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When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations.

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.

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]

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]

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]

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]

Introduction Methods Results Conclusion Hyperkalemia is frequently encountered and associated with cardio‐vascular mortality in chronic hemodialysis (HD) patients. While online hemodiafiltration (OL‐HDF) is thought to offer clinical benefit over high‐flux HD, the impact of convective clearance on intra‐dialytic potassium removal is unknown.Chronic dialysis patients undergoing outpatient HD or OL‐HDF at a single center attached to a university hospital were recruited in a prospective observational study. Spent dialysate along with clinical and biological variables were collected during a single mid‐week session.We included 141 patients, with 21 treated with HD and 120 with OL‐HDF. Mean age was 65.7 ± 15.6 years with 87 (61.7%) men. Mean intra‐dialytic potassium removal was 69.9 ± 34.2 mmol. Patients on OL‐HDF and HD have similar intra‐dialytic potassium removal, with mean values of 69.1 ± 34.2 and 74.3 ± 35.0, respectively. In multivariate analysis, factors associated with intra‐dialytic potassium removal were (decreasing order of effect size): dialysate potassium (β −15.5, p < 0.001), pre‐HD serum potassium (β 9.1, p < 0.001), and session time (β 7.8, p = 0.003). In OL‐HDF patients, substitution flow was not associated with potassium removal.In chronic dialysis patients, convective therapy provided by OL‐HDF does not affect potassium removal when compared with high‐flux HD. Moreover, the importance of convective volume is not associated with potassium clearance in OL‐HDF. Overall, session length and serum‐to‐dialysate potassium gradient are the main determinants of potassium clearance regardless of dialysis modality. Those results should inform clinicians on the optimal therapy in chronic dialysis patients in the era of OL‐HDF. [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]

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]

[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]

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]

Introduction Methods Results Conclusions BK polyomavirus (BKPyV)‐DNAemia is a common complication in kidney transplant recipients (KTRs). The significance of achieving viral clearance at different time intervals is not well understood.All adult KTRs transplanted between January 1, 2015 and December 31, 2017 who developed BKPyV‐DNAemia were included. Outcomes were analyzed based on persistent clearance of BKPyV‐DNAemia at 3‐month intervals up to 2 years after initial detection, and for recipients with persistent BKPyV‐DNAemia at last follow‐up. Uncensored graft failure, death‐censored graft failure (DCGF), and a composite outcome of DCGF or fall in estimated glomerular filtration rate (eGFR) by ≥50% from the time of initial BKPyV‐DNAemia were outcomes of interest.Of 224 KTRs with BKPyV‐DNAemia, 58 recipients (26%) achieved viral clearance by 3 months after initial detection, 105 (47%) by 6 months, 120 (54%) by 9 months, 141 (63%) by 12 months, 155 (69%) by 15 months, 167 (75%) by 18 months, 180 (80%) by 21 months, and 193 (86%) by 24 months. Nine recipients (4%) had persistent BKPyV‐DNAemia at last follow‐up. Compared to recipients who achieved viral clearance by 3 months, those who achieved clearance by 6 months (adjusted odds ratio [aOR]: 3.15; 95% confidence interval [CI]: 1.22–8.12; p = .02) and 9 months (aOR: 3.69; 95% CI: 1.02–13.43; p = .04) had significantly increased risk for uncensored graft failure. There was no significant association between time to viral clearance and DCGF or composite outcomes.We found a trend of increased risk for uncensored graft failure among those who cleared BKPyV‐DNAemia more slowly. Aiming to clear viremia early, without risking rejection, may be beneficial for allograft function and patient morbidity and mortality. [ABSTRACT FROM AUTHOR]

When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations. [Display omitted] [ABSTRACT FROM AUTHOR]

