Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

Trust in the public sector: Is there any evidence for a long-term decline?

Concerns with declining public trust in government have become a permanent element of the contemporary political discourse. This concern also extends to levels of citizens’ trust in the public administration and public services. Trust is said to be declining, and this decline is generally seen as detrimental to public service delivery. In this article, we examine the main elements in this discussion, review the existing international survey data and summarise the main findings for OECD countries. Citizens’ trust in the public sector is found to fluctuate, and the data generally do not show consistently declining levels of trust. Furthermore, in some countries there simply is insufficient data to come to any conclusions at all about time trends in citizen trust in the public sector. Points for practitioners This article summarises some of the survey material on citizens’ trust in the public administration. It allows practitioners to compare trends in public trust in their country across time and space. The findings lead us to reject the hypothesis of a universal decline of trust in the public sector. The article warns against using opinion poll results without considering context. The long-term and comparative perspective on citizens’ trust in the public sector is all too often absent from the policy discourse that is frequently based on assumptions and ad-hoc approaches

Executive Agencies, Ministers, and Departments: Can Policy and Management Ever be Separated?

The creation of executive agencies outside core departments has been a major element of administrative reforms throughout Europe during the past two decades, driven by a managerial logic, which also has been at the core of most academic works on "agencification." In this article, the authors take a different perspective by focusing on executive agencies' influence in the policy process. The authors analyze the policy influence of a large executive agency with service delivery tasks in the context of a parliamentary system of government (Flanders, Belgium). A comparison of the agency's influence in two major policy processes shows that a complex interplay of policy content, patterns of interaction, and mutual trust with the political leadership and organizational characteristics helps in explaining the observed patterns of influence. The findings also raise normative concerns regarding potential problems of disconnecting operations from policy formulation via agencification. © 2012 SAGE Publications

Quantification of vancomycin and clindamycin in human plasma and synovial fluid applying ultra-performance liquid chromatography tandem mass spectrometry

Periprosthetic joint infection is a challenging infection involving the joint prosthesis and adjacent tissue, such as synovial fluid, synovial tissue, and bone tissue. The current treatment consists of multiple surgical revisions and long-term antibiotic therapy. Treatment failure can cause poor functional outcome and reduced quality of life. Further research on the extent of antibiotic penetration into the infected tissues is of great importance. Our work aimed to develop and validate a novel ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of the commonly administered antibiotics vancomycin and clindamycin in plasma and synovial fluid. An extraction procedure consisting of zinc sulfate precipitation and dilution with eluent was used for both analytes. Chromatographic separation was performed on a Waters Acquity UPLC HSS T3 C18 column (1.8 µm, 2.1 × 100 mm), and quantification was carried out by a Waters Xevo TQ-S micro mass spectrometer. Stable isotope-labeled vancomycin-d10 served as internal standard. The method validation was performed based on the guidelines of the EMA and FDA. The calibration curves were linear over the range of 0.5–50 mg/L, with a coefficient of determination above 0.990. The validation results for precision and accuracy, specificity, matrix effects and stability were all within the acceptance range. An accurate and rapid method for the simultaneous quantification of vancomycin and clindamycin in human plasma and synovial fluid on the UPLC-MS/MS was developed, optimized and validated. The analysis has a run time of 5.2 min and 50 µL sample volume is needed. This developed method was successfully applied in eight patients with PJI and is suitable to determine the exposure of antibiotics in plasma and synovial fluid in patients during current PK/PD studies.</p

Clinical pharmacokinetics of antipsychotics in pediatric populations:a scoping review focusing on dosing regimen

Introduction:Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations. Areas covered: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented. Expert opinion: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.</p

Pausing propofol during neurosurgery to record intraoperative electrocorticography is feasible;10 years of clinical experience

Objective: Intraoperative electrocorticography (ioECoG) during neurosurgery is influenced by anesthetics. In our center we stop the propofol to enable interpretation of ioECoG. We reported our clinical experience and evaluated awareness and hemodynamic changes during the propofol-free periods (PFP). Methods: We retrospectively included surgeries with paused propofol administration to record ioECoG (period: 2008–2019). Clinical reports were screened for symptoms of awareness. We compared mean arterial blood pressure (MAP; mmHg) and heart rate (HR;bpm) during PFP to baseline (ten minutes preceding PFP). An increase &gt; 15% was defined as clinically relevant. The association between hemodynamic changes and clinical characteristics was analyzed using logistic regression models. Results: Propofol administration was paused 742 times in 352 surgeries (mean PFP duration 9 ± 5 min). No signs of awareness were reported. MAP and HR increased &gt; 15% in 54 and six PFPs. Five PFPs showed both MAP and HR increases. Prolonged PFP was associated with having MAP and HR increase during surgery (OR=1.18, 95%CI [1.12–1.26]). Conclusions: Signs of inadequate sedation depth were rare. MAP and HR increases were related to the length of PFP. Significance: We summarize 10 years of clinical experience with pausing propofol administration during epilepsy surgery to record ioECoG without evidence of awareness

