Temporal interference (TI) stimulation, a novel non-invasive stimulation strategy, has recently been shown to modulate neural activity in deep brain regions of living mice. Yet, it is uncertain if this method is applicable to larger brains and whether the electric field produced under traditional safety currents can penetrate deep regions as observed in mice. Despite recent model-based simulation studies offering positive evidence at both macro- and micro-scale levels, the absence of electrophysiological data from actual brains hinders comprehensive understanding and potential application of TI. This study aims to directly measure the spatiotemporal properties of the interfered electric field in the rhesus monkey brain and to validate the effects of TI on the human brain. Two monkeys were involved in the measurement, with implantation of several stereo-electroencephalography (SEEG) depth electrodes. TI stimulation was applied to anesthetized monkeys using two pairs of surface electrodes at differing stimulation parameters. Model-based simulations were also conducted and subsequently compared with actual recordings. Additionally, TI stimulation was administered to patients with motor disorders to validate its effects on motor symptoms. Through the integration of computational electric field simulation with empirical measurements, it was determined that the temporally interfering electric fields in the deep central regions are capable of attaining a magnitude sufficient to induce a subthreshold modulation effect on neural signals. Additionally, an improvement in movement disorders was observed as a result of TI stimulation. This study is the first to systematically measure the TI electric field in living non-human primates, offering empirical evidence that TI holds promise as a more focal and precise method for modulating neural activities in deep regions of a large brain. This advancement paves the way for future applications of TI in treating neuropsychiatric disorders.

BACKGROUND: Delayed or missed doses are inevitable in epilepsy pharmacotherapy. The current remedial measures recommended by the United States Food and Drug Administration (FDA) for non-adherence are generic and lack clinical evidence.
OBJECTIVE: To assess remedial strategies for delayed or missed pregabalin doses in patients with epilepsy using Monte Carlo simulations.
METHODS: Monte Carlo simulations were performed using a published population pharmacokinetic model for pregabalin. The applicability of five proposed remedial regimens as well as FDA recommendations was evaluated by simulating various poor adherence scenarios in eight populations, including those with renal dysfunction.
RESULTS: All proposed remedial strategies were associated with delay duration and renal function. When delays are relatively short, an immediate regular dose is advised. The cut-off time points for taking the regular dose as a remedial regimen were 1, 2, 4, and 12 h for patients with mild renal impairment and normal renal function, moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively. However, when delay aligns closely with a dosing interval, a regular dose combined with a partial dose proves effective. Generally, supplementing 1.3-fold the regular dose at the next scheduled time adequately compensates for the missed dose.
CONCLUSIONS: Model-based simulations provided quantitative evidence for the effectiveness and feasibility of remedial strategies for missed or delayed pregabalin doses.

Cobotic applications require a good knowledge of human behaviour in order to be cleverly, securely and fluidly performed. For example, to make a human and a humanoid robot perform a co-navigation or a co-manipulation task, a model of human walking trajectories is essential to make the robot follow or even anticipate the human movements. This paper aims to study the Center of Mass (CoM) path during locomotion and generate human-like trajectories with an optimal control scheme. It also proposes a metric which allows to assess this model compared to the human behaviour. CoM trajectories during locomotion of 10 healthy subjects were recorded and analysed as part of this study. Inverse optimal control was used to find the optimal cost function which best fits the model to the measurements. Then, the measurements and the generated data were compared in order to assess the performance of the presented model. Even if the experiments show a great variability in human behaviours, the model presented in this study gives an accurate approximation of the average human walking trajectories. Furthermore, this model gives an approximation of human locomotion good enough to improve cobotic tasks allowing a humanoid robot to anticipate the human behaviour.

Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients.
Retrospective pharmacokinetics study.
Two large, academic, tertiary-care medical center.
Two hundred nineteen plasma trough concentrations (Cmin ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non-cirrhotic patients were included.
Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model-based simulation was used to optimize voriconazole dosage regimens.
Voriconazole-related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold Cmin for AE was 5.12 mg/L. A two-compartment model with first-order elimination adequately described the data. The Child-Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non-cirrhotic, Child-Pugh class A and B cirrhotic (CP-A/B) and Child-Pugh class C cirrhotic (CP-C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model-based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally led to 65.0-75.7% of voriconazole Cmin in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously or orally for CP-A/B patients, and 50 mg/12 hours and 100 mg/24 hours intravenously or orally for CP-C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady-state was 66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients.
These results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/B patients compared to that for patients with normal liver function.

The low ammonium concentration, low temperature, presence of organic matter, and large variation of influent ammonium load pose serious challenges for the application of PN/AMX (partial nitrification-anammox) reactor in the mainstream wastewater treatment. Previous mathematical simulation studies of PN/AMX granule reactor mainly concentrated on the steady-state modeling. The steady-state simulation cannot be used for developing control strategies under dynamic condition. In this study, four control strategies were evaluated on their abilities to minimize the impact of feed disturbances on autotrophic nitrogen removal in mainstream wastewater. The four control strategies included are the following: (A) direct airflow adjustment to maintain the fixed NH4+ set point, (B) fixed NH4+ set point control manipulated by DO concentration with DO limit, (C) constant DO control strategy, and (D) adaptive change of NH4+ set point control based on the feed disturbance (NH4+ set point value achieved by DO concentration manipulation with DO limit). The results indicated that the control strategy A successfully implemented for high NH4+ strength wastewater treatment cannot be directly transferred into the mainstream wastewater treatment, in which high NO2- accumulation was resulted during the NH4+ peaks at the low-temperature period. Satisfactory TN removal could be achieved by maintaining either fixed or variable bulk NH4+ set point values calculated based on the feed disturbances (control strategies B and D). The DO limit imposed on the DO concentration manipulation to derive the desired NH4+ set point values was essential for the successful implementation of control strategies B and D. The control strategy C with constant DO concentration was not feasible for the PN/AMX process under dynamic feed disturbances. The control simulation results and the control variable sensitivity analysis indicated that the NH4+ concentration was a better control variable than the DO concentration.