The evaluation the magnitude radiation exposure dose rate in digital radiography room design

NASA Astrophysics Data System (ADS)

Dwiyanto, Agung; Setia Budi, Wahyu; Hardiman, Gagoek

2017-12-01

This study discusses the dose rate in digital radiography room, buit according to meet the provisions of KEMENKES No.1014 / Menkes / SK / XI / 2008 and Regulation of BAPETEN No. 8 / 2011. The provisions primary concern of radiation safety, not comfort, by considering the space design. There are five aspects to consider in designing the space: functionality, comfort, security, movement activities and aesthetics. However provisions only met three aspects of the design, which are a function, security and movement activity. Therefore, it is necessary to evaluate digital radiography room in terms of its ability to control external radiation exposure to be safe and comfortable The dose rate is measured by the range of primary and secondary radiation in the observation points by using Surveymeter. All data are obtained by the preliminary survey prior to the study. Furthermore, the review of digital radiography room is done based on architectural design theory. The dose rate for recommended improvement room is recalculated using the same method as the actual room with the help of computer modeling. The result of dose rate calculation at the inner and outer part of digital radiography observation room shows that in-room dose for a week at each measuring point exceeds the allowable dose limit both for staff and public. During a week of observation, the outdoor dose at some measuring points exceeds the dose limit set by the KEMENKES No.1014 / Menkes / SK / XI / 2008 and Regulation BEPETEN No 8/2011. Meanwhile, the result of dose rate calculation in the inner and outer part of the improved digital radiography room can meet the applicable regulations better.

A simple and fast physics-based analytical method to calculate therapeutic and stray doses from external beam, megavoltage x-ray therapy

PubMed Central

Wilson, Lydia J; Newhauser, Wayne D

2015-01-01

State-of-the-art radiotherapy treatment planning systems provide reliable estimates of the therapeutic radiation but are known to underestimate or neglect the stray radiation exposures. Most commonly, stray radiation exposures are reconstructed using empirical formulas or lookup tables. The purpose of this study was to develop the basic physics of a model capable of calculating the total absorbed dose both inside and outside of the therapeutic radiation beam for external beam photon therapy. The model was developed using measurements of total absorbed dose in a water-box phantom from a 6 MV medical linear accelerator to calculate dose profiles in both the in-plane and cross-plane direction for a variety of square field sizes and depths in water. The water-box phantom facilitated development of the basic physical aspects of the model. RMS discrepancies between measured and calculated total absorbed dose values in water were less than 9.3% for all fields studied. Computation times for 10 million dose points within a homogeneous phantom were approximately 4 minutes. These results suggest that the basic physics of the model are sufficiently simple, fast, and accurate to serve as a foundation for a variety of clinical and research applications, some of which may require that the model be extended or simplified based on the needs of the user. A potentially important advantage of a physics-based approach is that the model is more readily adaptable to a wide variety of treatment units and treatment techniques than with empirical models. PMID:26040833

A simple and fast physics-based analytical method to calculate therapeutic and stray doses from external beam, megavoltage x-ray therapy.

PubMed

Jagetic, Lydia J; Newhauser, Wayne D

2015-06-21

State-of-the-art radiotherapy treatment planning systems provide reliable estimates of the therapeutic radiation but are known to underestimate or neglect the stray radiation exposures. Most commonly, stray radiation exposures are reconstructed using empirical formulas or lookup tables. The purpose of this study was to develop the basic physics of a model capable of calculating the total absorbed dose both inside and outside of the therapeutic radiation beam for external beam photon therapy. The model was developed using measurements of total absorbed dose in a water-box phantom from a 6 MV medical linear accelerator to calculate dose profiles in both the in-plane and cross-plane direction for a variety of square field sizes and depths in water. The water-box phantom facilitated development of the basic physical aspects of the model. RMS discrepancies between measured and calculated total absorbed dose values in water were less than 9.3% for all fields studied. Computation times for 10 million dose points within a homogeneous phantom were approximately 4 min. These results suggest that the basic physics of the model are sufficiently simple, fast, and accurate to serve as a foundation for a variety of clinical and research applications, some of which may require that the model be extended or simplified based on the needs of the user. A potentially important advantage of a physics-based approach is that the model is more readily adaptable to a wide variety of treatment units and treatment techniques than with empirical models.