In individuals highly exposed to HCV, reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection. Broad neutralising antibodies (nAbs) and Envelope 2 (E2)-specific memory B cell (MBC) responses were examined longitudinally in 15 individuals with varied reinfection outcomes. Broad nAb responses were associated with MBC recall, but not with clearance of reinfection. Strong evidence of antigen imprinting was found, and the B-cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single-cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection. MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development. HCV continues to have a major health burden globally. Limitations in the health infrastructure for diagnosis and treatment, as well as high rates of reinfection, indicate that a vaccine that can protect against chronic HCV infection will greatly complement current efforts to eliminate HCV-related disease. With alternative approaches to testing vaccines, such as controlled human inoculation trials under consideration, we desperately need to identify the correlates of immune protection. In this study, in a small but rare cohort of high-risk injecting drug users who were reinfected multiple times, breadth of neutralisation was not associated with ultimate clearance of the reinfection event. Alternatively, characteristics of the HCV-specific B-cell response associated with B-cell proliferation were. This study indicates that humoral responses are important for protection and suggests that for genetically very diverse viruses, such as HCV, it may be beneficial to look beyond just antibodies as correlates of protection. [Display omitted] • Protection from persistent reinfection was associated with expansion of E2-specific B cells upon reinfection. • E2-specific B cells have a transcriptomic profile associated with activation and proliferation prior to clearance of reinfection. • We observed evidence of antigen imprinting in HCV reinfection. [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]

Toxic and prescribed drug ingestions are a significant cause of pediatric morbidity and mortality. Management of the poisoned patient begins with a thorough evaluation, identification of the agent(s) involved, and assessment of severity and symptoms. Therapy consists of the provision of supportive care, prevention of poison absorption, use of antidotes, and, when appropriate, the use of renal replacement therapy (RRT) to enhance the elimination of the poison. Among several elimination techniques, extracorporeal treatment such as RRT can be lifesaving as it rapidly removes the toxin independent of the patient’s indigenous clearance. Hemodialysis remains the most commonly used RRT for toxin removal, and the role of continuous RRT and therapeutic plasma exchange is emerging. To properly utilize the RRT, the clinician should understand the chemical properties of the toxins and the underlying mechanism of clearance by the concerned RRT technique. Although pediatric literature is mainly limited to case reports, timely initiation of RRT helps manage children with poisoning and drug overdose.

Abstract Soluble biomarkers are paramount to personalized medicine. However, the in vivo turnover and biodistribution of soluble proteins is seldom characterized. The cleaved extracellular domain of the AXL receptor (sAXL) is a prognostic biomarker in several diseases and a predictive marker of AXL targeting agents. Plasma sAXL reflects a balance between production in tissues with lymphatic transport into the circulation and removal from blood by degradation or excretion. It is unclear how this transport cycle affects plasma sAXL levels that are the metric for biomarker development. Radiolabeled mouse sAxl was monitored after intravenous injection to measure degradation and urinary excretion of sAxl, and after intradermal injection to mimic tissue or tumor production. sAxl was rapidly taken-up and degraded by the liver and kidney cortex. Surprisingly, intact sAxl was detectable in urine, indicating passage through the glomerular filter and a unique sampling opportunity. The structure of sAxl showed an elongated, flexible molecule with a length of 18 nm and a thickness of only 3 nm, allowing passage through the glomerulus and excretion into the urine. Intradermally injected sAxl passed through local and distant lymph nodes, followed by uptake in liver and kidney cortex. Low levels of sAxl were seen in the plasma, consistent with an extended transit time from local tissue to circulation. The rapid plasma clearance of sAxl suggests that steady-state levels in blood will sensitively and dynamically reflect the rate of production of sAxl in the tissues but will be influenced by perturbations of liver and kidney function.

Purpose of the study. To analyze the change in the thickness of the sub­lens water layer depending on the time of wearing lenses in patients using scleral lenses using the SkyOptix Laboratory lenses as an example.Patients and methods. To determine the thickness of the sublens water layer in the vertical and horizontal meridians, a study was performed in 33 people in 46 eyes. Among the patients there were 25 men and 8 women, from 18 to 59 years old (mean 37.3 ± 9.5 years). The main indication for the use of scleral lenses was the ineffectiveness of other methods of vision correction.Results. The mean sublens water layer thickness reduction in the total group of examined patients using scleral lenses was 9.3 % or 37.73 μm after 1 hour of wear and 20.8 % or 84.48 μm after 4 hours of wear compared to initial values.Conclusions. The largest and clinically significant changes in the thickness of the sublens water layer occur during the first hour of lens wear, which, according to our study, is approximately 40 microns. Considering the temporal dynamics of changes in the thickness of the sublens water layer, the final calculation of the parameters must be made no earlier than after 1 hour of wearing the scleral lens. The thickness of the sublens water layer should be assessed in relation to the time spent in the scleral lens. According to our survey, over the entire period of observation in all patients using scleral lenses, there is a decrease in the thickness of the sublens water layer over time of wearing, which requires further additional research to determine identifying the exact causes and factors underlying this process.

