Design and prospective validation of a dosing instrument for continuous infusion of vancomycin: a within-population approach

Introduction

The clinical application of continuous infusion (CoI) of vancomycin has gained interest in recent years. Since no international guidelines on initial dosing of vancomycin CoI exist, there is a need for methods to facilitate the switch from intermittent to continuous vancomycin dosing algorithms in clinically infected populations. Therefore, the aim of this study was to design and validate an a priori dosing schedule for CoI of vancomycin in clinical practice.

Methods

A dosing table for CoI of vancomycin based on estimated glomerular filtration rate (eGFR) was developed by simulation of continuous infusion of vancomycin using pharmacokinetic (PK) software and a PK population model designed from historical within-population data in intermittently dosed patients. The target range for the first vancomycin serum concentrations drawn approximately 24 h after start of infusion’ (C24) was set at 15–20 mg/L corresponding with an area under the curve (AUC) of at least 350 mg·h·L^?1. The performance of the dosing schedule was primarily assessed by describing the percentages of patients attaining the predefined target.

Results

An eGFR-derived dosing schedule for CoI of vancomycin was established and implemented in clinical practice. Prospective assessment in 35 general ward and 45 intensive care unit patients showed that the C24 target was reached in 69 and 63 % and the AUC target was attained in 80 and 72 % of patients, respectively.

Conclusions

An easy method to design and validate an eGFR-derived dosing algorithm for the continuous infusion of vancomycin to switch from intermittent to continuous dosing of vancomycin was developed.     

Elevated Concentrations of Neurofilament Light Chain in the Cerebrospinal Fluid of Bipolar Disorder Patients

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.     

Synthesis and Characterisation of Nanocomposite Mo-Fe-B Thin Films Deposited by Magnetron Sputtering

Several ternary phases are known in the Mo-Fe-B system. Previous ab initio calculations have predicted that they should exhibit a tempting mix of mechanical and magnetic properties. In this study, we have deposited Mo-Fe-B films with a Fe-content varying from 0–37 at.% using non-reactive DC (direct current) magnetron sputtering. The phase composition, microstructure, and mechanical properties were investigated using X-ray diffraction, scanning transmission electron microscopy, and nanoindentation measurements. Films deposited at 300 °C and with >7 at.% Fe are nanocomposites consisting of two amorphous phases: a metal-rich phase and a metal-deficient phase. Hardness and elastic modulus were reduced with increasing Fe-content from ~29 to ~19 GPa and ~526 to ~353 GPa, respectively. These values result in H³/E² ratios of 0.089–0.052 GPa, thereby indicating brittle behaviour of the films. Also, no indication of crystalline ternary phases was observed at temperatures up to 600 °C, suggesting that higher temperatures are required for such films to form.     

Permanent Deformation and Stiffness Degradation of Open Hole Glass/PA6 UD Thermoplastic Composite in Tension and Compression

UD glass/PA6 coupons with an open hole are subjected to tensile and compressive loading. Three layups: [0/90]_5s, [+45/−45]_5s and [+45/0/−45/90]_3s with a shape based on ASTM D5766 were tested. Both monotonic loading as well as loading–unloading–reloading tests were executed. The strain field on the sample surface was measured with digital image correlation. This allowed identifying the distribution of the strain field during loading, permanent deformation and the evolution of the sample elastic modulus. This information is not frequently measured. Yet, it is vital for the development and validation of advanced failure models. The results indicate that the thermoplastic matrix allows large plastic deformation under tensile loading for the specimens with layup [+45/−45]_5s. In addition, the specimen elastic modulus reduces by about 70%. The other layups show minor permanent deformation, while the elastic modulus reduces by up to 15%. Furthermore, the quasi-isotropic laminate shows a significant post-failure load-bearing capacity under compression loading. The results are complemented with post-mortem damage and fracture observations using optical microscopy and ultrasound inspection.     

Experimental Investigation of the Performance of a Hybrid Self-Healing System in Porous Asphalt under Fatigue Loadings

Self-healing asphalt, which is designed to achieve autonomic damage repair in asphalt pavement, offers a great life-extension prospect and therefore not only reduces pavement maintenance costs but also saves energy and reduces CO₂ emissions. The combined asphalt self-healing system, incorporating both encapsulated rejuvenator and induction heating, can heal cracks with melted binder and aged binder rejuvenation, and the synergistic effect of the two technologies shows significant advantages in healing efficiency over the single self-healing method. This study explores the fatigue life extension prospect of the combined healing system in porous asphalt. To this aim, porous asphalt (PA) test specimens with various healing systems were prepared, including: (i) the capsule healing system, (ii) the induction healing system, (iii) the combined healing system and (iv) a reference system (without extrinsic healing). The fatigue properties of the PA samples were characterized by an indirect tensile fatigue test and a four-point bending fatigue test. Additionally, a 24-h rest period was designed to activate the built-in self-healing system(s) in the PA. Finally, a damaging and healing programme was employed to evaluate the fatigue damage healing efficiency of these systems. The results indicate that all these self-healing systems can extend the fatigue life of porous asphalt, while in the combined healing system, the gradual healing effect of the released rejuvenator from the capsules may contribute to a better induction healing effect in the damaging and healing cycles.     

Biochemical and Biophysical Characterization of the dsDNA Packaging Motor from the Lactococcus lactis Bacteriophage Asccphi28

Double-stranded DNA viruses package their genomes into pre-assembled protein procapsids. This process is driven by macromolecular motors that transiently assemble at a unique vertex of the procapsid and utilize homomeric ring ATPases to couple genome encapsidation to ATP hydrolysis. Here, we describe the biochemical and biophysical characterization of the packaging ATPase from Lactococcus lactis phage asccφ28. Size-exclusion chromatography (SEC), analytical ultracentrifugation (AUC), small angle X-ray scattering (SAXS), and negative stain transmission electron microscopy (TEM) indicate that the ~45 kDa protein formed a 443 kDa cylindrical assembly with a maximum dimension of ~155 Å and radius of gyration of ~54 Å. Together with the dimensions of the crystallographic asymmetric unit from preliminary X-ray diffraction experiments, these results indicate that gp11 forms a decameric D5-symmetric complex consisting of two pentameric rings related by 2-fold symmetry. Additional kinetic analysis shows that recombinantly expressed gp11 has ATPase activity comparable to that of functional ATPase rings assembled on procapsids in other genome packaging systems. Hence, gp11 forms rings in solution that likely reflect the fully assembled ATPases in active virus-bound motor complexes. Whereas ATPase functionality in other double-stranded DNA (dsDNA) phage packaging systems requires assembly on viral capsids, the ability to form functional rings in solution imparts gp11 with significant advantages for high-resolution structural studies and rigorous biophysical/biochemical analysis.