Gestational treatment with methylazoxymethanol (MAM) that disrupts hippocampal-dependent memory does not alter behavioural response to cocaine.

PubMed

Featherstone, Robert E; Burton, Christie L; Coppa-Hopman, Romina; Rizos, Zoë; Sinyard, Judy; Kapur, Shitij; Fletcher, Paul J

2009-10-01

Schizophrenia is associated with increased rates of substance abuse that are thought to be the result of changes in cortical and mesolimbic dopamine activity. Previous work has shown that gestational methylazoxymethanol acetate (MAM) treatment induces increased mesolimbic dopamine activity when given around the time of embryonic day 17 (ED17), suggesting that MAM treatment may model some aspects of schizophrenia. Given that increased dopaminergic activity facilitates aspects of drug self-administration and reinstatement of drug seeking, the current experiments sought to assess cocaine self-administration in MAM treated animals. Experiment 1 examined the acquisition of cocaine self-administration in ED17 MAM and saline treated rats using a sub-threshold dose of cocaine. In experiment 2 ED17 MAM and saline treated animals were trained to self-administer cocaine and were then assessed under varying doses of cocaine (dose-response), followed by extinction and drug-induced reinstatement of responding. A subset of these animals was trained on a win-shift radial maze task, designed to detect impairments in hippocampal-dependent memory. In experiment 3, MAM and saline treated animals were assessed on a progressive ratio schedule of cocaine delivery. Finally, in experiment 4 MAM and saline treated animals were assessed on cocaine-induced locomotor activity across a range of doses of cocaine. MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed.

The Dynamics of Drug Resistance: A Mathematical Perspective

PubMed Central

Lavi, Orit; Gottesman, Michael M.; Levy, Doron

2012-01-01

Resistance to chemotherapy is a key impediment to successful cancer treatment that has been intensively studied for the last three decades. Several central mechanisms have been identified as contributing to the resistance. In the case of multidrug resistance (MDR), the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Mathematical models of drug resistance have dealt with many of the known aspects of this field, such as pharmacologic sanctuary and location/diffusion resistance, intrinsic resistance that is therapy independent, therapy-dependent cellular alterations including induced resistance (dose-dependent) and acquired resistance (dose-independent). In addition, there are mathematical models that take into account the kinetic/phase resistance, and models that investigate intra-cellular mechanisms based on specific biological functions (such as ABC transporters, apoptosis and repair mechanisms). This review covers aspects of MDR that have been mathematically studied, and explains how, from a methodological perspective, mathematics can be used to study drug resistance. We discuss quantitative approaches of mathematical analysis, and demonstrate how mathematics can be used in combination with other experimental and clinical tools. We emphasize the potential benefits of integrating analytical and mathematical methods into future clinical and experimental studies of drug resistance. PMID:22387162

Dosimetry in nuclear medicine therapy: radiobiology application and results.

PubMed

Strigari, L; Benassi, M; Chiesa, C; Cremonesi, M; Bodei, L; D'Andrea, M

2011-04-01

The linear quadratic model (LQM) has largely been used to assess the radiobiological damage to tissue by external beam fractionated radiotherapy and more recently has been extended to encompass a general continuous time varying dose rate protocol such as targeted radionuclide therapy (TRT). In this review, we provide the basic aspects of radiobiology, from a theoretical point of view, starting from the "four Rs" of radiobiology and introducing the biologically effective doses, which may be used to quantify the impact of a treatment on both tumors and normal tissues. We also present the main parameters required in the LQM, and illustrate the main models of tumor control probability and normal tissue complication probability and summarize the main dose-effect responses, reported in literature, which demonstrate the tentative link between targeted radiotherapy doses and those used in conventional radiotherapy. A better understanding of the radiobiology and mechanisms of action of TRT could contribute to describe the clinical data and guide the development of future compounds and the designing of prospective clinical trials.