Abstract 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.

Yuelin Zhang, Xue Lin, Xinxin Chen, Weixiang Fang, Kailing Yu, Wenting Gu, Yinghui Wei, Hangsheng Zheng, Jigang Piao, Fanzhu Li School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of ChinaCorrespondence: Fanzhu Li; Ji-Gang Piao, Email lifanzhu@zcmu.edu.cn; jgpiao@zcmu.edu.cnAbstract: Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges. Keywords: mesoporous silica nanoparticles, degradation, clearance, biodistribution, strategies

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 paper introduces innovative solutions for worm gears, aiming at adaptive reduction of side clearance to improve accuracy. It addresses manufacturing challenges affecting tooth dimensions and deviations in shape, examining the impact of adjustment settings on clearance components. The document outlines patented solutions and identifies the causes of inaccuracies in worm gears, with a specific focus on the efficiency of a compliant worm in reducing side clearance. Comprehensive analyses were conducted using Matlab, CAD, and empirical data to investigate the impact of adjustments on clearance statistics, correlation, and spectral analyses before and after corrections. It establishes correlations between clearance parameters and assesses positioning accuracy using a rolling screw system. By demonstrating significant improvements in accuracy without the need for gear disassembly during operation, the developed gear compensates for manufacturing deviations. The paper also suggests assembly procedures for precision worm gears in small-scale production, taking into account various criteria for accuracy assessment. • Design solutions for worm gears. • Backlash statistics. • The correlation analysis, and spectral analysis of backlash. [ABSTRACT FROM AUTHOR]

The well-stirred model (WSM) is commonly used to predict the hepatic clearance in vivo (CL H) of drugs. The necessary intrinsic clearance of the unbound drug (CL int-in vitro-unbound) is generated in the in vitro assays in the presence of microsomes or hepatocytes but in the absence of plasma proteins. The value of CL int-in vitro-unbound can be extrapolated with the fraction unbound determined in vitro in plasma (fu p) only if the fraction unbound in vivo in liver is the same. However, this approach resulted to a systematic underprediction bias of CL H. With the goal of reducing this bias, two new models of fraction unbound were published in this journal. These models estimate the binding kinetics of the rates of association and dissociation of the drug-protein complex and propose that more dissociation in the liver compared to plasma will increase the fraction unbound available for the metabolism. Consequently, these two models generated higher values of fraction unbound, implying a lower underprediction bias of CL H with the WSM. The first model was developed by Poulin et al. and is referring to the value of fu p that is adjusted (fu -adjusted) to quantify the effect of a full dissociation of the drug-protein complex at the hepatocyte membrane in accordance with the theory of the albumin-facilitated hepatic uptake. A second model was developed by Yan et al. who presented a dynamic fraction unbound (fu -dynamic) measuring the real dissociation kinetics of the drug-protein complex with a new in vitro assay in the presence and absence of a recombinant liver enzyme in plasma. Therefore, the objective of this study was to make the first comparative assessment between these two models. The results indicate that, in general, the WSM combined with the values of fu -adjusted was the most accurate approach for predicting CL H. The WSM combined with the values of fu -dynamic has underperformed particularly with the acidic and neutral drugs binding to the albumin and presenting a low metabolic turnover in vitro. Therefore, the new in vitro assay for fu -dynamic gave an underprediction bias of CL H for these drug properties. However, the values of fu -adjusted are significantly higher than those values of fu -dynamic , and, this resulted to no underprediction bias, which is reinforcing the theory of the ALB-facilitated hepatic uptake. For the other neutral and acidic drugs, the models of fu -dynamic and fu -adjusted are in closer agreement. Finally, for the basic drugs, the models of fu -adjusted and fu -dynamic as well as a third model only considering a pH gradient effect on fu p are almost accurately equivalent. [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]

