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Introduction: An unsafe injection practice is one of the major contributors to new hepatitis C virus (HCV) infections; thus, people who inject drugs are a key population to prioritize to achieve HCV elimination. The introduction of highly effective and well-tolerated pangenotypic direct-acting antivirals, including glecaprevir/pibrentasvir (GLE/PIB), has revolutionized the HCV treatment landscape. Glecaprevir is a weak cytochrome P450 3A4 (CYP3A4) inhibitor, so there is the potential for drug–drug interactions (DDIs) with some opioids metabolized by CYP3A4, such as fentanyl. This study estimated the impact of GLE/PIB on the pharmacokinetics of intravenous fentanyl by building a physiologically based pharmacokinetic (PBPK) model. Methods: A PBPK model was developed for intravenous fentanyl by incorporating published information on fentanyl metabolism, distribution, and elimination in healthy individuals. Three clinical DDI studies were used to verify DDIs within the fentanyl PBPK model. This model was integrated with a previously developed GLE/PIB PBPK model. After model validation, DDI simulations were conducted by coadministering GLE 300 mg + PIB 120 mg with a single dose of intravenous fentanyl (0.5 µg/kg). Results: The predicted maximum plasma concentration ratio between GLE/PIB + fentanyl and fentanyl alone was 1.00, and the predicted area under the curve ratio was 1.04, suggesting an increase of only 4% in fentanyl exposure. Conclusion: The administration of a therapeutic dose of GLE/PIB has very little effect on the pharmacokinetics of intravenous fentanyl. This negligible increase would not be expected to increase the risk of fentanyl overdose beyond the inherent risks related to the amount and purity of the fentanyl received during recreational use. [ABSTRACT FROM AUTHOR]

Venetoclax is an approved, orally bioavailable, B‐cell lymphoma type 2 (BCL‐2) inhibitor that is primarily metabolized by cytochrome P450 3A (CYP3A). Polypharmacy is common in patients undergoing treatment for hematological malignancies such as acute myeloid leukemia or chronic lymphocytic leukemia, and although venetoclax exposure has been well characterized with 1 concomitant CYP3A inhibitor, complex drug–drug interactions (DDIs) involving more than 1 inhibitor have not been systematically evaluated. Here, we aimed to describe the potential impact of multiple concomitant CYP3A inhibitors on venetoclax pharmacokinetics (PK) using physiologically based pharmacokinetic (PBPK) and population PK modeling. The modeling approaches were informed by clinical data in the presence of single or multiple CYP3A inhibitors, and the effects of 1 or more inhibitors were systematically considered within these modeling frameworks. The PBPK modeling approach was independently validated against clinical data involving more than 1 CYP3A inhibitor along with CYP3A substrates other than venetoclax. Both approaches indicated that combining a strong CYP3A inhibitor with another competitive CYP3A inhibitor does not seem to result in any additional increase in venetoclax exposure, beyond what would be expected with a strong inhibitor alone. This suggests that the current dose reductions recommended for venetoclax would be appropriate even when 2 or more CYP3A inhibitors are taken concomitantly. However, the results indicate that the involvement of time‐dependent inhibition might lead to additional inhibitory effects over and above the effect of a single strong CYP3A inhibitor. Thus, the clinical management of such interactions must consider the underlying mechanism of the interactions. [ABSTRACT FROM AUTHOR]

The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of ∼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8–1.25 for both Cmax and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies. [ABSTRACT FROM AUTHOR]

This article proposes a guidance strategy that enables the interceptor to control its impact time against stationary targets, while also meeting the field-of-view (FOV) constraints of the on-board seeker. The guidance strategy, so designed, always keeps the target within its FOV using its seeker. A barrier Lyapunov function is used to meet the FOV constraints, and an approximate expression for the interceptor's lead angle is obtained analytically. This facilitates the computation, as well as control, of impact time. The proposed guidance consists of two stages, with the former stage being deviated pursuit, while during the latter stage, the deviation angle or lead angle decreases to zero. This, in turn, ensures a zero terminal lateral acceleration. Furthermore, through a cooperative selection of tuning parameters, simultaneous interception of the target by multiple interceptors (also called salvo) can be achieved. Simulations, that are run for different engagement scenarios and with varying tuning parameters, vindicate the efficacy of the proposed strategy. [ABSTRACT FROM AUTHOR]