Dose Dependent Dopaminergic Modulation of Reward-Based Learning in Parkinson's Disease

ERIC Educational Resources Information Center

van Wouwe, N. C.; Ridderinkhof, K. R.; Band, G. P. H.; van den Wildenberg, W. P. M.; Wylie, S. A.

2012-01-01

Learning to select optimal behavior in new and uncertain situations is a crucial aspect of living and requires the ability to quickly associate stimuli with actions that lead to rewarding outcomes. Mathematical models of reinforcement-based learning to select rewarding actions distinguish between (1) the formation of stimulus-action-reward…

Moles of a Substance per Cell Is a Highly Informative Dosing Metric in Cell Culture

PubMed Central

Wagner, Brett A.; Buettner, Garry R.

2015-01-01

Background The biological consequences upon exposure of cells in culture to a dose of xenobiotic are not only dependent on biological variables, but also the physical aspects of experiments e.g. cell number and media volume. Dependence on physical aspects is often overlooked due to the unrecognized ambiguity in the dominant metric used to express exposure, i.e. initial concentration of xenobiotic delivered to the culture medium over the cells. We hypothesize that for many xenobiotics, specifying dose as moles per cell will reduce this ambiguity. Dose as moles per cell can also provide additional information not easily obtainable with traditional dosing metrics. Methods Here, 1,4-benzoquinone and oligomycin A are used as model compounds to investigate moles per cell as an informative dosing metric. Mechanistic insight into reactions with intracellular molecules, differences between sequential and bolus addition of xenobiotic and the influence of cell volume and protein content on toxicity are also investigated. Results When the dose of 1,4-benzoquinone or oligomycin A was specified as moles per cell, toxicity was independent of the physical conditions used (number of cells, volume of medium). When using moles per cell as a dose-metric, direct quantitative comparisons can be made between biochemical or biological endpoints and the dose of xenobiotic applied. For example, the toxicity of 1,4-benzoquinone correlated inversely with intracellular volume for all five cell lines exposed (C6, MDA-MB231, A549, MIA PaCa-2, and HepG2). Conclusions Moles per cell is a useful and informative dosing metric in cell culture. This dosing metric is a scalable parameter that: can reduce ambiguity between experiments having different physical conditions; provides additional mechanistic information; allows direct comparison between different cells; affords a more uniform platform for experimental design; addresses the important issue of repeatability of experimental results, and could increase the translatability of information gained from in vitro experiments. PMID:26172833

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

PubMed

Dean, J A; Welsh, L C; Wong, K H; Aleksic, A; Dunne, E; Islam, M R; Patel, A; Patel, P; Petkar, I; Phillips, I; Sham, J; Schick, U; Newbold, K L; Bhide, S A; Harrington, K J; Nutting, C M; Gulliford, S L

2017-04-01

A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

PubMed

Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

2017-11-01

A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres

PubMed Central

Alp, Murat; Cucinotta, Francis A.

2017-01-01

Changes to cognition, including memory, following radiation exposure are a concern for cosmic ray exposures to astronauts and in Hadron therapy with proton and heavy ion beams. The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. A challenge for biophysical models of neuronal damage is the large sizes (>100 μm) and variability in volumes of possible dendritic segments and pre-synaptic elements (spines and filopodia). We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3He and 12C particles at energies corresponding to a distance of 1 cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure. We investigate the optimal axis length of dendritic segments to evaluate microscopic ED and hit probabilities along the dendritic branches at a given macroscopic dose. Because of large computation times to analyze ED in volumes of varying sizes, we developed an analytical method to find the mean primary dose in spheres that can guide numerical methods to find the primary dose distribution for cylinders. Considering cylindrical segments of varying aspect ratio at constant volume, we assess the chord length distribution, mean number of hits and ED profiles by primary particles and secondary electrons (δ-rays). For biophysical modeling applications, segments on dendritic branches are proposed to have equal diameters and axes lengths along the varying diameter of a dendritic branch. PMID:28554507

Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres

NASA Astrophysics Data System (ADS)

Alp, Murat; Cucinotta, Francis A.

