Effective bolus dose of remimazolam for i-gel® insertion in nonparalyzed patients: a dose-finding study.

PURPOSE: Remimazolam is a recently developed ultra-short-acting benzodiazepine used for anesthesia induction and maintenance. Nevertheless, the effective bolus dose of remimazolam for i-gel® (Intersurgical Ltd., Wokingham, Berkshire, UK) insertion without the use of neuromuscular blocking agents (NMBAs) has not been well established. METHODS: This study included 25 adult patients scheduled for surgery under general anesthesia who were eligible for i-gel use. Anesthesia was induced with predetermined bolus doses of remimazolam, starting at 0.3 mg·kg-1 for the first patient, without the use of NMBAs. All patients concurrently received remifentanil using target-controlled infusion (TCI) at a fixed effect-site concentration (Ce) of 3.0 ng·mL-1. Insertion of the i-gel was attempted 90 sec after remimazolam administration, and insertion conditions were assessed. Subsequent doses of remimazolam were decreased or increased by 0.05 mg·kg-1, depending on the success or failure of i-gel insertion. RESULTS: The mean (standard deviation) 50% effective dose (ED50) of a remimazolam bolus for successful i-gel insertion as determined by the modified Dixon's up-and-down method was 0.100 (0.027) mg·kg-1. The ED50 and ED95 estimated by isotonic regression were 0.111 (83% confidence interval [CI], 0.096 to 0.131) mg·kg-1 and 0.182 (95% CI, 0.144 to 0.195) mg·kg-1, respectively. None of the patients required treatment for hypotension or bradycardia during anesthesia induction. CONCLUSION: Based on the ED95 of remimazolam bolus dose determined in our study, we recommend using 0.182 mg·kg-1 of remimazolam in combination with remifentanil TCI at a Ce of 3.0 ng·mL-1 for successful i-gel insertion without NMBAs in adult patients. This regimen seems effective with a low risk of hemodynamic instability during anesthesia induction. STUDY REGISTRATION: ClinicalTrials.gov ( NCT05298228 ); first submitted 6 March 2022.

RéSUMé: OBJECTIF: Le remimazolam est une benzodiazépine à action ultra-courte récemment mise au point et utilisée pour l'induction et le maintien de l'anesthésie. Toutefois, la dose efficace en bolus de remimazolam pour l'insertion de l'i-gel® (Intersurgical Ltd., Wokingham, Berkshire, Royaume-Uni) sans utiliser de bloqueurs neuromusculaires (BNM) n'a pas été bien établie. MéTHODE: Cette étude a inclus 25 adultes devant bénéficier d'une intervention chirurgicale sous anesthésie générale qui étaient éligibles à l'utilisation d'un i-gel. L'anesthésie a été induite avec des doses prédéterminées en bolus de remimazolam, à partir de 0,3 mg·kg−1 pour la première personne, sans utiliser de BNM. Toutes les personnes anesthésiées ont reçu en parallèle du rémifentanil en perfusion à objectif de concentration à une concentration au site effecteur (Ce) de 3,0 ng·mL−1. L'insertion de l'i-gel a été tentée 90 secondes après l'administration de remimazolam, et les conditions d'insertion ont été évaluées. Les doses subséquentes de remimazolam ont été diminuées ou augmentées de 0,05 mg·kg−1, en fonction du succès ou de l'échec de l'insertion de l'i-gel. RéSULTATS: La dose efficace moyenne (écart type) de 50 % (DE50) d'un bolus de remimazolam pour une insertion réussie de l'i-gel, telle que déterminée par la méthode « up-and-down ¼ de Dixon modifiée, était de 0,100 (0,027) mg·kg−1. Les DE50 et DE95 estimées par régression isotonique étaient de 0,111 (intervalle de confiance [IC] à 83 %, 0,096 à 0,131) mg·kg−1 et 0,182 (IC 95 %, 0,144 à 0,195) mg·kg−1, respectivement. Aucun·e patient·e n'a eu besoin de traitement pour une hypotension ou une bradycardie pendant l'induction de l'anesthésie. CONCLUSION: D'après la DE95 de la dose de remimazolam en bolus déterminée dans notre étude, nous recommandons d'utiliser 0,182 mg·kg−1 de remimazolam en association avec une perfusion à objectif de concentration de rémifentanil à une Ce de 3,0 ng·mL−1 pour réussir l'insertion de l'i-gel sans BNM chez la patientèle adulte. Ce schéma semble efficace avec un faible risque d'instabilité hémodynamique lors de l'induction de l'anesthésie. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05298228); première soumission le 6 mars 2022.

Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies.

Acute administration of trastuzumab (TZB) may induce various forms of cognitive impairment. These cancer-related cognitive changes (CRCC) are regulated by an adverse biological process involving cancer stem cells (CSCs) and IL-6. Recent studies have reported that atorvastatin (ATV) may change the dynamic of cognitive impairment in a combination (TZB+ATV) therapy. In this study, we investigate the mutual interactions between cancer stem cells and the tumor cells that facilitate cognitive impairment during long term TZB therapy by developing a mathematical model that involves IL-6 and the key apoptotic regulation. These include the densities of tumor cells and CSCs, and the concentrations of intracellular signaling molecules (NFκB, Bcl-2, BAX). We apply the mathematical model to a single or combination (ATV+TZB) therapy used in the experiments to demonstrate that the CSCs can enhance CRCC by secreting IL-6 and ATV may interfere the whole regulation. We show that the model can both reproduce the major experimental observation on onset and prevention of CRCC, and suggest several important predictions to guide future experiments with the goal of the development of new anti-tumor and anti-CRCC strategies. Moreover, using this model, we investigate the fundamental mechanism of onset of cognitive impairment in TZB-treated patients and the impact of alternating therapies on the anti-tumor efficacy and intracellular response to different treatment schedules.

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural insights from a computational model.

Lung cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by hijacking immune system for active growth and aggressive metastasis. Neutrophils, which in their original form should establish immune activities to the tumor as a first line of defense, are undermined by tumor cells to promote tumor invasion in several ways. In this study, we investigate the mutual interactions between the tumor cells and the neutrophils that facilitate tumor invasion by developing a mathematical model that involves taxis-reaction-diffusion equations for the critical components in the interaction. These include the densities of tumor and neutrophils, and the concentrations of signaling molecules and structure such as neutrophil extracellular traps (NETs). We apply the mathematical model to a Boyden invasion assay used in the experiments to demonstrate that the tumor-associated neutrophils can enhance tumor cell invasion by secreting the neutrophil elastase. We show that the model can both reproduce the major experimental observation on NET-mediated cancer invasion and make several important predictions to guide future experiments with the goal of the development of new anti-tumor strategies. Moreover, using this model, we investigate the fundamental mechanism of NET-mediated invasion of cancer cells and the impact of internal and external heterogeneity on the migration patterning of tumour cells and their response to different treatment schedules.

Role of senescent tumor cells in building a cytokine shield in the tumor microenvironment: mathematical modeling.

Cellular senescence can induce dual effects (promotion or inhibition) on cancer progression. While immune cells naturally respond and migrate toward various chemotactic sources from the tumor mass, various factors including senescent tumor cells (STCs) in the tumor microenvironment may affect this chemotactic movement. In this work, we investigate the mutual interactions between the tumor cells and the immune cells that either inhibit or facilitate tumor growth by developing a mathematical model that consists of taxis-reaction-diffusion equations and receptor kinetics for the key players in the interaction network. We apply a mathematical model to a transwell Boyden chamber invasion assay used in the experiments to illustrate that STCs can play a pivotal role in negating immune attack through tight regulation of intra- and extra-cellular signaling molecules. In particular, we show that senescent tumor cells in cell cycle arrest can block intratumoral infiltration of CD8+ T cells by secreting a high level of CXCL12, which leads to significant reduction its receptors, CXCR4, on T cells, and thus impaired chemotaxis. The predictions of nonlinear responses to CXCL12 were in good agreement with experimental data. We tested several hypotheses on immune-tumor interactions under various biochemical conditions in the tumor microenvironment and developed new concepts for anti-tumor strategies targeting senescence induced immune impairment.

Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy.

In the present work, we investigated the role of natural killer (NK) cells in combination therapy with oncolytic virus (OV) and bortezomib, a proteasome inhibitor. NK cells display rapid and potent immunity to metastatic and hematological cancers, and they overcome immunosuppressive effects of tumor microenvironment. We developed a mathematical model to address the question of how the density of NK cells affects the growth of the tumor. We found that the antitumor efficacy increases when the endogenous NKs are depleted and also when exogenous NK cells are injected into the tumor. These predictions were validated by our in vivo and in vitro experiments.

Simultaneous measurement of the surface shape and thickness for an optical flat with a wavelength-tuning Fizeau interferometer with suppression of drift error.

Two types of phase-shifting algorithms were developed for simultaneous measurement of the surface and thickness variation of an optical flat. During wavelength tuning, phase-shift nonlinearity can cause a spatially nonuniform error and spatially uniform DC drift error. A 19-sample algorithm was developed that eliminates the effect of the spatially uniform error by expanding the 17-sample algorithm with characteristic polynomial theory. The 19-sample algorithm was then altered to measure the surface shape of the optical flat by rotation of the characteristic diagram. The surface shape and thickness variation were measured with these two algorithms and a wavelength-tuning Fizeau interferometer.

Joint model for recurrent event data with a cured fraction and a terminal event.

In a longitudinal study where the recurrence of an event and a terminal event such as death are observed, a certain portion of the subjects may experience no event during a long follow-up period; this often denoted as the cure group which is assumed to be the risk-free from both recurrent events and death. However, this assumption ignores the possibility of death, which subjects in the cure group may experience. In the present study, such misspecification is investigated with the addition of a death hazard model to the cure group. We propose a joint model using a frailty effect, which reflects the association between a recurrent event and death. For the estimation, an expectation-maximization (EM) algorithm was developed and PROC NLMIXED in SAS was incorporated under a piecewise constant baseline. Simulation studies were performed to check the performance of the suggested method. The proposed method was applied to leukemia patients experiencing both infection and death after bone marrow transplant.

Interferometric profile measurement of optical-thickness by wavelength tuning with suppression of spatially uniform error.

Wavelength-tuning interferometry has been widely used for measuring the thickness variation of optical devices used in the semiconductor industry. However, in wavelength-tuning interferometry, the nonlinearity of phase shift causes a spatially uniform error in the calculated phase distribution. In this study, the spatially uniform error is formulated using Taylor series. A new 9-sample phase-shifting algorithm is proposed, with which the uniform spatial phase error can be eliminated. The characteristics of 9-sample algorithm is discussed using Fourier representation and RMS error analysis. Finally, optical-thickness variation of transparent plate is measured using the proposed algorithm and wavelength-tuning Fizeau interferometer and the error is compared with 7-sample algorithm.

Canceling the momentum in a phase-shifting algorithm to eliminate spatially uniform errors.

In phase-shifting interferometry, phase modulation nonlinearity causes both spatially uniform and nonuniform errors in the measured phase. Conventional linear-detuning error-compensating algorithms only eliminate the spatially variable error component. The uniform error is proportional to the inertial momentum of the data-sampling weight of a phase-shifting algorithm. This paper proposes a design approach to cancel the momentum by using characteristic polynomials in the Z-transform space and shows that an arbitrary M-frame algorithm can be modified to a new (M+2)-frame algorithm that acquires new symmetry to eliminate the uniform error.

Compensation for correlated error in multilayer interferometer.

Wavelength tuning interferometry is used to measure and estimate the surface shape of a sample. However, in multilayer interferometry (e.g., a lithium niobate [LNB] crystal wafer attached to a supporting plate), the correlated error between the higher harmonics and the phase-shift error causes considerable error in the calculated phase. In this study, the correlated errors calculated by various types of windowed phase-shifting algorithms are analyzed in connection with the characteristic polynomial theory and Fourier representation of the algorithms. The surface shape and optical thickness variation of the LNB wafer are measured simultaneously using the windowed phase-shifting algorithms. The results are compared in terms of the observed ripples and measurement repeatability. The experimental results show that the 4N-3 algorithm is optimal and possesses the smallest repeatability error.