Purpose: Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically. Methods: Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug–drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios. Results: The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range. Conclusions: The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD. [ABSTRACT FROM AUTHOR]

This article proposes sliding-mode-control-based guidance strategies for a team comprised of aircraft and a defending interceptor against an attacker. The proposed guidance strategies are based on the line-of-sight guidance concept. Problems such as performance degradation under large heading angle errors, arising from linearization of engagement dynamics, are circumvented due to the nonlinear framework considered here. We show that knowledge of the bound on attacker acceleration suffices to ensure interception of an attacking interceptor. Cooperative strategies are derived for the aircraft–defender team, corresponding to cost functions based on the $\ell _p$ norm, using static optimization at each time instant. Simulations validate the efficacy of the proposed strategies. [ABSTRACT FROM AUTHOR]

A cooperative salvo guidance strategy using fixed finite-time consensus is proposed here. The consensus algorithm is based on sliding mode control. The cooperative salvo attack problem is transformed to a consensus problem over a cycle digraph. This aids in designing a guidance strategy through selection of heterogeneous gains. The proposed strategy guarantees convergence to a common impact time for all the interceptors, within a fixed time, from a wide range of initial heading angles. Subsequently, the guidance strategy is extended to cooperatively intercept a constant velocity target. The efficacy of the proposed algorithm is vindicated through simulations on both stationary and constant velocity targets. Numerical simulations are also performed on realistic missile models that account for aerodynamic parameter variations, yielding satisfactory performance. [ABSTRACT FROM AUTHOR]

Summary: This paper studies a bearing‐only–based formation control problem for a group of single‐integrator agents with directed cycle sensing topology. In a 2‐dimensional space, a necessary and sufficient condition for the set of desired bearing vectors to be feasible is derived. Then, we propose a bearing‐only control law for every agent and prove that the formation asymptotically converges to a formation specified by a set of feasible desired bearing vectors. Analysis of the equilibrium formations in the plane for a 3‐agent system and subsequent extension to an n‐agent system is provided. We further extend the analysis on directed triangular formation into a 3‐dimensional space. Finally, simulations validate the theoretical results. [ABSTRACT FROM AUTHOR]

Odontogenic tumours are a group of heterogeneous diseases that range from hamartomatous or non-neoplastic tissue proliferations to benign neoplasms to malignant tumours with metastatic potential. They are rare, comprising about <2-3% of all oral and maxillofacial biopsy specimens. The aim of the present study was to determine the clinico-pathological presentation of this heterogeneous group of lesions and review of literature. The present study was conducted in the ENT department of a Government Medical College and Hospital, West Bengal, India, over the period of 5 years from January 2011 to December 2015. It included a total of 15 patients who were clinico-radiologically diagnosed as odontogenic tumours, and were given appropriate treatment. Their diagnostic and management approaches are discussed. Among 15 odontogenic tumours, 13 were benign and two were malignant. Male to female ratio was 2:3. Mandible to maxilla ratio was 1.8:1. The patients were in between 4 and 56 years of age with highest incidence in 3rd decade of life. All patients are doing well till date with a minimum follow-up of 1 year. Incisional biopsy is considered as gold standard for preoperative diagnosis but FNAC can offer clinicians a less invasive alternative. CT is the choice of investigation for study of lesion, analysis of its extension and surgical planning. The challenge to proper management lies in balancing between conservative and radical approach to reduce morbidity and recurrence both. Final diagnosis is made by post-operative histopathological examination. [ABSTRACT FROM AUTHOR]