ADHD medication dispensing trends in Dutch youth before and after the implementation of the Youth Act (2010–2022)

Objective: The Youth Act, implemented by the Dutch government in 2015, aimed to provide more efficient, coherent, and cost-effective care tailored to the specific needs of children, while also reducing medicalization. Between 2003 and 2013, there was a four-fold increase in methylphenidate prescriptions among Dutch children aged 4 to 18 years. However, the impact of the Youth Act on the ADHD medication dispensing remains unassessed. This study investigated changes in ADHD medication dispensing patterns among Dutch youth following the implementation of the Youth Act. Method: A before-after retrospective cohort study was conducted using data from the Dutch community pharmacy-based IADB.nl database among 137,684 youths aged 0–19 years using ADHD medication between 2010 and 2022. Results: A significant decrease in overall ADHD medication dispensing prevalence rates per thousand youths was observed in 2022 compared to 2015 (35.2 vs. 45.7, p &lt; 0.001). Methylphenidate accounted for approximately 87% of all ADHD medication dispensing. Incidence rates decreased significantly among children aged 7–12 from 2015 to 2022 (9 vs. 7.3, p &lt; 0.001), while incidence rates increased significantly in adolescent youths (4 vs. 4.8, p = 0.008), particularly among adolescent females (3.5 vs. 5.3, p &lt; 0.001). Females had lower prevalence rates and shorter durations of ADHD medication use compared to males, with no difference in daily dose observed. Conclusion: ADHD medication dispensing among Dutch youth declined following the 2015 implementation of the Youth Act. However, other factors such as the DSM-5 revision, COVID-19, and medication shortages likely contributed to this decrease, suggesting a multifactorial explanation for the observed changes in ADHD medication dispensing.</p

Pausing propofol during neurosurgery to record intraoperative electrocorticography is feasible;10 years of clinical experience

Objective: Intraoperative electrocorticography (ioECoG) during neurosurgery is influenced by anesthetics. In our center we stop the propofol to enable interpretation of ioECoG. We reported our clinical experience and evaluated awareness and hemodynamic changes during the propofol-free periods (PFP). Methods: We retrospectively included surgeries with paused propofol administration to record ioECoG (period: 2008–2019). Clinical reports were screened for symptoms of awareness. We compared mean arterial blood pressure (MAP; mmHg) and heart rate (HR;bpm) during PFP to baseline (ten minutes preceding PFP). An increase > 15% was defined as clinically relevant. The association between hemodynamic changes and clinical characteristics was analyzed using logistic regression models. Results: Propofol administration was paused 742 times in 352 surgeries (mean PFP duration 9 ± 5 min). No signs of awareness were reported. MAP and HR increased > 15% in 54 and six PFPs. Five PFPs showed both MAP and HR increases. Prolonged PFP was associated with having MAP and HR increase during surgery (OR=1.18, 95%CI [1.12–1.26]). Conclusions: Signs of inadequate sedation depth were rare. MAP and HR increases were related to the length of PFP. Significance: We summarize 10 years of clinical experience with pausing propofol administration during epilepsy surgery to record ioECoG without evidence of awareness

Complete sequencing of ape genomes.

The most dynamic and repetitive regions of great ape genomes have traditionally been excluded from comparative studies. Consequently, our understanding of the evolution of our species is incomplete. Here we present haplotype-resolved reference genomes and comparative analyses of six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang. We achieve chromosome-level contiguity with substantial sequence accuracy (\u3c 1 error in 2.7 megabases) and completely sequence 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, to provide in-depth evolutionary insights. Comparative analyses enabled investigations of the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference genome. Such regions include newly minted gene families in lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes and subterminal heterochromatin. This resource serves as a comprehensive baseline for future evolutionary studies of humans and our closest living ape relatives