Two-Year Results of a Five-Year Personalized Integrative Obesity Coaching Program (IBO) Based upon a Systems Health Perspective and an Evolutionary Longitudinal Study Approach.

This study presents the outcomes of a 5-year personalized integrative coaching program for adults with obesity (body mass index BMI ≥ 30 kg/m), based upon a systems health perspective, during the first 2 years. This longitudinal study, which had an evolutionary design, included all adults who enrolled in the program. Health-related quality of life (HRQoL) was measured with the Short Form-36 (SF-36), and physical outcomes included weight, waist circumference, aerobic capacity, lipid profile, and HbA1c.

Individual Workplace Well-Being Captured into a Literature- and Stakeholders-Based Causal Loop Diagram.

This study demonstrates an innovative approach to capture the complexity of individual workplace well-being, improving our understanding of multicausal relationships and feedback loops involved. The literature shows that a high number of interacting factors are related to individual workplace well-being. However, many studies focus on subsets of factors, and causal loops are seldomly studied.

Developing a Personalized Integrative Obesity-Coaching Program: A Systems Health Perspective.

Current obesity management strategies are failing to achieve sustainable and favorable long-term results. We propose a more personalized, dynamic, and systemic perspective on the interactions of key determinants and coaching advice on obesity. The aim of this study was to use a systems view on overweight, complexity science, and a transdisciplinary process to develop a five-year personalized integrative obesity-coaching and research program.

Link-based influence maximization in networks of health promotion professionals.

The influence maximization problem (IMP) as classically formulated is based on the strong assumption that "chosen" nodes always adopt the new product. In this paper we propose a new influence maximization problem, referred to as the "Link-based Influence Maximization Problem" (LIM), which differs from IMP in that the decision variable of the spreader has changed from choosing an optimal seed to selecting an optimal node to influence in order to maximize the spread. Based on our proof that LIM is NP-hard with a monotonic increasing and submodular target function, we propose a greedy algorithm, GLIM, for optimizing LIM and use numerical simulation to explore the performance in terms of spread and computation time in different network types.

An Innovative Approach for Decision-Making on Designing Lifestyle Programs to Reduce Type 2 Diabetes on Dutch Population Level Using Dynamic Simulations.

The number of individuals suffering from type 2 diabetes is dramatically increasing worldwide, resulting in an increasing burden on society and rising healthcare costs. With increasing evidence supporting lifestyle intervention programs to reduce type 2 diabetes, and the use of scenario simulations for policy support, there is an opportunity to improve population interventions based upon cost-benefit analysis of especially complex lifestyle intervention programs through dynamic simulations. In this article, we used the System Dynamics (SD) modeling methodology aiming to develop a simulation model for policy makers and health professionals to gain a clear understanding of the patient journey of type 2 diabetes mellitus and to assess the impact of lifestyle intervention programs on total cost for society associated with prevention and lifestyle treatment of pre-diabetes and type 2 diabetes in The Netherlands.

A Proof-of-Concept System Dynamics Simulation Model of the Development of Burnout and Recovery Using Retrospective Case Data.

The phenomenon of burnout is a complex issue, which despite major efforts from researchers and organizations remains hard to prevent. The current literature highlights an increasing global prevalence of employees that are dealing with burnout. What has been largely missing is a more systemic, dynamic, and personal perspective on the interactions of the key determinants of burnout.

A higher throughput and physiologically relevant two-compartmental human ex vivo intestinal tissue system for studying gastrointestinal processes.

A majority of the preclinical intestinal screening models do not properly reflect the complex physiology of the human intestinal tract, resulting in low translational value to the clinical situation. The often used cell lines such as Caco-2 or HT-29 are not well suited to investigate the different processes that predict oral bioavailability in real life, or processes involved in general gut health aspects. Therefore, highly realistic models resembling the human in vivo situation are needed; application of ex vivo intestinal tissue is an interesting and feasible alternative.

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated.

Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants.

Background: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples.

Methods: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples.

Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes.

Many different methods are used for mass-spectrometry-based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various methods are comparable. Here, we compared six different mass spectrometry-based proteomics methods by measuring the expression of clinically relevant drug transporters and metabolizing enzymes in human liver.

Regional Expression Levels of Drug Transporters and Metabolizing Enzymes along the Pig and Human Intestinal Tract and Comparison with Caco-2 Cells.

Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to characterize better available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine, and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum; = 4), in human intestine (jejunum; = 9), and Caco-2 cells.

Grip on health: A complex systems approach to transform health care.

This article addresses the urgent need for a transition in health care to deal with the increasing prevalence of chronic diseases and associated rapid rise of health care costs. Chronic diseases evolve and are predominantly related to lifestyle and environment. A shift is needed from a reductionist repair mode of thinking, toward a more integrated biopsychosocial way of thinking about health.

Nutrient-induced glucagon like peptide-1 release is modulated by serotonin.

Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction.

Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life.

Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10 transporters in liver tissue from fetuses, infants, and adults.

Predicting carrier-mediated hepatic disposition of rosuvastatin in man by scaling from individual transfected cell-lines in vitro using absolute transporter protein quantification and PBPK modeling.

In contrast to primary hepatocytes, estimating carrier-mediated hepatic disposition by using a panel of single transfected cell-lines provides direct information on the contribution of the individual transporters to the net disposition. The most direct way to correct for differences in transporter abundance between cell-lines and tissue is by using absolute protein quantification. In the present study, the performance of this strategy to predict human hepatic uptake transport was investigated and compared with traditional scaling from primary human hepatocytes.

Steviol glycoside rebaudioside A induces glucagon-like peptide-1 and peptide YY release in a porcine ex vivo intestinal model.

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are hormones important for satiation and are involved in the process called "ileal brake". The aim of this study was to investigate the GLP-1- and PYY-stimulating efficacy of rebaudioside A, casein, and sucrose. This was studied using tissue segments collected from various regions of the pig small intestine.

A new approach to predict human intestinal absorption using porcine intestinal tissue and biorelevant matrices.

A reliable prediction of the oral bioavailability in humans is crucial and of high interest for pharmaceutical and food industry. The predictive value of currently used in silico methods, in vitro cell lines, ex vivo intestinal tissue and/or in vivo animal studies for human intestinal absorption, however, is often insufficient, especially when food-drug interactions are evaluated. Ideally, for this purpose healthy human intestinal tissue is used, but due to its limited availability there is a need for alternatives.

Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3.

Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes.

Protein transport across the small intestine in food allergy.

In view of the imminent deficiency of protein sources for human consumption in the near future, new protein sources need to be identified. However, safety issues such as the risk of allergenicity are often a bottleneck, due to the absence of predictive, validated and accepted methods for risk assessment. The current strategy to assess the allergenic potential of proteins focuses mainly on homology, stability and cross-reactivity, although other factors such as intestinal transport might be of added value too.

Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4.

Renal proximal tubule transporters can play a key role in excretion, pharmacokinetic interactions, and toxicity of immunosuppressant drugs. Basolateral organic anion transporters (OATs) and apical multidrug resistance-associated proteins (MRPs) contribute to the active tubular uptake and urinary efflux of these drugs, respectively. We studied the interaction of 12 immunosuppressants with OAT1- and OAT3-mediated [(3)H]-methotrexate (MTX) uptake in cells, and adenosine triphosphate-dependent [(3)H]-MTX transport in membrane vesicles isolated from human embryonic kidney 293 cells overexpressing human MRP2 and MRP4.

Ex vivo systems to study host-microbiota interactions in the gastrointestinal tract.

It is increasingly apparent that the microbial ecosystems in the mammalian gastrointestinal tract play an intricate role in health and disease. There is a growing interest in the development of targeted strategies for modulating health through the modification of these microbiota. Ecologists are faced with the challenge of understanding the structure and function of ecosystems, the component parts of which interact with each other in complex and diffuse ways.

Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactions.

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC₅₀ ([I₁]/IC₅₀) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC₅₀ ([I₂]/IC₅₀) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC₅₀ values generated by 23 laboratories.

Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories).

Measurement of palmitoylethanolamide and other N-acylethanolamines during physiological and pathological conditions.

Palmitoylethanolamide (PEA) belongs to the N-acyl ethanolamines (NAEs), a group of endogenous compounds involved in a variety of physiological processes, including energy homeostasis and inflammation. This review focuses on the analysis of PEA in plasma and tissues and discusses effects of diet and some pathological processes on PEA levels. Originally isolated from egg yolk, PEA has been detected in a variety of tissues and plasma of different species.