Model-informed precision dosing in vancomycin treatment

Introduction: While vancomycin remains a widely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity.Methods: The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling.Results and discussion: This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10 days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection

Identification of HLA-A*2402-restricted HCMV immediate early-1 (IE-1) epitopes as targets for CD8+ HCMV-specific cytotoxic T lymphocytes

<p>Abstract</p> <p>Background</p> <p>To identify novel HLA-A*2402-restricted human cytomegalovirus (HCMV) immediate early-1 (IE-1) epitopes for adoptive immunotherapy, we explored 120 overlapping 15-amino acid spanning IE-1.</p> <p>Methods</p> <p>These peptides were screened by measuring the frequency of polyclonal CD8+ T cells producing intracellular interferon-γ (IFN-γ) using flow cytometry and the epitopes were validated with a HCMV-infected target Cr release cytotoxicity assay.</p> <p>Results</p> <p>Initial screening was performed with 12 mini-pools of 10 consecutive peptides made from 120 overlapping peptides15-amino acids in length that spanned IE-1. When peripheral blood mononuclear cells (PBMCs) from HLA-A*2402 HCMV-seropositive donors were sensitized with each of the 12 mini-pools, mini-pools 1 and 2 induced the highest frequency of CD8+ cytotoxic T lymphocytes (CTLs) producing IFN-γ. When PBMCs were stimulated with each of the twenty peptides belonging to mini-pools 1 and 2, peptides IE-1_1–15MESSAKRKMDPDNPD and IE-1_5–19AKRKMDPDNPDEGPS induced the greatest quantities of IFN-γ production and cytotoxicity of HLA-matched HCMV-infected fibroblasts. To determine the exact HLA-A*2402-restricted epitopes within the two IE-1 proteins, we synthesized a total of twenty-one overlapping 9- or 10 amino acid peptides spanning IE-1_1–15and IE-1_5–19. Peptide IE-1_3–12SSAKRKMDPD induced the greatest quantities of IFN-γ production and target cell killing by CD8+ CTLs.</p> <p>Conclusion</p> <p>HCMV IE-1_3–12SSAKRKMDPD is a HLA-A*2402-restricted HCMV IE-1 epitope that can serve as a common target for CD8+ HCMV-specific CTLs.</p

Angiotensin converting enzyme inhibitors versus angiotensin II type 1 receptor blockers in patients with acute myocardial infarction and prediabetes after successful implantation of newer-generation drug-eluting stents

Background: Because limited data are available, the present study investigated 2-year major clinical outcomes after angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) therapy in patients with acute myocardial infarction (AMI) and prediabetes after successful implantation of newer-generation drug-eluting stents (DESs). Methods: Overall, 2932 patients with AMI and prediabetes were classified into two groups — the ACEIs group (n = 2059) and the ARBs group (n = 873). The primary endpoint was the occurrence of patient-oriented composite outcome (POCO), defined as all-cause death, recurrent myocardial infarction (Re-MI), or any repeat revascularization. The secondary endpoint was definite or probable stent thrombosis (ST). Results: The cumulative incidences of POCO (adjusted hazard ratio [aHR]: 1.020; 95% confidence interval [CI]: 0.740–1.404; p = 0.906), all-cause death (aHR: 1.394; 95% CI: 0.803–2.419; p = 0.238), Re-MI (aHR: 1.210; 95% CI: 0.626–2.340; p = 0.570), any repeat revascularization (aHR: 1.150; 95% CI: 0.713–1.855; p = 0.568), and ST (aHR: 1.736; 95% CI: 0.445–6.766; p = 0.427) were similar between the groups. These results were confirmed after propensity score-adjusted analysis. Conclusions: In this study, patients with AMI and prediabetes who received ACEIs or ARBs showed comparable clinical outcomes during the 2-year follow-up period

Developing a Framework for Data-Driven Generation of Building Information Modeling from Sketches: Enhancing Efficiency in Space Configuration and Building Performance Analysis

The demand for compact housing is on the rise, driven by the need for floor plans that accommodate stakeholders’ preferences. However, clients frequently struggle to convey their spatial needs to professionals, such as architects, due to a lack of means to present evidence, such as spatial configurations or cost projections. This study seeks to develop a methodology that translates sketched, data-driven spatial requirements into 3D building components within BIM (Building Information Modeling) to enhance spatial comprehension and offer building performance analysis, assisting in budget considerations during the initial design stages. The research methodology encompasses the formulation of a process model, its implementation, and subsequent validation. The process model outlines the data flow within the system and delineates necessary functionalities. Implementation includes the creation of systems and user interfaces for the integration of various components. Validation confirms the system’s capability to automatically transform sketched spatial requirements into BIM model elements, such as walls, floors, and roofs, and to autonomously compute material and energy expenses based on the BIM model. This system enables clients to effectively generate 3D building components from sketches, aiding stakeholders in spatial understanding and building performance evaluation through the generated BIM models

