29 research outputs found
Population pharmacokinetic modeling of multiple-dose intravenous fosfomycin in critically ill patients during continuous venovenous hemodialysis
The aim of this study was to investigate the pharmacokinetics of multiple-dose intravenous (i.v.)
fosfomycin in critically ill patients during continuous venovenous hemodialysis (CVVHD). Noncompartmental analysis and population pharmacokinetic modeling were used to simulate diferent
dosing regimens. We evaluated 15 critically ill patients with renal insufciency and CVVHD undergoing
anti-infective treatment with fosfomycin in our ICU. Five grams of fosfomycin were administered
for 120 min every 6 h. Plasma concentrations were determined with and without CVVHD.
Pharmacokinetic analysis and simulations were performed using non-linear mixed efects modelling
(NONMEM). A two-compartment model with renal and dialysis clearance was most accurate in
describing the pharmacokinetics of i.v. fosfomycin during CVVHD. Population parameter estimates
were 18.20 L and 20.80 L for the central and peripheral compartment volumes, and 0.26 L/h and
5.08 L/h for renal and intercompartmental clearance, respectively. Urinary creatinine clearance (CLCR)
represented a considerable component of renal clearance. Central compartment volume increased
over time after the frst dose. For patients with CLCR > 50 (90) mL/min and CVVHD, dosage should be
increased toâ„ 15 (16) grams of i.v. fosfomycin across three (four) daily doses. Individual CLCR must be
considered when dosing i.v. fosfomycin in critically ill patients during CVVHD
EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of EnvarsusÂź versus Advagrafâą in liver transplant recipients
Background
Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as PrografÂź and Advagrafâą, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagrafâą, was developed (vs 2x/day PrografÂź). Benefits of Advagrafâą are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain PrografÂź-equivalent troughs. EnvarsusÂź is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDoseâą drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, EnvarsusÂź proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of EnvarsusÂź vs Advagrafâą in de novo liver transplant (LTx) recipients.
Methods
The EnGraft compares bioavailability and tests superiority of EnvarsusÂź (test arm) versus Advagrafâą (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period.
Discussion
C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022
Warmth and competence perceptions of key protagonists are associated with containment measures during the COVID-19 pandemic: Evidence from 35 countries
It is crucial to understand why people comply with measures to contain viruses and their effects during pandemics. We provide evidence from 35 countries (Ntotalâ=â12,553) from 6 continents during the COVID-19 pandemic (between 2021 and 2022) obtained via cross-sectional surveys that the social perception of key protagonists on two basic dimensionsâwarmth and competenceâplays a crucial role in shaping pandemic-related behaviors. Firstly, when asked in an open question format, heads of state, physicians, and protest movements were universally identified as key protagonists across countries. Secondly, multiple-group confirmatory factor analyses revealed that warmth and competence perceptions of these and other protagonists differed significantly within and between countries. Thirdly, internal meta-analyses showed that warmth and competence perceptions of heads of state, physicians, and protest movements were associated with support and opposition intentions, containment and prevention behaviors, as well as vaccination uptake. Our results have important implications for designing effective interventions to motivate desirable health outcomes and coping with future health crises and other global challenges.publishedVersio
Reactive metal additive manufacturing : Surface near ZrN - metallic glass composite formation and mechanical properties
ZrN formation in a Zr-based bulk metallic glass is observed after processing using reactive laser powder bed fusion. Two processing routes employing nitrogen as a reactive process gas are explored: (1) Standard inert processing in argon followed by reactive remelting in nitrogen and (2) reactive processing in nitrogen. Incorporation of nitrogen is depth-dependent and both approaches result in a dispersion of ZrN nanocrystals in the amorphous matrix close to the surface. The process parameters can be adjusted to control the volume fraction of crystalline phases formed. Hence, it is shown that reactive additive manufacturing can be utilised to form bulk metallic glass-ceramic composites in surface near regions. Thereby we demonstrate that the reactive gas atmosphere utilised during additive manufacturing enables local tailoring of structure, composition, and mechanical properties in the vicinity of the surface
Is the Level of Motor Development at School Entry Related to the Use of Municipal Exercise Programs? A Social-Differential Analysis
Children’s motor development is socially unevenly distributed despite many municipal exercise programs (EXP). It has not been sufficiently investigated whether and how they appeal to children from different social backgrounds. This study investigates the use of municipal EXP in preschool age and the association between participation and motor development considering social circumstances. In school entry health examinations, parents were asked about participating in various EXP (response = 65.5%; n = 6480). Motor development, i.e., body coordination and visual-motor coordination, were assessed by a social pediatric development screening, and social circumstances by migration background (MB) and parental education (PE). Poisson regression estimated adjusted Incidence Rate Ratios (IRR; 95% confidence interval, 95%—CI) for relationships between social circumstances and participation in programs and participation and body coordination/visual-motor coordination. Children with MB (IRR 0.73; 95%—CI 0.71–0.75) and low PE (IRR 0.45; 95%—CI 0.40–0.50) used EXP less often. Children participating less often have a finding in body- (IRR 0.76; 95%-CI 0.63–0.90) and visual-motor coordination (IRR 0.47; 95%—CI 0.35–0.62). Significant effects were found for children with and without MB and higher PE. Municipalities should make EXP more attractive for families with MB and low PE
A dynamic timeâtoâevent model for prediction of acute graftâversusâhost disease in patients after allogeneic hematopoietic stem cell transplantation
Abstract Background Acute graftâversusâhost disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. Methods In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and timeâdependent risk factors on the development of grades IIâIV aGvHD within 100âdays postâHSCT. Results Using a dynamic longitudinal timeâtoâevent model, we observed a nonâmonotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11âdays. Multivariable analysis revealed significant timeâdependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades IIâIV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after alloâHSCT are associated with an increased incidence of grades IIâIV aGvHD within 100âdays indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades IIâIV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Conclusion Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and timeâdependent risk factors for the prediction of aGvHD
A dynamic timeâtoâevent model for prediction of acute graftâversusâhost disease in patients after allogeneic hematopoietic stem cell transplantation
Background
Acute graft-versus-host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification.
Methods
In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades IIâIV aGvHD within 100âdays post-HSCT.
Results
Using a dynamic longitudinal time-to-event model, we observed a non-monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11âdays. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades IIâIV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades IIâIV aGvHD within 100âdays indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades IIâIV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios.
Conclusion
Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD