Altered developmental programming of the mouse mammary gland in female offspring following perinatal dietary exposures : a systems-biology perspective.

Mishaps in prenatal development can influence mammary gland development and, ultimately, affect susceptibility to factors that cause breast cancer. This research was based on the underlying hypothesis that maternal dietary composition during pregnancy can alter developmental (fetal) programming of the mammary gland. We used a computational systems-biology approach and Bayesian-based stochastic search variable selection algorithm (SSVS) to identify differentially expressed genes and biological themes and pathways. Postnatal growth trajectories and gene expression in the mammary gland at 10-weeks of age in female mice were investigated following different maternal diet exposures during prenatal-lactational-early-juvenile development. This correlated a decrease in expression of energy pathways with a reciprocal increase in cytokine and inflammatory-signaling pathways. These findings suggest maternal dietary fat exposure significantly influences postnatal growth trajectories, metabolic programming, and signaling networks in the mammary gland of female offspring. In addition, the adipocytokine pathway may be a sensitive trigger to dietary changes and may influence or enhance activation of an immune response, a key event in cancer development

Digital and Strategic Innovation for Alpine Health Tourism

This open access book presents a set of practical tools and collaborative solutions in multi-disciplinary settings to foster the Alpine Space health tourism industry’s innovation and competitiveness. The proposed solutions emerge as the result of the synergy among health, environment, tourism, digital, policy and strategy professionals. The approach underlines the pivotal role of a sustainable and ecomedical use of Alpine natural resources for health tourism destinations, and highlights the need of integrating aspects of natural resources’ healing effects, a shared knowledge of Alpine assets through digital solutions, and frames strategic approaches for the long-term development of the sector. The volume exploits the results of the three-years long EU research project HEALPS 2, which involved several stakeholders from the health tourism, healthcare and sustainable tourism industries. This book is relevant for health tourism destinations and facilities (hotels, clinics, wellness and spa companies), regional and local authorities (policy makers), business support organizations, researchers involved in digital healthcare and geoinformatics

Digital and Strategic Innovation for Alpine Health Tourism

This open access book presents a set of practical tools and collaborative solutions in multi-disciplinary settings to foster the Alpine Space health tourism industry’s innovation and competitiveness. The proposed solutions emerge as the result of the synergy among health, environment, tourism, digital, policy and strategy professionals. The approach underlines the pivotal role of a sustainable and ecomedical use of Alpine natural resources for health tourism destinations, and highlights the need of integrating aspects of natural resources’ healing effects, a shared knowledge of Alpine assets through digital solutions, and frames strategic approaches for the long-term development of the sector. The volume exploits the results of the three-years long EU research project HEALPS 2, which involved several stakeholders from the health tourism, healthcare and sustainable tourism industries. This book is relevant for health tourism destinations and facilities (hotels, clinics, wellness and spa companies), regional and local authorities (policy makers), business support organizations, researchers involved in digital healthcare and geoinformatics

Multiscale Modeling of Tuberculosis Disease and Treatment to Optimize Antibiotic Regimens

