The Effect of Ongoing Exposure Dynamics in Dose Response Relationships

Characterizing infectivity as a function of pathogen dose is integral to microbial risk assessment. Dose-response experiments usually administer doses to subjects at one time. Phenomenological models of the resulting data, such as the exponential and the Beta-Poisson models, ignore dose timing and assume independent risks from each pathogen. Real world exposure to pathogens, however, is a sequence of discrete events where concurrent or prior pathogen arrival affects the capacity of immune effectors to engage and kill newly arriving pathogens. We model immune effector and pathogen interactions during the period before infection becomes established in order to capture the dynamics generating dose timing effects. Model analysis reveals an inverse relationship between the time over which exposures accumulate and the risk of infection. Data from one time dose experiments will thus overestimate per pathogen infection risks of real world exposures. For instance, fitting our model to one time dosing data reveals a risk of 0.66 from 313 Cryptosporidium parvum pathogens. When the temporal exposure window is increased 100-fold using the same parameters fitted by our model to the one time dose data, the risk of infection is reduced to 0.09. Confirmation of this risk prediction requires data from experiments administering doses with different timings. Our model demonstrates that dose timing could markedly alter the risks generated by airborne versus fomite transmitted pathogens

Predicting Health Impacts of the World Trade Center Disaster: 1. Halogenated hydrocarbons, symptom syndromes, secondary victimization, and the burdens of history

The recent attack on the World Trade Center, in addition to direct injury and psychological trauma, has exposed a vast population to dioxins, dibenzofurans, related endocrine disruptors, and a multitude of other physiologically active chemicals arising from the decomposition of the massive quantities of halogenated hydrocarbons and other plastics within the affected buildings. The impacts of these chemical species have been compounded by exposure to asbestos, fiberglass, crushed glass, concrete, plastic, and other irritating dusts. To address the manifold complexities of this incident we combine recent theoretical perspectives on immune, CNS, and sociocultural cognition with empirical studies on survivors of past large toxic fires, other community-scale chemical exposure incidents, and the aftereffects of war. Our analysis suggests the appearance of complex, but distinct and characteristic, spectra of synergistically linked social, psychosocial, psychological and physical symptoms among the 100,000 or so persons most directly affected by the WTC attack. The different 'eigenpatterns' should become increasingly comorbid as a function of exposure. The expected outcome greatly transcends a simple 'Post Traumatic Stress Disorder' model, and may resemble a particularly acute form of Gulf War Syndrome. We explore the role of external social factors in subsequent exacerbation of the syndrome -- secondary victimization -- and study the path-dependent influence of individual and community-level historical patterns of stress. We suggest that workplace and other organizations can act as ameliorating intermediaries. Those without acess to such buffering structures appear to face a particularly bleak future

Leveraging Epidemiology to Improve Risk Assessment.

The field of environmental public health is at an important crossroad. Our current biomonitoring efforts document widespread exposure to a host of chemicals for which toxicity information is lacking. At the same time, advances in the fields of genomics, proteomics, metabolomics, genetics and epigenetics are yielding volumes of data at a rapid pace. Our ability to detect chemicals in biological and environmental media has far outpaced our ability to interpret their health relevance, and as a result, the environmental risk paradigm, in its current state, is antiquated and ill-equipped to make the best use of these new data. In light of new scientific developments and the pressing need to characterize the public health burdens of chemicals, it is imperative to reinvigorate the use of environmental epidemiology in chemical risk assessment. Two case studies of chemical assessments from the Environmental Protection Agency Integrated Risk Information System database are presented to illustrate opportunities where epidemiologic data could have been used in place of experimental animal data in dose-response assessment, or where different approaches, techniques, or studies could have been employed to better utilize existing epidemiologic evidence. Based on the case studies and what can be learned from recent scientific advances and improved approaches to utilizing human data for dose-response estimation, recommendations are provided for the disciplines of epidemiology and risk assessment for enhancing the role of epidemiologic data in hazard identification and dose-response assessment

Performance of Cpred/Cobs concentration ratios as a metric reflecting adherence to antidepressant drug therapy