Microstructure and texture evolution of pure niobium in cold-drawn Mg+B/Nb/Cu wires

In this study, Mg+B wires were prepared by powder in tube method using Nb and Cu tubes as barrier and sheath, respectively, followed by cold drawing. Microstructural, textural, and mechanical properties of the Nb barrier at different drawing strains ( ε _d ) were investigated. The results showed that the Nb barrier demonstrated a saturation hardness of 159.4 HV. The microstructure of the Nb barrier became elongated along the drawing direction increasing ε _d . Sub-grains existing inside the deformed grains rotated from low-angle grain boundaries to high-angle grain boundaries and developed into new grains. The main textural components of the Nb barrier were {111}  γ -fiber and {hkl}〈110 〉  α -fiber. Recrystallized grains exhibited a low maximum orientation distribution function intensity, weak {100}〈110 〉  α -fibers, and strong {111}〈110 〉  γ -fibers as compared to those of the deformed grains. The relationship between the microstructure evolution and mechanical properties of the Nb barrier and the changes in the cross-sectional area fractions of the materials constituting the Mg+B composite wire are discussed. The current study provides details about the misorientation profile inside deformed grains and continuous dynamic recrystallization mechanism of the cold-drawn Nb barrier

Role of cellular structure on deformation twinning and hetero-deformation induced strengthening of laser powder-bed fusion processed CuSn alloy

© 2022 Elsevier B.V.The sub-grain cellular dislocation structure has been reported to be the primary reason for the enhanced mechanical properties in laser powder-bed fusion (LPBF) parts. In the current work, the contribution of the cellular dislocation structure to the yield strength of LPBF processed CuSn alloy is estimated to be ~45%. In addition, this work shows that the cellular dislocation structure significantly controls the deformation behavior of LPBF processed CuSn alloy by suppressing the formation of deformation twinning. Post-LPBF heat treatment with fully recrystallized microstructures devoid of cellular dislocation structure showed pronounced twinning activity. The reduced homogeneous slip length due to the fine dislocation cell structure ~600 nm and increased stacking fault energy due to the cellular Sn segregation significantly increased the activation energy for the nucleation and propagation of the partial dislocations and suppressed the deformation twinning in the as-built samples. Furthermore, the present work shows that cellular dislocation structure contributes significantly to the hetero-deformation induced strengthening, much higher than the heterogeneous grain structure in the LPBF samples.11Nsciescopu

Changes in ginsenoside compositions and antioxidant activities of hydroponic-cultured ginseng roots and leaves with heating temperature

Background: This study evaluated changes in ginsenoside compositions and antioxidant activities in hydroponic-cultured ginseng roots (HGR) and leaves (HGL) with heating temperature. Methods: Heat treatment was performed at temperatures of 90°C, 110°C, 130°C, and 150°C for 2 hours. Results: The ginsenoside content varied significantly with heating temperature. The levels of ginsenosides Rg1 and Re in HGR decreased with increasing heating temperature. Ginsenosides F2, F4, Rk3, Rh4, Rg3 (S form), Rg3 (R form), Rk1, and Rg5, which were absent in the raw ginseng, were formed after heat treatment. The levels of ginsenosides Rg1, Re, Rf, and Rb1 in HGL decreased with increasing heating temperature. Conversely, ginsenosides Rk3, Rh4, Rg3 (R form), Rk1, and Rg5 increased with increasing heating temperature. In addition, ginsenoside contents of heated HGL were slightly higher than those of HGR. The highest extraction yield was 14.39% at 130°C, whereas the lowest value was 10.30% at 150°C. After heating, polyphenol contents of HGR and HGL increased from 0.43 mg gallic acid equivalent/g (mg GAE eq/g) and 0.74 mg GAE eq/g to 6.16 mg GAE eq/g and 2.86 mg GAE eq/g, respectively. Conclusion: Antioxidant activities of HGR and HGL, measured by 1,1-diphenyl-2-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging ability, increased with increasing heating temperature. These results may aid in improving the biological activity and quality of ginseng subjected to heat treatments