Interferometric measurement of surface shape by wavelength tuning suppressing random intensity error.

In this research, the susceptibility of the phase-shifting algorithms to the random intensity error is formulated and estimated. The susceptibility of the random intensity error of conventional windowed phase-shifting algorithms is discussed, and the 7N-6 phase-shifting algorithm is developed to minimize the random intensity error using the characteristic polynomial theory. Finally, the surface shape of the transparent wedge plate is measured using a wavelength-tuning Fizeau interferometer and the 7N-6 algorithm. The experimental results indicate that the surface shape measurement accuracy for the transparent plate is 2.5 nm.

Measurement of optical thickness variation of BK7 plate by wavelength tuning interferometry.

This paper presents the derivation of a 17-sample phase-shifting algorithm that can compensate the miscalibration and first-order nonlinearity of phase shift error, coupling error, and bias modulation of the intensity and satisfy the fringe contrast maximum condition. The phase error of measurements performed using the 17-sample algorithm is discussed and compared with those of measurements obtained using other algorithms. Finally, the optical thickness variation of a BK7 optically transparent plate obtained using a wavelength tuning Fizeau interferometer and the 17-sample algorithm are presented. The experimental results indicate that the optical thickness variation measurement accuracy for the BK7 plate was 3 nm.

Absolute optical thickness measurement of transparent plate using excess fraction method and wavelength-tuning Fizeau interferometer.

The absolute optical thickness of a transparent plate 6-mm thick and 10 mm in diameter was measured by the excess fraction method and a wavelength-tuning Fizeau interferometer. The optical thickness, defined by the group refractive index at the central wavelength, was measured by wavelength scanning. The optical thickness deviation, defined by the ordinary refractive index, was measured using the phase-shifting technique. Two kinds of optical thicknesses, measured by discrete Fourier analysis and the phase-shifting technique, were synthesized to obtain the optical thickness with respect to the ordinary refractive index using Sellmeier equation and least-square fitting.

Simultaneous measurement of surface shape and optical thickness using wavelength tuning and a polynomial window function.

In this study, a 6N - 5 phase shifting algorithm comprising a polynomial window function and discrete Fourier transform is developed for the simultaneous measurement of the surface shape and optical thickness of a transparent plate with suppression of the coupling errors between the higher harmonics and phase shift error. The characteristics of the 6N - 5 algorithm were estimated by connection with the Fourier representation in the frequency domain. The phase error of the measurements performed using the 6N - 5 algorithm is discussed and compared with those of measurements obtained using other algorithms. Finally, the surface shape and optical thickness of a transparent plate were measured simultaneously using the 6N - 5 algorithm and a wavelength tuning interferometer.

Measurement of absolute optical thickness of mask glass by wavelength-tuning Fourier analysis.

Optical thickness is a fundamental characteristic of an optical component. A measurement method combining discrete Fourier-transform (DFT) analysis and a phase-shifting technique gives an appropriate value for the absolute optical thickness of a transparent plate. However, there is a systematic error caused by the nonlinearity of the phase-shifting technique. In this research the absolute optical-thickness distribution of mask blank glass was measured using DFT and wavelength-tuning Fizeau interferometry without using sensitive phase-shifting techniques. The error occurring during the DFT analysis was compensated for by using the unwrapping correlation. The experimental results indicated that the absolute optical thickness of mask glass was measured with an accuracy of 5 nm.

Surface measurement of indium tin oxide thin film by wavelength-tuning Fizeau interferometry.

Indium-tin oxide (ITO) thin films have been widely used in displays such as liquid crystal displays and touch panels because of their favorable electrical conductivity and optical transparency. The surface shape and thickness of ITO thin films must be precisely measured to improve their reliability and performance. Conventional measurement techniques take single point measurements and require expensive systems. In this paper, we measure the surface shape of an ITO thin film on top of a transparent plate using wavelength-tuning Fizeau interferometry. The surface shape was determined by compensating for the phase error introduced by optical interference from the thin film, which was calculated using the phase and amplitude distributions measured by wavelength-tuning. The proposed measurement method achieved noncontact, large-aperture, and precise measurements of transparent thin films. The surface shape of the sample was experimentally measured to an accuracy of 5.13 nm.