2017-05-01

Changes to cognition, including memory, following radiation exposure are a concern for cosmic ray exposures to astronauts and in Hadron therapy with proton and heavy ion beams. The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. A challenge for biophysical models of neuronal damage is the large sizes (> 100 μm) and variability in volumes of possible dendritic segments and pre-synaptic elements (spines and filopodia). We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3He and 12C particles at energies corresponding to a distance of 1 cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure. We investigate the optimal axis length of dendritic segments to evaluate microscopic ED and hit probabilities along the dendritic branches at a given macroscopic dose. Because of large computation times to analyze ED in volumes of varying sizes, we developed an analytical method to find the mean primary dose in spheres that can guide numerical methods to find the primary dose distribution for cylinders. Considering cylindrical segments of varying aspect ratio at constant volume, we assess the chord length distribution, mean number of hits and ED profiles by primary particles and secondary electrons (δ-rays). For biophysical modeling applications, segments on dendritic branches are proposed to have equal diameters and axes lengths along the varying diameter of a dendritic branch.

Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres.

PubMed

Alp, Murat; Cucinotta, Francis A

2017-05-01

Changes to cognition, including memory, following radiation exposure are a concern for cosmic ray exposures to astronauts and in Hadron therapy with proton and heavy ion beams. The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. A challenge for biophysical models of neuronal damage is the large sizes (> 100µm) and variability in volumes of possible dendritic segments and pre-synaptic elements (spines and filopodia). We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3 He and 12 C particles at energies corresponding to a distance of 1cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure. We investigate the optimal axis length of dendritic segments to evaluate microscopic ED and hit probabilities along the dendritic branches at a given macroscopic dose. Because of large computation times to analyze ED in volumes of varying sizes, we developed an analytical method to find the mean primary dose in spheres that can guide numerical methods to find the primary dose distribution for cylinders. Considering cylindrical segments of varying aspect ratio at constant volume, we assess the chord length distribution, mean number of hits and ED profiles by primary particles and secondary electrons (δ-rays). For biophysical modeling applications, segments on dendritic branches are proposed to have equal diameters and axes lengths along the varying diameter of a dendritic branch. Copyright © 2017. Published by Elsevier Ltd.

A Monte Carlo model for photoneutron generation by a medical LINAC

NASA Astrophysics Data System (ADS)

Sumini, M.; Isolan, L.; Cucchi, G.; Sghedoni, R.; Iori, M.

2017-11-01

For an optimal tuning of the radiation protection planning, a Monte Carlo model using the MCNPX code has been built, allowing an accurate estimate of the spectrometric and geometrical characteristics of photoneutrons generated by a Varian TrueBeam Stx© medical linear accelerator. We considered in our study a device working at the reference energy for clinical applications of 15 MV, stemmed from a Varian Clinac©2100 modeled starting from data collected thanks to several papers available in the literature. The model results were compared with neutron and photon dose measurements inside and outside the bunker hosting the accelerator obtaining a complete dose map. Normalized neutron fluences were tallied in different positions at the patient plane and at different depths. A sensitivity analysis with respect to the flattening filter material were performed to enlighten aspects that could influence the photoneutron production.

A Web-Based System for Bayesian Benchmark Dose Estimation.

PubMed

Shao, Kan; Shapiro, Andrew J

2018-01-11

Benchmark dose (BMD) modeling is an important step in human health risk assessment and is used as the default approach to identify the point of departure for risk assessment. A probabilistic framework for dose-response assessment has been proposed and advocated by various institutions and organizations; therefore, a reliable tool is needed to provide distributional estimates for BMD and other important quantities in dose-response assessment. We developed an online system for Bayesian BMD (BBMD) estimation and compared results from this software with U.S. Environmental Protection Agency's (EPA's) Benchmark Dose Software (BMDS). The system is built on a Bayesian framework featuring the application of Markov chain Monte Carlo (MCMC) sampling for model parameter estimation and BMD calculation, which makes the BBMD system fundamentally different from the currently prevailing BMD software packages. In addition to estimating the traditional BMDs for dichotomous and continuous data, the developed system is also capable of computing model-averaged BMD estimates. A total of 518 dichotomous and 108 continuous data sets extracted from the U.S. EPA's Integrated Risk Information System (IRIS) database (and similar databases) were used as testing data to compare the estimates from the BBMD and BMDS programs. The results suggest that the BBMD system may outperform the BMDS program in a number of aspects, including fewer failed BMD and BMDL calculations and estimates. The BBMD system is a useful alternative tool for estimating BMD with additional functionalities for BMD analysis based on most recent research. Most importantly, the BBMD has the potential to incorporate prior information to make dose-response modeling more reliable and can provide distributional estimates for important quantities in dose-response assessment, which greatly facilitates the current trend for probabilistic risk assessment. https://doi.org/10.1289/EHP1289.

