Tsuyoshi Nakai

Background/Objectives: The risk of fractures associated with immune checkpoint inhibitors (ICIs) is increasing; however, the relationship between fracture risk and potential factors, such as osteoporosis and hyperthyroidism, remains unclear. Methods: Using VigiBase, the World Health Organization's global pharmacovigilance database, we investigated the signals for osteoporosis, hyperthyroidism, and fractures associated with ICIs (nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, and tremelimumab) by calculating information components (ICs) and their 95% confidence intervals (CIs). Furthermore, we estimated the association between the occurrence of fractures in patients receiving ICIs and osteoporosis or hyperthyroidism. Results: Signals of hyperthyroidism (IC = 4.66, 95% CI: 4.58–4.73), but not osteoporosis (IC = −1.79, 95% CI: −2.22 to −1.36) or fractures (IC = −0.21, 95% CI: −0.36 to −0.06), were detected in patients using ICIs. Osteoporosis (odds ratio: 118.00, 95% CI: 61.00–230.00) was associated with an increased reporting frequency of fractures related to ICIs, whereas hyperthyroidism (odds ratio: 0.60, 95% CI: 0.19–1.87) was not associated with such an increase. Conclusions: The VigiBase analysis indicates that the use of ICIs does not increase the reporting frequency of osteoporosis or fractures. Additionally, hyperthyroidism did not increase the reporting frequency of fractures associated with ICIs.

Abstract Purpose Tranexamic acid (TXA) is widely used as an antifibrinolytic drug. However, studies to determine the optimal blood concentration of TXA have produced inconsistent results. During cardiac surgery, cardiopulmonary bypass (CPB) has serious effects on drug distribution, elimination, and plasma concentration. Therefore, we aimed to establish a population pharmacokinetics model of TXA in patients undergoing cardiac surgery with CPB that considers renal function as a covariate, thereby facilitating personalized treatment. Methods In total, 453 TXA plasma samples were prospectively collected from 77 patients who underwent cardiac surgery with CPB. Plasma concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model of TXA was analyzed using nonlinear mixed-effects modeling. Results The two-compartment–based model with combined errors was determined as the best. The final model included the effect of bodyweight and CL_cr may be summarized as V ₁ (L) = 12.77 × (bodyweight / 61.4)^0.911, V ₂ (L) = 6.857, CL₁ (L/h) = 3.263 × [CL_cr (L/h) / 61.0]^0.752, CL₂ (L/h) = 2.859. Conclusion Patients who undergo cardiac surgery with CPB may require an adjusted dose of TXA tailored to CPB due to lower CL₁ and increased V ₁. Our TXA population pharmacokinetic model may be useful for developing individualized dosing designs for TXA in patients who undergo cardiac surgery with CPB.

The budding yeast Saccharomyces cerevisiae is commonly used as an expression platform for the production of valuable compounds. Yeast‐based genetic research can uniquely utilize auxotrophy in transformant selection: auxotrophic complementation by an auxotrophic marker gene on exogenous DNA (such as plasmids). However, the number of required auxotrophic nutrients restricts the number of plasmids maintained by the cells. We, therefore, developed novel Δ10 strains that are auxotrophic for 10 different nutrients and new plasmids with two multiple cloning sites and auxotrophic markers for use in Δ10 strains. We confirmed that Δ10 strains were able to maintain 10 types of plasmids. Using plasmids encoding model proteins, we detected the co‐expression of 17 different genes in Δ10 cell lines. We also constructed Δ9 strains that exhibited auxotrophy for nine nutrients and increased growth compared to Δ10. This study opens a new avenue for the co‐expression of a large number of genes in eukaryotic cells.