Cyclic pursuit has been an important connection topology in multi-agent systems. Many variants of the classical cyclic pursuit law have been analysed by researchers. Among these variants are homogeneous and heterogeneous cyclic pursuit, or single layer and hierarchical cyclic pursuit. In this paper hierarchical cyclic pursuit, with heterogeneous gains, has been considered. This paper generalizes existing results by allowing both heterogeneity in the gains, and extension of the single layer information flow graph to a multi-layer hierarchical structure. Some new results are presented about the reachability of agents in hierarchical cyclic pursuit. It is shown that the existing results may be obtained as special cases of the results obtained in this paper. Simulation results are provided to support the theoretical findings. [ABSTRACT FROM AUTHOR]

Brain abscess is the ultimate otogenic complication, both in severity and difficulty of management. In developing countries with high incidence of cholesteatoma, brain abscess is not a rare complication. In India, brain abscesses constitute about 8 % of all intracranial lesions. The surgical treatment of brain abscess is very controversial. This prospective study was done in ENT department of a tertiary care hospital in Kolkata, during the period from May 2009 to April 2014. 22 such cases of otogenic brain abscess managed by single-stage trans-mastoid drainage along with meticulous mastoid clearance. On the basis of clinical, radiological and operative findings, data of all patients with otogenic brain abscess were analyzed. There was male predominance and 9 (40.91 %) of them were younger than 20 years. 15 (68.18 %) cases were of cerebellar abscess and in 7 (31.82 %) cases were of the temporal abscess. Lateral sinus thrombosis was the most common associated complication found (22.73 %) in our study. All the patients peri-operatively revealed cholesteatoma. All the patients recovered well and there was no recurrence of symptoms on a minimum 15 months follow-up. This approach suits the otologists in clearing the cause and effect of pathology, at the same sitting. This single-stage approach decreases the peri-operative morbidity and mortality of the two-stage procedure. It also decreases the hospital stay and financial burden. [ABSTRACT FROM AUTHOR]

Increasing use of engineered nanomaterials (ENMs) in consumer products may result in widespread human inhalation exposures. Due to their high surface area per unit mass, inhaled ENMs interact with multiple components of the pulmonary system, and these interactions affect their ultimate fate in the body. Modeling of ENM transport and clearance in vivo has traditionally treated tissues as well-mixed compartments, without consideration of nanoscale interaction and transformation mechanisms. ENM agglomeration, dissolution and transport, along with adsorption of biomolecules, such as surfactant lipids and proteins, cause irreversible changes to ENM morphology and surface properties. The model presented in this article quantifies ENM transformation and transport in the alveolar air to liquid interface and estimates eventual alveolar cell dosimetry. This formulation brings together established concepts from colloidal and surface science, physics, and biochemistry to provide a stochastic framework capable of capturing essential in vivo processes in the pulmonary alveolar lining layer. The model has been implemented for in vitro solutions with parameters estimated from relevant published in vitro measurements and has been extended here to in vivo systems simulating human inhalation exposures. Applications are presented for four different ENMs, and relevant kinetic rates are estimated, demonstrating an approach for improving human in vivo pulmonary dosimetry. [ABSTRACT FROM AUTHOR]

This paper analyses deviated linear cyclic pursuit in which an agent pursues its leader with an angle of deviation in both the continuous- and discrete-time domains, while admitting heterogeneous gains and deviations for the agents. Sufficient conditions for the stability of such systems, in both the domains, are presented in this paper along with the derivation of the reachable set, which is a set of points where the agents may converge asymptotically. The stability conditions are derived based on Gershgorin's theorem. Simulations validating the theoretical results presented in this paper are provided. [ABSTRACT FROM AUTHOR]

Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population. [ABSTRACT FROM AUTHOR]