Background: Nonadherence is very common among subjects undergoing pharmacotherapy for schizophrenia and depression. This study aimed to evaluate the performance of the ratio of the nonlinear mixed effects pharmacokinetic model predicted concentration to observed drug concentration (ratio of population predicted to observed concentration (Cpred/Cobs) and ratio of individual predicted to observed concentration (Cipred/Cobs) as a measure of erratic drug exposure, driven primarily by variable execution of the dosage regimen and unknown true dosage history. Methods: Modeling and simulation approaches in conjunction with dosage history information from the Medication Event Monitoring System (MEMS, provided by the "Depression: The search for treatment relevant phenotypes" study), was applied to evaluate the consistency of exposure via simulation studies with scenarios representing a long half-life drug (escitalopram). Adherence rates were calculated based on the percentage of the prescribed doses actually taken correctly during the treatment window of interest. The association between Cpred/Cobs, Cipred/Cobs ratio, and adherence rate was evaluated under various assumptions of known dosing history. Results: Simulations for those scenarios representing a known dosing history were generated from historical MEMS data. Simulations of a long half-life drug exhibited a trend for overprediction of concentrations in patients with a low percentage of doses taken and underprediction of concentrations in patients taking more than their prescribed number of doses. Overall, the ratios did not predict adherence well, except when the true adherence rates were extremely high (greater than 100% of prescribed doses) or extremely low (complete nonadherence). In general, the Cipred/Cobs ratio was a better predictor of adherence rate than the Cpred/Cobs ratio. Correct predictions of extreme (high, low) 7-day adherence rates using Cipred/Cobs were 73.8% and 64.0%. Conclusion: This simulation study demonstrated the limitations of the Cpred/obs and Cipred/obs ratios as metrics for actual dosage intake history, and identified that use of MEMS dosing history monitoring combined with sparse pharmacokinetic sampling is a more reliable approach. © 2011 Feng et al

An Environmental Science and Engineering Framework for Combating Antimicrobial Resistance

On June 20, 2017, members of the environmental engineering and science (EES) community convened at the Association of Environmental Engineering and Science Professors (AEESP) Biennial Conference for a workshop on antimicrobial resistance. With over 80 registered participants, discussion groups focused on the following topics: risk assessment, monitoring, wastewater treatment, agricultural systems, and synergies. In this study, we summarize the consensus among the workshop participants regarding the role of the EES community in understanding and mitigating the spread of antibiotic resistance via environmental pathways. Environmental scientists and engineers offer a unique and interdisciplinary perspective and expertise needed for engaging with other disciplines such as medicine, agriculture, and public health to effectively address important knowledge gaps with respect to the linkages between human activities, impacts to the environment, and human health risks. Recommendations that propose priorities for research within the EES community, as well as areas where interdisciplinary perspectives are needed, are highlighted. In particular, risk modeling and assessment, monitoring, and mass balance modeling can aid in the identification of “hot spots” for antibiotic resistance evolution and dissemination, and can help identify effective targets for mitigation. Such information will be essential for the development of an informed and effective policy aimed at preserving and protecting the efficacy of antibiotics for future generations

Evolutionary-thinking in agricultural weed management

Agricultural weeds evolve in response to crop cultivation. Nevertheless, the central importance of evolutionary ecology for understanding weed invasion, persistence and management in agroecosystems is not widely acknowledged. This paper calls for more evolutionarily-enlightened weed management, in which management principles are informed by evolutionary biology to prevent or minimize weed adaptation and spread. As a first step, a greater knowledge of the extent, structure and significance of genetic variation within and between weed populations is required to fully assess the potential for weed adaptation. The evolution of resistance to herbicides is a classic example of weed adaptation. Even here, most research focuses on describing the physiological and molecular basis of resistance, rather than conducting studies to better understand the evolutionary dynamics of selection for resistance. We suggest approaches to increase the application of evolutionary-thinking to herbicide resistance research. Weed population dynamics models are increasingly important tools in weed management, yet these models often ignore intrapopulation and interpopulation variability, neglecting the potential for weed adaptation in response to management. Future agricultural weed management can benefit from greater integration of ecological and evolutionary principles to predict the long-term responses of weed populations to changing weed management, agricultural environments and global climate

Pharmacokinetics and Pharmacodynamics in Space

The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic regimens

The Challenges of Place, Capacity, and Systems Change: The Story of Yes we can!

· Yes we can!, a comprehensive community initiative (CCI) funded by the W. K. Kellogg Foundation, was designed to improve educational and economic outcomes within the foundation’s hometown of Battle Creek, Mich. Since 2002, Yes we can! has supported five core strategies designed to trigger the systems changes needed to reduce educational and economic inequities in Battle Creek. · Yes we can! has achieved some important wins to date; for example, more residents are involved, more neighborhoods have stronger neighborhood associations, and more organizations are engaging residents in their decision-making processes. However, the scale of wins remains small, and the targeted systemic changes have not yet emerged. · Some common CCI design elements featured in Yes we can! may have inadvertently bounded its success: a) community building efforts targeted small-scale places, restricting the scale and scope of wins; b) demands for current work competed with building capacities for future work; and c) local partners who were implementing their individual grants struggled to maintain a focus on the larger vision and collective work