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Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan. [ABSTRACT FROM AUTHOR]

The electronic, optical, and mechanical properties of vanadium dioxide (VO2) can be significantly altered by external stimuli such as heat, electric field, and so on, due to its metal-insulator transition (MIT). While the properties and potential applications of this material have been widely studied, minimal efforts were pursued to integrate VO2 into existing microfabrication processes. Here, in this paper, we present a process for fabricating VO2/TiO2-coated microstring resonators, where the stability of both films was monitored during the entire process. RIE, vapour HF, ablation, and ICP etching were used throughout the process and their effects on the VO2/TiO2 films, as well as the structural and masking layers was studied. Certain processes required the use of a metal hard mask rather than photo resist. VO2 shows excellent etch selectivity over the metal mask layer with RIE. Of all metals examined, Cr was found to be the most stable as a hard mask. Once fabricated, the mechanical and electrical characterizations of the microstring were carried out by measuring resonance frequency (fr) and electrical resistance which show over 6 % alteration in fr and two orders of magnitude change in resistance during the MIT, with a reversible transition and minimal hysteresis. This report provides a foundation for future processing of VO2 based MEMS/MOEMS devices. [ABSTRACT FROM AUTHOR]

Owing to remarkable thermochromic, electrochromic, and photochromic properties which arise from a first-order phase transition from insulator to metal at 68 °C, vanadium dioxide (VO 2 ) has an enormous range of potential applications. However, due to such narrow thermodynamic stability, there is a major challenge surrounding selective phase deposition of vanadium dioxide thin films. Here, we present a report that establishes precise conditions for the deposition of three major polymorphs of VO 2 by pulsed laser deposition. By a systematic study of the synergistic effects of the deposition conditions using a robust design of experiment (Taguchi design), we are able to deposit the VO 2 (M1), VO 2 (T), and VO 2 (A) phases onto thermal oxide (Si/SiO 2 ) substrates with remarkable precision. By electrically probing the temperature induced phase transformation from insulator to metal of each of these polymorphs, we find not only a strong dependence on the phase, but that the nature of the deposition conditions influences the magnitude and hysteresis width of the temperature cycle. [ABSTRACT FROM AUTHOR]

This article presents the population pharmacokinetic (PopPK) analysis and exposure‐response analyses for the primary efficacy end point—acute graft‐versus‐host disease (aGVHD) day 28 response—and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double‐blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK data set contained sparse data from patients with aGVHD and select enriched data from healthy volunteers. The structural model was a 2‐compartment model with first‐order elimination and dose‐dependent nonlinear absorption with dual first‐order absorption pathways with lag times. Strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily to 200 mg once daily, 400 mg once daily to 300 mg once daily, and 600 mg once daily to 400 mg once daily. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure‐response relationship was characterized between itacitinib exposure and probability of aGVHD day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection. [ABSTRACT FROM AUTHOR]

Hybrid vehicle fuel economy and drive quality are coupled through the "energy management" controller that regulates power flow among the various energy sources and sinks. This paper studies energy management controllers designed using shortest path stochastic dynamic programming (SP-SDP), a stochastic optimal control design method which can respect constraints on drivetrain activity while minimizing fuel consumption for an assumed distribution of driver power demand. The performance of SP-SDP controllers is evaluated through simulation on large numbers of real-world drive cycles and compared to a baseline industrial controller provided by a major auto manufacturer. On real-world driving data, the SP-SDP-based controllers yield 10% better fuel economy than the baseline industrial controller, for the same engine and gear activity. The SPSDP controllers are further evaluated for robustness to the drive cycle statistics used in their design. Simplified drivability metrics introduced in previous work are validated on large real-world data sets. [ABSTRACT FROM AUTHOR]

An energy management controller based on shortest path stochastic dynamic programming (SP-SDP) is implemented and tested in a prototype vehicle. The controller simultaneously optimizes fuel economy and powertrain activity, namely gear shifts and engine on-off events. Previous work reported on the controller's design and its extensive simulation-based evaluation. This paper focuses on implementation of the controller algorithm in hardware. Practical issues concerning real-time computability, driver perception, and command timing are highlighted and addressed. The SP-SDP controllers are shown to run in real-time, gracefully handle variations in engine start and gear-shift-completion times, and operate in a manner that is transparent to the driver. A hardware problem with the test vehicle restricted its maximum engine torque, which prevented a reliable fuel economy assessment of the. SP-SDP controller. The data that were collected indicated that SP-SDP controllers could be straightforwardly designed to operate at different points of the fuel economy tradeoff curve and that their fuel economy may equal or exceed that of a baseline industrial controller designed for the vehicle. [ABSTRACT FROM AUTHOR]

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 Cmax by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers. [ABSTRACT FROM PUBLISHER]

Background: Pathogenesis of atopic dermatitis (AD) involves the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. A cream formulation of ruxolitinib, a potent selective JAK1/JAK2 inhibitor, was developed for topical delivery. Method: Pharmacokinetic data were obtained from three double-blind, vehicle-controlled studies in patients with AD: a phase II study with ruxolitinib cream 0.15%, 0.5%, or 1.5% once daily or 1.5% twice daily (BID), and two phase III studies with 0.75% or 1.5% BID. Effects of baseline characteristics on pharmacokinetics were examined. Correlations were attempted between plasma concentrations and change in hematological parameters over time. Results: Ruxolitinib plasma concentrations at steady-state (Css) increased with cream strength in a less-than-dose-proportional manner. In the phase III studies, overall mean (standard deviation [SD]) Css after ruxolitinib cream 0.75% and 1.5% BID (23.8 [35.0] and 35.7 [55.0] nM) were a fraction of the half-maximal inhibitory concentration for thrombopoietin-stimulated phosphorylated STAT3 inhibition (281 nM), a JAK/STAT signaling marker. Three covariates were identified for Css: dose, percent body surface area (%BSA) treated, and baseline Investigator's Global Assessment score. Mean (SD) bioavailability of ruxolitinib cream 1.5% BID was 6.22% (7.66%). There were no correlations between Css and any hematological changes except for a transient increase in platelets at week 2. Conclusions: Plasma ruxolitinib concentrations after treatment with topical ruxolitinib cream in patients with up to 20% BSA affected by AD are not expected to lead to systemic plasma concentrations that may be associated with adverse effects commonly associated with oral JAK inhibitors. ClinicalTrials.gov: NCT03011892; NCT03745638; NCT03745651. [ABSTRACT FROM AUTHOR]

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC0-∞) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)–6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC0-∞ by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin. [ABSTRACT FROM PUBLISHER]