Engineered nanomaterials (ENMs) possess unique characteristics affecting their interactions in biological media and biological tissues. Systematic investigation of the effects of particle properties on biological toxicity requires a comprehensive modeling framework which can be used to predict ENM particokinetics in a variety of media. The Agglomeration-diffusion-sedimentation-reaction model (ADSRM) described here is stochastic, using a direct simulation Monte Carlo method to study the evolution of nanoparticles in biological media, as they interact with each other and with the media over time. Nanoparticle diffusion, gravitational settling, agglomeration, and dissolution are treated in a mechanistic manner with focus on silver ENMs (AgNPs). The ADSRM model utilizes particle properties such as size, density, zeta potential, and coating material, along with medium properties like density, viscosity, ionic strength, and pH, to model evolving patterns in a population of ENMs along with their interaction with associated ions and molecules. The model predictions for agglomeration and dissolution are compared with in vitro measurements for various types of ENMs, coating materials, and incubation media, and are found to be overall consistent with measurements. The model has been implemented for an in vitro case in cell culture systems to inform in vitro dosimetry for toxicology studies, and can be directly extended to other biological systems, including in vivo tissue sub-systems by suitably modifying system geometry. [ABSTRACT FROM AUTHOR]

This paper addresses the problem of controlling impact time against various types of target – stationary, constant velocity, or maneuvering. Analytical expression of time-to-go, that is exact for non-maneuvering target but approximate for maneuvering ones, is first presented based on true-proportional-navigation guidance concepts. Guidance strategies are then derived, using Lyapunov theory, to meet impact time constraints, without linearizing the engagement dynamics. Hence, the proposed strategies remain effective even for large initial heading errors. Further, a cooperative guidance strategy to achieve simultaneous target interception by multiple interceptors is also proposed. Guidance commands that ensure consensus among the time-to-go values of the interceptors are utilized for this purpose. Using judicious choices of gains, the common time of target interception may be either pre-fixed, or the same may be decided cooperatively during the engagement. Stability analysis of the possible equilibria in heading angle dynamics, for different choices of parameters, is also performed. For both one-to-one and cooperative homing, simulation results are presented for various engagement scenarios to demonstrate the effectiveness of the proposed strategies. [ABSTRACT FROM AUTHOR]

Engineered nanoparticles (NPs) have been widely demonstrated to induce toxic effects to various cell types. In vitro cell exposure systems have high potential for reliable, high throughput screening of nanoparticle toxicity, allowing focusing on particular pathways while excluding unwanted effects due to other cells or tissue dosimetry. The work presented here involves a detailed biologically based computational model of cellular interactions with NPs; it utilizes measurements performed in human cell culture systems in vitro, to develop a mechanistic mathematical model that can support analysis and prediction of in vivo effects of NPs. The model considers basic cellular mechanisms including proliferation, apoptosis, and production of cytokines in response to NPs. This new model is implemented for macrophages and parameterized using in vitro measurements of changes in cellular viability and mRNA levels of cytokines: TNF, IL-1b, IL-6, IL-8, and IL-10. The model includes in vitro cellular dosimetry due to nanoparticle transport and transformation. Furthermore, the model developed here optimizes the essential cellular parameters based on in vitro measurements, and provides a "stepping stone" for the development of more advanced in vivo models that will incorporate additional cellular and NP interactions. [ABSTRACT FROM AUTHOR]

A computational, multiscale toxicodynamic model has been developed to quantify and predict pulmonary effects due to uptake of engineered nanomaterials (ENMs) in mice. The model consists of a collection of coupled toxicodynamic modules, that were independently developed and tested using information obtained from the literature. The modules were developed to describe the dynamics of tissue with explicit focus on the cells and the surfactant chemicals that regulate the process of breathing, as well as the response of the pulmonary system to xenobiotics. Alveolar type I and type II cells, and alveolar macrophages were included in the model, along with surfactant phospholipids and surfactant proteins, to account for processes occurring at multiple biological scales, coupling cellular and surfactant dynamics affected by nanoparticle exposure, and linking the effects to tissue-level lung function changes. Nanoparticle properties such as size, surface chemistry, and zeta potential were explicitly considered in modeling the interactions of these particles with biological media. The model predictions were compared with in vivo lung function response measurements in mice and analysis of mice lung lavage fluid following exposures to silver and carbon nanoparticles. The predictions were found to follow the trends of observed changes in mouse surfactant composition over 7 days post dosing, and are in good agreement with the observed changes in mouse lung function over the same period of time. [ABSTRACT FROM AUTHOR]