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]

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]

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]

BackgroundTubular secretion is an important kidney function responsible for the clearance of numerous medications, including antibiotics and antivirals. It is unknown whether persons living with HIV have lower secretion compared with HIV-uninfected persons, which might predispose them to the risk of progressive kidney disease or adverse drug events.Setting and methodsWe evaluated a panel of 6 endogenous secretory solutes in 199 women living with HIV (WLWH) and 100 women without HIV enrolled in the Women's Interagency HIV Study. Secretory clearance was estimated as the urine-to-plasma ratio of each solute, with adjustment for urine tonicity. Using multivariable linear regression analysis, we compared differences in levels of secretory solute clearance between women with and without HIV and evaluated characteristics associated with secretion.ResultsWLWH were older (median 40 vs. 38 years) but had similar estimated glomerular filtration rate (eGFR, 96 vs. 100 mL/minute/1.73 m 2 ) compared with those without HIV. African American and Latino race, diabetes, diastolic blood pressure, smoking, hepatitis C, peak HIV viral load, and current and nadir CD4 count were associated with differences in clearance of at least 1 marker after multivariable adjustment. The secretory clearance of 3 solutes (cinnamoylglycine, kynurenic acid, and pyridoxic acid) were on average 10%-15% lower among WLWH compared with those without HIV independent of eGFR, albuminuria and chronic kidney disease risk factors, including HCV, and injection drug use.ConclusionsHIV is associated with reduced secretion among women with preserved eGFR. The implications of these findings for drug dosing and adverse events need to be evaluated.

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.

Background: Clearance of human papillomavirus (HPV) among adolescent men who have sex with men (MSM) is not well studied. This study aimed to evaluate the clearance of HPV DNA and antibodies among adolescent MSM. Methods: In our cohort study, we enrolled adolescent MSM in Melbourne between October 2010 and September 2013. At baseline, 3, 6, and 12 months, anal and penile swabs for HPV DNA and serum for HPV antibodies against genotypes 6, 11, 16, and 18, were collected. Definite clearance was defined as HPV DNA (same site) /antibodies for the same genotype undetected following a positive HPV DNA /antibodies test at baseline or month 3. Possible clearance was defined as HPV DNA (same site) /antibodies for the same genotype undetected at month 12 following a positive HPV DNA/antibodies test at month 6. Overall clearance was defined as either definite or possible clearance. The agreement between HPV DNA clearance and antibodies clearance was calculated. Results: A total of 183 MSM were included (median age: 19 years, interquartile [IQR]: 18 to 20). At the anus, overall clearance rate was 21.6 (95 % confidence interval[CI]: 7.9 to 47.0), 44.8 (19.3 to 88.3), 51.9 (20.9 to 106.9) and 33.7 (7.0 to 98.5) per 1000 person months (PM) for HPV 6, 11, 16 and 18. At the penis, overall clearance rate was 64.5 (13.3 to 188.5), 71.3 (14.7 to 208.2), 96.5 (31.3 to 225.3) and 333.3 (8.4 to 1857.2) per 1000 PM for HPV 6, 11, 16 and 18. For antibodies, overall clearance rate was 22.2 (9.6 to 43.7), 18.8 (3.9 to 55.0), 10.8 (0.3 to 60.1) and 19.0 (2.3 to 68.8) per 1000 PM. Agreement between anal/penile HPV DNA clearance and antibodies clearance was low: kappa = -0.18 (95 % CI: −0.28 to 0.08)/-0.13 (−0.24 to −0.02), 0.04 (−0.29 to 0.36)/0.22 (−0.32 to 0.76), −0.10 (−0.27 to 0.08)/-0.14 (−0.37 to 0.10) and −0.14 (−0.28 to 0.01)/-0.14 (−0.33 to 0.06) for HPV 6, 11, 16 and 18, respectively. Conclusion: Clearance rates of HPV DNA were low and varied by genotypes and anatomical sites among adolescent MSM. Antibodies against HPV were stable during the study period.