A new model for volume recombination in plane-parallel chambers in pulsed fields of high dose-per-pulse

NASA Astrophysics Data System (ADS)

Gotz, M.; Karsch, L.; Pawelke, J.

2017-11-01

In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 μs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 μs at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates.

A new model for volume recombination in plane-parallel chambers in pulsed fields of high dose-per-pulse.

PubMed

Gotz, M; Karsch, L; Pawelke, J

2017-11-01

In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 μs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 [Formula: see text] at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates.

WE-AB-209-07: Explicit and Convex Optimization of Plan Quality Metrics in Intensity-Modulated Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Engberg, L; KTH Royal Institute of Technology, Stockholm; Eriksson, K

Purpose: To formulate objective functions of a multicriteria fluence map optimization model that correlate well with plan quality metrics, and to solve this multicriteria model by convex approximation. Methods: In this study, objectives of a multicriteria model are formulated to explicitly either minimize or maximize a dose-at-volume measure. Given the widespread agreement that dose-at-volume levels play important roles in plan quality assessment, these objectives correlate well with plan quality metrics. This is in contrast to the conventional objectives, which are to maximize clinical goal achievement by relating to deviations from given dose-at-volume thresholds: while balancing the new objectives means explicitlymore » balancing dose-at-volume levels, balancing the conventional objectives effectively means balancing deviations. Constituted by the inherently non-convex dose-at-volume measure, the new objectives are approximated by the convex mean-tail-dose measure (CVaR measure), yielding a convex approximation of the multicriteria model. Results: Advantages of using the convex approximation are investigated through juxtaposition with the conventional objectives in a computational study of two patient cases. Clinical goals of each case respectively point out three ROI dose-at-volume measures to be considered for plan quality assessment. This is translated in the convex approximation into minimizing three mean-tail-dose measures. Evaluations of the three ROI dose-at-volume measures on Pareto optimal plans are used to represent plan quality of the Pareto sets. Besides providing increased accuracy in terms of feasibility of solutions, the convex approximation generates Pareto sets with overall improved plan quality. In one case, the Pareto set generated by the convex approximation entirely dominates that generated with the conventional objectives. Conclusion: The initial computational study indicates that the convex approximation outperforms the conventional objectives in aspects of accuracy and plan quality.« less

Dose-response-a challenge for allelopathy?

PubMed

Belz, Regina G; Hurle, Karl; Duke, Stephen O

2005-04-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

Impact of chemical proportions on the acute neurotoxicity of a mixture of seven carbamates in preweanling and adult rats.

PubMed

Moser, Virginia C; Padilla, Stephanie; Simmons, Jane Ellen; Haber, Lynne T; Hertzberg, Richard C

2012-09-01

Statistical design and environmental relevance are important aspects of studies of chemical mixtures, such as pesticides. We used a dose-additivity model to test experimentally the default assumptions of dose additivity for two mixtures of seven N-methylcarbamates (carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, and propoxur). The best-fitting models were selected for the single-chemical dose-response data and used to develop a combined prediction model, which was then compared with the experimental mixture data. We evaluated behavioral (motor activity) and cholinesterase (ChE)-inhibitory (brain, red blood cells) outcomes at the time of peak acute effects following oral gavage in adult and preweanling (17 days old) Long-Evans male rats. The mixtures varied only in their mixing ratios. In the relative potency mixture, proportions of each carbamate were set at equitoxic component doses. A California environmental mixture was based on the 2005 sales of each carbamate in California. In adult rats, the relative potency mixture showed dose additivity for red blood cell ChE and motor activity, and brain ChE inhibition showed a modest greater-than additive (synergistic) response, but only at a middle dose. In rat pups, the relative potency mixture was either dose-additive (brain ChE inhibition, motor activity) or slightly less-than additive (red blood cell ChE inhibition). On the other hand, at both ages, the environmental mixture showed greater-than additive responses on all three endpoints, with significant deviations from predicted at most to all doses tested. Thus, we observed different interactive properties for different mixing ratios of these chemicals. These approaches for studying pesticide mixtures can improve evaluations of potential toxicity under varying experimental conditions that may mimic human exposures.

Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents.

PubMed

Sear, J W

2011-03-01

The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA). ED(50) induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC(50) plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was eltanolone. The final CoMFA model for the ED(50) induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q(2)=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r(2)=0.988 and q(2)=0.852. Although there was a correlation between -log ED(50) and -log EC(50) (r(2)=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1). Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.

Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study

PubMed Central

Kessler, Sudha Kilaru; Minhas, Preet; Woods, Adam J.; Rosen, Alyssa; Gorman, Casey; Bikson, Marom

2013-01-01

Transcranial direct current stimulation (tDCS) is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1) differences in neurophysiology and disease, and 2) variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1) further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2) further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation. PMID:24086698

ALARA at nuclear power plants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baum, J.W.

1990-01-01

Implementation of the As Low As Reasonably Achievable (ALARA) principle at nuclear power plants presents a continuing challenge for health physicists at utility corporate and plant levels, for plant designers, and for regulatory agencies. The relatively large collective doses at some plants are being addressed though a variety of dose reduction techniques. It is planned that this report will include material on historical aspects, management, valuation of dose reduction, quantitative and qualitative aspects of optimization, design, operational considerations, and training. The status of this work is summarized in this report. 30 refs., 1 fig., 6 tabs.

Causation in risk assessment and management: models, inference, biases, and a microbial risk-benefit case study.

PubMed

Cox, L A; Ricci, P F

2005-04-01

Causal inference of exposure-response relations from data is a challenging aspect of risk assessment with important implications for public and private risk management. Such inference, which is fundamentally empirical and based on exposure (or dose)-response models, seldom arises from a single set of data; rather, it requires integrating heterogeneous information from diverse sources and disciplines including epidemiology, toxicology, and cell and molecular biology. The causal aspects we discuss focus on these three aspects: drawing sound inferences about causal relations from one or more observational studies; addressing and resolving biases that can affect a single multivariate empirical exposure-response study; and applying the results from these considerations to the microbiological risk management of human health risks and benefits of a ban on antibiotic use in animals, in the context of banning enrofloxacin or macrolides, antibiotics used against bacterial illnesses in poultry, and the effects of such bans on changing the risk of human food-borne campylobacteriosis infections. The purposes of this paper are to describe novel causal methods for assessing empirical causation and inference; exemplify how to deal with biases that routinely arise in multivariate exposure- or dose-response modeling; and provide a simplified discussion of a case study of causal inference using microbial risk analysis as an example. The case study supports the conclusion that the human health benefits from a ban are unlikely to be greater than the excess human health risks that it could create, even when accounting for uncertainty. We conclude that quantitative causal analysis of risks is a preferable to qualitative assessments because it does not involve unjustified loss of information and is sound under the inferential use of risk results by management.

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4–5 December 2014)

PubMed Central

Manolis, E; Holford, N; Cheung, SYA; Friberg, LE; Ogungbenro, K; Posch, M; Yates, JWT; Berry, S; Thomas, N; Corriol‐Rohou, S; Bornkamp, B; Bretz, F; Hooker, AC; Van der Graaf, PH; Standing, JF; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-01-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. PMID:28722322

Web-based training related to NRC staff review of dose modeling aspects of license termination and decommissioning plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

LePoire, D.; Arnish, J.; Cheng, J.J.