Design of phase shifting algorithms: fringe contrast maximum.

In phase shifting interferometry, the fringe contrast is preferred to be at a maximum when there is no phase shift error. In the measurement of highly-reflective surfaces, the signal contrast is relatively low and the measurement would be aborted when the contrast falls below a threshold value. The fringe contrast depends on the design of the phase shifting algorithm. The condition for achieving the fringe contrast maximum is derived as a set of linear equations of the sampling amplitudes. The minimum number of samples necessary for constructing an error-compensating algorithm that is insensitive to the jth harmonic component and to the phase shift error is discussed. As examples, two new algorithms (15-sample and (3N - 2)-sample) were derived that are useful for the measurement for highly-reflective surfaces.

Multiple-surface interferometry of highly reflective wafer by wavelength tuning.

The surface shape and optical thickness variation of a lithium niobate (LNB) wafer were measured simultaneously using a wavelength-tuning interferometer with a new phase-shifting algorithm. It is necessary to suppress the harmonic signals for testing a highly reflective sample such as a crystal wafer. The LNB wafer subjected to polishing, which is in optical contact with a fused-silica (FS) supporting plate, generates six different overlapping interference fringes. The reflectivity of the wafer is typically 15%, yielding significant harmonic signals. The new algorithm can flexibly select the phase-shift interval and effectively suppress the harmonic signals and crosstalk. Experimental results indicated that the optical thickness variation of the LNB wafer was measured with an accuracy of 2 nm.

Modeling the role of TGF-ß in regulation of the Th17 phenotype in the LPS-driven immune system.

Airway exposure levels of lipopolysaccharide (LPS) are known to determine type I versus type II helper T cell induced experimental asthma. While low doses of LPS derive Th2 inflammatory responses, high (and/or intermediate) LPS levels induce Th1- or Th17-dominant responses. The present paper develops a mathematical model of the phenotypic switches among three Th phenotypes (Th1, Th2, and Th17) in response to various LPS levels. In the present work, we simplify the complex network of the interactions between cells and regulatory molecules. The model describes the nonlinear cross-talks between the IL-4/Th2 activities and a key regulatory molecule, transforming growth factor ß (TGF-ß), in response to high, intermediate, and low levels of LPS. The model characterizes development of three phenotypes (Th1, Th2, and Th17) and predicts the onset of a new phenotype, Th17, under the tight control of TGF-ß. Analysis of the model illustrates the mono-, bi-, and oneway-switches in the key regulatory parameter sets in the absence or presence of time delays. The model also predicts coexistence of those phenotypes and Th1- or Th2-dominant immune responses in a spatial domain under various biochemical and bio-mechanical conditions in the microenvironment.

Mechanistic modeling of the effects of myoferlin on tumor cell invasion.

Myoferlin (MYOF) is a member of the evolutionarily conserved ferlin family of proteins, noted for their role in a variety of membrane processes, including endocytosis, repair, and vesicular transport. Notably, ferlins are implicated in Caenorhabditis elegans sperm motility (Fer-1), mammalian skeletal muscle development and repair (MYOF and dysferlin), and presynaptic transmission in the auditory system (otoferlin). In this paper, we demonstrate that MYOF plays a previously unrecognized role in cancer cell invasion, using a combination of mathematical modeling and in vitro experiments. Using a real-time impedance-based invasion assay (xCELLigence), we have shown that lentiviral-based knockdown of MYOF significantly reduced invasion of MDA-MB-231 breast cancer cells in Matrigel bioassays. Based on these experimental data, we developed a partial differential equation model of MYOF effects on cancer cell invasion, which we used to generate mechanistic hypotheses. The mathematical model predictions revealed that matrix metalloproteinases (MMPs) may play a key role in modulating this invasive property, which was supported by experimental data using quantitative RT-PCR screens. These results suggest that MYOF may be a promising target for biomarkers or drug target for metastatic cancer diagnosis and therapy, perhaps mediated through MMPs.