Tuberculosis (TB) is one of the world’s deadliest infectious diseases. Caused by the pathogen Mycobacterium tuberculosis (Mtb), the standard regimen for treating TB consists of treatment with multiple antibiotics for at least six months. There are a number of complicating factors that contribute to the need for this long treatment duration and increase the risk of treatment failure. Person-to-person variability in antibiotic absorption and metabolism leads to varying levels of antibiotic plasma concentrations, and consequently lower concentrations at the site of infection. The structure of granulomas, lesions forming in lungs in response to Mtb infection, creates heterogeneous antibiotic distributions that limit antibiotic exposure to Mtb. Microenvironments in the granuloma can shift Mtb to phenotypic states that have higher tolerances to antibiotics. We can use computational modeling to represent and predict how each of these factors impacts antibiotic regimen efficacy and granuloma sterilization. In this thesis, we utilize an agent-based, computational model called GranSim that simulates granuloma formation, function and treatment. We present a method of incorporating sources of heterogeneity and variability in antibiotic pharmacokinetics to simulate treatment. Using GranSim to simulate treatment while accounting for these sources of heterogeneity and variability, we discover that individuals that naturally have low plasma antibiotic concentrations and granulomas with high bacterial burden are at greater risk of failing to sterilize granulomas during antibiotic treatment. Importantly, we find that changes to regimens provide greater improvements in granuloma sterilization times for these individuals. We also present a new pharmacodynamic model that incorporates the synergistic and antagonistic interactions associated with combinations of antibiotics. Using this model, we show that in vivo antibiotic concentrations impact the strength of these interactions, and that accounting for the actual concentrations within granulomas provides greater predictive power to determine the efficacy of a given antibiotic combination. A goal in improving antibiotic treatment for TB is to find regimens that can shorten the time it takes to sterilize granulomas while minimizing the amount of antibiotic required. With the number of potential combinations of antibiotics and dosages, it is prohibitively expensive to exhaustively simulate all combinations to achieve these goals. We present a method of utilizing a surrogate-assisted optimization framework to search for optimal regimens using GranSim and show that this framework is accurate and efficient. Comparing optimal regimens at the granuloma scale shows that there are alternative regimens using the antibiotic combination of isoniazid, rifampin, ethambutol and pyrazinamide that could improve sterilization times for some granulomas in TB treatment. In virtual clinical trials, these alternative regimens do not outperform the regimen of standard doses but could be acceptable alternatives. Focusing on identifying alternative regimens that can improve treatment for high risk patients could help to significantly decrease the global burden for TB. Overall, this thesis presents a computational tool to evaluate antibiotic regimen efficacy while accounting for the complicating factors in TB treatment and improves our ability to predict new regimens that can improve clinical treatment of TB.PHDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/166103/1/cicchese_1.pd

Record of the meeting of the Advisory Committee on Immunization Practices : February 26-27, 2003

2003_2 minutes.pdf2003607

Digital and Strategic Innovation for Alpine Health Tourism

This open access book presents a set of practical tools and collaborative solutions in multi-disciplinary settings to foster the Alpine Space health tourism industry’s innovation and competitiveness. The proposed solutions emerge as the result of the synergy among health, environment, tourism, digital, policy and strategy professionals. The approach underlines the pivotal role of a sustainable and ecomedical use of Alpine natural resources for health tourism destinations, and highlights the need of integrating aspects of natural resources’ healing effects, a shared knowledge of Alpine assets through digital solutions, and frames strategic approaches for the long-term development of the sector. The volume exploits the results of the three-years long EU research project HEALPS 2, which involved several stakeholders from the health tourism, healthcare and sustainable tourism industries. This book is relevant for health tourism destinations and facilities (hotels, clinics, wellness and spa companies), regional and local authorities (policy makers), business support organizations, researchers involved in digital healthcare and geoinformatics

Reticulate Evolution: Symbiogenesis, Lateral Gene Transfer, Hybridization and Infectious heredity