This work proposes two different cooperative integrated guidance and control schemes for a group of interceptors, each steered by combined effects of canard and tail aerodynamic surfaces, aiming a simultaneous interception of a non-maneuvering target. The first approach is based on a leader-follower framework, in which the time of interception can be prescribed before homing, while the second approach is of a leaderless framework, in which the time of interception is decided during engagement. The proposed integrated guidance and control design for multi-body engagement is carried out under nonlinear settings, with time-to-go formulations that relax the restrictive assumption of interceptors' small heading angles. This facilitates wide applicability of the proposed design in scenarios necessitating large terminal time requirements. In addition to the nonlinearity in kinematics of engagement and interceptors' dynamics, effect of actuators are also considered, making the design suitable for practical implementation. Since canard and tail aerodynamic surfaces have different capabilities, a weighted effort allocation scheme is devised to apportion the total effort in both control surfaces in a suitable manner. Finally, various engagement scenarios have been considered in simulations to substantiate the efficacy of the proposed schemes. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is one of the most common types of allergy worldwide. It has significant negative impact on the quality of life (QOL). One of the available causal treatments of AR is allergen specific immunotherapy which remains effective even after the end of treatment course, unlike symptomatic drugs. AR patients aged above five years, allergic to unavoidable allergen like house dust, mite etc., and refractory to maximal pharmacotherapy were included in present study. Patients allergic to avoidable allergen, taking beta-blocker medication, having other immunological disease, and who were pregnant, breast-feeding or lost to follow up, were excluded from the study. All patients included in the study underwent sublingual immunotherapy (SLIT). The impact of treatment is measured by calculating the difference between SNOT-20 score before and after treatment (which is 6 months interval). Total 30 patients were studied. Paired-t test calculated value of cumulative score and nasal symptom score are 7.853 and 6.85 respectively. Both are greater than table value of 2.46. So paired-t test shows that SLIT is very much effective in treatment of AR. The present study re-establish the fact that SLIT not only reduces AR symptoms, it also improves the QOL. It has very good patient compliance with minimal side effects. [ABSTRACT FROM AUTHOR]

This paper proposes integrated guidance and control design to intercept a target, which may execute various motions, at a pre-specified time of interception. The problem is addressed considering nonlinear engagement kinematics and the interceptor is steered using the combined effects of canard as well as tail configurations (dual-controlled interceptors). Different formulations of time-to-go, without the restrictive assumption of interceptor's small heading angle, have been used in deriving the guidance commands, allowing the proposed strategy to remain effective over a wide range of impact time values. A weighted effort allocation scheme, in canard and tail deflections, has been proposed to generate the required lateral acceleration. The overall design uses sliding mode control owing to its simplicity of design, while a nonlinear finite-time disturbance observer is used to estimate the target's maneuver. Finally, simulations are presented for various target motions, and time-constrained interception with an impaired actuator is also shown, vindicating the efficacy of the proposed technique. [ABSTRACT FROM AUTHOR]

This paper deals with nonsingular guidance and control design for an interceptor, using a decoupled approach, steered by the combined effects of both canard and tail, to intercept a moving but non-maneuvering target at a time specified a priori. First, interceptor's desired lateral acceleration, consisting of nominal and corrective components, is derived using deviated pursuit guidance. While the nominal component is the pursuit guidance law, the corrective component drives the time-to-go error to zero within a finite-time in an optimal manner. Using a desired error dynamics and a meaningful performance index, the lateral acceleration demand is minimized during the transient phase. With exact knowledge of time-to-go and the consideration of nonlinear kinematic model, the proposed design circumvents the errors arising out of any approximations. Interceptor's canard and tail deflection commands are derived using predefined-time convergent sliding mode control, which allows the autopilot to precisely track the commanded lateral acceleration within a time specified during design. Finally, simulations are presented for various cases to demonstrate the efficacy of the proposed design. [ABSTRACT FROM AUTHOR]