Modeling of Large Pharmacokinetic Data Using Nonlinear Mixed-Effects: A Paradigm Shift in Veterinary Pharmacology. A Case Study With Robenacoxib in Cats

The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed‐effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first‐order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (Ka = 0.68 h−1) was lower than beta (median, 1.08 h−1), unveiling flip‐flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population

Protein import into the endosymbiotic organelles of apicomplexan parasites

The organelles of endosymbiotic origin, plastids, and mitochondria, evolved through the serial acquisition of endosymbionts by a host cell. These events were accompanied by gene transfer from the symbionts to the host, resulting in most of the organellar proteins being encoded in the cell nuclear genome and trafficked into the organelle via a series of translocation complexes. Much of what is known about organelle protein translocation mechanisms is based on studies performed in common model organisms; e.g., yeast and humans or Arabidopsis. However, studies performed in divergent organisms are gradually accumulating. These studies provide insights into universally conserved traits, while discovering traits that are specific to organisms or clades. Apicomplexan parasites feature two organelles of endosymbiotic origin: a secondary plastid named the apicoplast and a mitochondrion. In the context of the diseases caused by apicomplexan parasites, the essential roles and divergent features of both organelles make them prime targets for drug discovery. This potential and the amenability of the apicomplexan Toxoplasma gondii to genetic manipulation motivated research about the mechanisms controlling both organelles’ biogenesis. Here we provide an overview of what is known about apicomplexan organelle protein import. We focus on work done mainly in T. gondii and provide a comparison to model organisms

Understanding Motivation to Lead in Nurses

Background: Nurse leaders are indispensable to the delivery of quality, patient-centered care. They are influential in the practice environment, contributing to front-line staff job satisfaction. They work to improve retention, turnover, organizational health, and patient outcomes. Yet, there is a dearth of research investigating the motivating factors that appeal to, encourage, discourage, and help retain nurse leaders in their roles. The forecast of a shortage of nurse leaders, along with the reluctance of nurses to assume leadership roles, is affecting healthcare organizations throughout the United States. An in-depth understanding of the underlying factors related to motivation that appeal to, encourage, discourage, and retain nurses in current leadership roles is needed for the development of recruitment strategies to mitigate the current and future shortage of nurse leaders. Purpose: The aim of this study was to better understand the underlying perspectives related to the motivation factors that appeal to, encourage, discourage, and retain nurses in leadership roles. Method: A descriptive qualitative approach, including semi-structured, audio-recorded individual interviews of 15 nurse leaders, was used to gain in-depth understanding of perspectives related to leadership motivation. Data were analyzed using a thematic content analysis approach. Findings: Findings suggest that nurse leaders are driven by a mixture of intrinsic and extrinsic motivation factors early in their career. This shifts to become more focused on intrinsic motivation factors surrounding making a difference, connecting with others, and mentoring later on in their career. A thematic content analysis of the data was organized into a conceptual framework to help understand the processes which motivate nurses in leadership roles. Six main themes emerged from the data: Pathway into nursing, Motives for assuming leadership roles, Pathway into leadership roles, Transition into leadership roles, Challenges of leadership roles, and Motives for remaining in leadership roles. These themes provide insight into the motivation processes that appeal to, encourage, discourage, and retain nurse leaders in leadership roles. Conclusion: Findings suggest that nurse leaders are driven by both intrinsic and extrinsic motivation factors throughout their career with the focus shifting later in their career to become more intrinsic motivation. Current nurse leaders should be encouraged to use this information to assist them as mentors and to create supportive mentoring relationships to develop the next generation of informal nurse leaders who can assume formal nurse leadership roles, thus creating a future pipeline of leaders to mitigate the nursing leader shortage

Mitochondrial behaviour throughout the lytic cycle of Toxoplasma gondii

Mitochondria distribution in cells controls cellular physiology in health and disease. Here we describe the mitochondrial morphology and positioning found in the different stages of the lytic cycle of the eukaryotic single-cell parasite Toxoplasma gondii. The lytic cycle, driven by the tachyzoite life stage, is responsible for acute toxoplasmosis. It is known that whilst inside a host cell the tachyzoite maintains its single mitochondrion at its periphery. We found that upon parasite transition from the host cell to the extracellular matrix, mitochondrion morphology radically changes, resulting in a reduction in peripheral proximity. This change is reversible upon return to the host, indicating that an active mechanism maintains the peripheral positioning found in the intracellular stages. Comparison between the two states by electron microscopy identified regions of coupling between the mitochondrion outer membrane and the parasite pellicle, whose features suggest the presence of membrane contact sites, and whose abundance changes during the transition between intra- and extra-cellular states. These novel observations pave the way for future research to identify molecular mechanisms involved in mitochondrial distribution in Toxoplasma and the consequences of these mitochondrion changes on parasite physiology

An Aging Society: Opportunity or Challenge?

macroeconomics, Aging Society