info:eu-repo/semantics/publishedVersio

Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Children

The following thesis chapters chronicle evolving efforts throughout 2016 – 2021 to support research toward improving the pediatric clinical pharmacology of monoclonal antibodies (mAbs). Translating the benefits of successful mAbs from adults to children (and even infants) has proved challenging since the first attempts in the early 2000s. Children tend to achieve low pharmacokinetic exposures and poor efficacy when the adult dose is scaled to children by body weight alone (mg/kg), with infliximab as the main example of this case. Physiologically-based pharmacokinetic (PBPK) models were selected as the tool of choice to explore this discrepancy based on their established success with pediatric extrapolation for small molecule drugs. PBPK models enable mechanistic representations of drug disposition in virtual individuals and can be used to identify the drivers of altered pharmacokinetics in anatomically or physiologically distinct special populations, such as children. The early chapters review the state of the field and the mechanistic underpinnings of mAb pharmacokinetics, and an example of an adult PBPK model for trastuzumab is provided. An open-source model for large molecule drugs was launched in 2018 inside the Open Systems Pharmacology software package, and shortly thereafter we trialed the use of this model to predict infliximab pharmacokinetics in children 4 – 17 years of age. Scaling pharmacokinetics to children by size alone failed to correctly predict the pharmacokinetics in this population, suggesting that other factors were at play. Therefore, a comprehensive review was conducted to generate physiological hypotheses to explain the observation with particular attention to infants (< 2 years of age), where the pharmacokinetic differences are most drastic. The following hypotheses were proposed: 1. The fraction of extracellular fluid volume in the body decreases with age and provides large weight-normalized volumes of distribution in infants. 2. Extravasation of antibodies into tissues occurs quickly in infants as they have a large capillary surface area per unit volume available for plasma protein exchange and a large proportion of “leaky” tissues, where capillary permeability is highest. 3. A fast rate of lymph flow in infants drives a fast rate of absorption after extravascular administration. 4. Infants have higher concentrations of circulating hematopoietic cells, which may contribute to extensive cellular uptake and fast elimination. 5. Intracellular metabolism and elimination may be increased due to low expression of FcRn – the neonatal salvage receptor – and the relatively high concentration of endogenous IgG competing for FcRn binding after birth. In 2019, the first four hypotheses were integrated into a PBPK model for mAbs in premature infants that was successful for characterizing pharmacokinetics in infants even 1 day old at 28 weeks gestational age. However, this parameterization was based on the mechanistic understanding of mAb disposition at that time, and it was destined for change. The results of the latest experiments in mice with site-specific FcRn deletion and macrophage knockdown prompted a reinvestigation of the contribution of hematopoietic cells – in particular monocytes and macrophages – to mAb pharmacokinetics. In this work, the role of the macrophage is redefined to a highly efficient protector of IgG, rather than an eliminating cell. A model-based analysis of the data revealed that it is very unlikely that a high concentration of circulating monocytes can contribute to explaining the fast weight-based clearance of mAbs in very young children. In the end, four of the five hypotheses remain, and the investigations continue. Pediatric extrapolation for mAbs is a modestly more achievable task because of the efforts herein, hopefully improving outcomes for this vulnerable population in the future. Other contributions of the thesis include highlighting the influence of cancer and inflammatory disease states on mAb pharmacokinetics, proposing an empirical exponent for scaling volume of distribution to children and formalizing a foundation of pediatric literature on which this field can continue to grow

Life Sciences Program Tasks and Bibliography

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1995. Additionally, this inaugural edition of the Task Book includes information for FY 1994 programs. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive Internet web pag

Fast But Right: Outbreak Surveillance And Foodborne Knowledge Infrastructure

This dissertation examines knowledge infrastructures for detecting and investigating national outbreaks of foodborne disease. Drawing on archival and ethnographic material from US public health and regulatory agencies, I investigate how officials have built and used surveillance systems to make foodborne outbreaks visible, reflecting the shape of the industrialized food supply. I describe how, in the course of conducting outbreak investigation work, officials confront the challenges of a "balancing act" of needing to be fast but right, facing dilemmas associated with wanting to protect the public health yet minimize economic impact to commercial entities, while grappling with the highly distributed nature of both the food system and a federalist system of public health governance. In the dissertation, I make three core arguments. First, during foodborne outbreak investigations, public health and regulatory officials manage time and uncertainty through systematization. Second, systematization has helped make visible a new kind of public health problem, rooted in the post World War II industrialization of the US food supply-national, diffuse outbreaks caused by contaminated food moving through interstate commerce. Third, despite the importance of and emphasis on systematization in this domain, the numerous and persistent challenges associated with needing to be fast but right preserves a need for expert judgment amidst formal systematization efforts. In addition to examining broader public health infrastructure, the dissertation features analyses of two surveillance systems for foodborne disease: an historical examination of the National Salmonella Surveillance Program from 1962-1976, and an historical and ethnographic study of the current early-warning, real-time system based on molecular subtyping. Through these analyses, I demonstrate how these systems made outbreaks visible not only from a technical perspective, but also from social, political, and economic perspectives as well