15, 19, 22, 26, and 28 °C) to above normal temperatures (32 °C) and metabolic traits (respiration and clearance rate) were measured. Both respiration and clearance rates were affected by temperature. Respiration rates increased at higher temperatures but were similar between the 26 and 32 °C treatments. Clearance rates decreased at temperatures >26 °C, indicating a drop in food intake that was not reflected by respiration rates. This decline in feeding, while maintaining high respiration rates, may indicate a negative energy balance that could affect this species under chronic or repeated thermal stress exposure. C. nucula will probably be a vulnerable species under climate change conditions, affecting its metabolic performance, ecological functioning and the ecosystem services it provides. [ABSTRACT FROM AUTHOR]

Background: Elevated levels of troponin-I (TnI) are common in out-of-hospital cardiac arrest (OHCA) patients. However, studies evaluating the prognostic value of TnI clearance in OHCA patients are lacking. We aimed to examine how TnI clearance (TnI-C) differed according to the neurological outcome group and mortality group at 6 months. Methods: This retrospective observational study involved adults (=18 years) who were treated for an OHCA between January 2019 and December 2022. The TnI-Cs were calculated for days 1 to 2 (TnI-C1st) and 2 to 3 (TnI-C2nd) after the return of spontaneous circulation (ROSC). The primary outcome was a poor neurological outcome at 6 months, defined by cerebral performance categories 3, 4, and 5. The secondary outcome was 6-month mortality. Results: A total of 227 patients were included. A poor neurological outcome and mortality at 6-months were reported in 150 (66.1%) and 118 (52.0%) patients, respectively. The TnI-C1st was significantly lower in patients with a poor outcome compared with good outcome patients (neurological outcome at 6 months, 54.4% vs. 42.3%; 6-month mortality, 52.1% vs. 42.7%, respectively). In the multivariable analyses, a TnI-C1st <50% was associated with a poor neurological outcome (odds ratio [OR] 2.078, 95% confidence interval [CI] 1.080-3.995, p = 0.028) and mortality (OR 2.131, 95% CI 1.114-4.078, p = 0.022) at 6 months. Conclusions: After ROSC, TnI-C1st <50% was associated with a poor neurological outcome and mortality at 6 months in OHCA patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by abnormal increase of Aβ peptide which is likely as the result of imbalanced homeostasis of its production and clearance mechanisms. Here, we briefly review that the uncleaned extracellular Aβ peptides are loaded into presynaptic neurons. The Aβ oligomers desperately affect pre- and post-synapse neuron activity and turn into plaques inside the presynaptic neurons over the time passes. [ABSTRACT FROM AUTHOR]

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Prophylaxis is the gold standard for the management of hemophilia A patients. It has been shown that prophylaxis regulated with pharmacokinetic (PK) data reduces frequency of bleeding and cost of treatment. To determine the best prophylaxis regimen, PK dosing tools using the Bayesian method have been developed. We aimed to compare two PK dosing tools. Blood samples were drawn before, 4, 24, and 48 h after FVIII infusions from patients with severe hemophilia A and inhibitor negative. FVIII levels were measured by PTT-based one-stage assay method. PK parameters obtained using WAPPS and myPKFiT, which are web-accessible PK dosing tools using Bayesian algorithm, and daily prophylaxis dose estimated by the programs were compared. Forty-two hemophilia A patients [median age 13 years (IQR 8.9–16.4)] included in the study. There was no difference between the daily dose of FVIII given for prophylaxis and the dose recommended by the myPKFiT for the 1% trough level; whereas, a significant difference was found with the WAPPS. The half-lives of FVIII did not differ between the two dosing tools; however, significant differences were found in the estimated dose, clearances, and times to 1% trough level. There was no significant difference between PK data of patients who received Advate® and those who received non-Advate® factor concentrates. Choice of PK dosing tool can affect recommended FVIII dose. However, target trough levels should be individualized according to bleeding phenotype and daily activity of patient. [ABSTRACT FROM AUTHOR]