Improving human-in-the-loop simulation to optimize soldier-systems integration.

OBJECTIVE: To identify requirements for human-in-the-loop simulation capabilities and improve their utility in predicting and optimizing soldier-systems integration. BACKGROUND: Technological development rates within the military are rapidly increasing. Emergent technologies often exclude in-depth consideration of human-system interactions until the physical prototyping phase. Human-in-the-loop simulation tools can allow for earlier consideration of humans in the development process; however, use remains limited. METHOD: Semi-structured interviews were conducted with key informants to yield perspectives on current human-in-the-loop simulation capabilities and utility specific to the military. An inductive approach to thematic analysis was used to extract critical themes from transcribed interview data. A scoping review was completed to supplement the data obtained from interviews and summarize knowledge regarding requirements for human-in-the-loop simulation and analysis capabilities targeted to the military. RESULTS: Interviews were conducted with five experts representing the sectors of Vehicle/Equipment Design, Simulation, and Army Research. A total of 2274 sources were identified, and 64 papers were retained for the scoping review. Thematic analysis of the combined data sources yielded six important themes to consider with respect to requirements for future human-in-the-loop simulation capabilities targeting soldier-systems integration. CONCLUSION: This study has identified eight key requirements to support the use of human-in-the-loop simulation tools to predict and optimize soldier-systems integration and performance. APPLICATION: Addressing key requirements will improve the ability of current human-in-the-loop simulation tools to accommodate the military's need for human consideration early in the design process.

Inhaled nintedanib is well-tolerated and delivers key pharmacokinetic parameters required to treat bleomycin-induced pulmonary fibrosis.

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF), Systemic Sclerosis-Associated Interstitial Lung Disease and Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype. While effective at slowing fibrosis progression, as an oral medicine nintedanib has limitations. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, inhalation was used as a tool to dissect the pharmacokinetic components required for nintedanib pulmonary anti-fibrotic activity. Following oral administration, nintedanib extensively partitioned into tissue and exhibited flip-flop pharmacokinetics, whereby resulting lung Cmax and AUC were substantially higher than plasma. By comparison, inhaled nintedanib was capable of delivering an oral-equivalent lung Cmax with lower local and systemic AUC. Using a multi-challenge bleomycin rat model, this distinct inhaled pharmacokinetic profile was dose responsive (0.05, 0.25 and 0.375 mg/kg), delivering oral-superior pulmonary anti-fibrotic activity with an equivalent delivered lung Cmax (QD inhaled 0.375 mg/kg versus BID oral 60 mg/kg). Possibly assisting this improvement, the infrequent high inhaled dose also improved bleomycin-challenged animal weight gain to levels equivalent to sham. By comparison, BID oral weight gain was substantially less than controls, suggesting a negative health impact on oral administered animals combating fibrosis. Both oral and inhaled administration exhibited anti-inflammatory activity, with oral achieving significance. In summary, inhalation (short-duration nintedanib lung Cmax without high local or systemic AUC) was well-tolerated and was effective reducing bleomycin-induced pulmonary fibrosis.

Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.

Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.