NRC licensees at decommissioning nuclear facilities submit License Termination Plans (LTP) or Decommissioning Plans (DP) to NRC for review and approval. To facilitate a uniform and consistent review of these plans, the NRC developed training for its staff. A live classroom course was first developed in 2005, which targeted specific aspects of the LTP and DP review process related to dose-based compliance demonstrations or modeling. A web-based training (WBT) course is being developed in 2006 to replace the classroom-based course. The advantage of the WBT is that it will allow for staff training or refreshers at any time, while themore » advantage of a classroom-based course is that it provides a forum for lively discussion and the sharing of experience of classroom participants. The training course consists of the core and advanced modules tailored to specific NRC job functions. Topics for individual modules include identifying the characteristics of simple and complex sites, identifying when outside expertise or consultation is needed, demonstrating how to conduct acceptance and technical reviews of dose modeling, and providing details regarding the level of justification needed for realistic scenarios for both dose modeling and derivation of DCGLs. Various methods of applying probabilistic uncertainty analysis to demonstrate compliance with dose-based requirements are presented. These approaches include 1) modeling the pathways of radiological exposure and estimating doses to receptors from a combination of contaminated media and radionuclides, and 2) using probabilistic analysis to determine an appropriate set of input parameters to develop derived concentration guideline limits or DCGLs (DCGLs are media- and nuclide-specific concentration limits that will meet dose-based, license termination rule criteria found in 10 CFR Part 20, Subpart E). Calculation of operational (field) DCGL's from media- and nuclide-specific DCGLs and use of operational DCGLs in conducting final status surveys are addressed in the WBT. Realistic case examples are presented and analyzed including the abstraction of a realistic site into a conceptual model and computer model. A case history is also used to demonstrate development of NRC review documents such as requests for additional information (RAIs). To enhance the web-based training experience, audio, animations, linked documents, quizzes, and scripts are being integrated with a commercial web-based training package that supports simple navigation. The course is also being integrated into both existing and state-of-the-art learning management systems. A testing group is being utilized to identify and help resolve training issues prior to deployment of the course. When completed, the course can be accessed for credited training with required modules dependent on the job category of the training participant. The modules will also be accessible to NRC staff for review or refresher following initial course completion. WBT promotes consistency in reviews and has the advantage of being able to be used as a resource to staff at any time. The WBT will provide reviewers with knowledge needed to perform risk-informed analyses (e.g., information related to development of realistic scenarios and use of probabilistic analysis). WBT on review of LTP or DP dose modeling will promote staff development, efficiency, and effectiveness in performing risk-informed, performance-based reviews of decommissioning activities at NRC-licensed facilities. (authors)« less

Some Considerations for Chelation Treatment and Surgical Excision Following Incorporation of Plutonium in Wounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poudel, Deepesh; Bertelli, Luiz; Klumpp, John A.

After a plutonium-contaminated wound, the role of an internal dosimetrist is to inform the patient and the physician of the dosimetric considerations. The doses averted due to medical treatments (excision or chelation) are higher if the treatments are administered early; therefore, the internal dosimetrist needs to rely on limited information on wound counts and process knowledge for advising the physician. For this study, several wound cases in the literature were reviewed to obtain estimates of the efficacies of surgical excision and chelation treatment after plutonium-contaminated wounds. The dose coefficients calculated by coupling the NCRP 156 wound model with the systemicmore » model were used to derive the decision guidelines that may indicate medical treatment based on 1) the concept of saved doses proposed by the NCRP 156 wound model, 2) the limits recommended by the CEC/DOE guidebook, and 3) the Clinical Decision Guidelines proposed in NCRP Report No. 161. These guidelines by themselves, however, are of limited use for several reasons, including 1) large uncertainties associated with wound measurements, 2) exposure to forms of radionuclides that cannot be assigned to a single category in the NCRP 156 framework, 3) inability of the NCRP 156 model to explain some of the wound cases in the literature, 4) neglect of the local doses to the wound site and the pathophysiological response of the tissue, 5) poorly understood relationship between effective doses and risks of late health effects, and 6) disregard of the psychological aspects of radionuclide intake.« less

Some Considerations for Chelation Treatment and Surgical Excision Following Incorporation of Plutonium in Wounds

DOE PAGES

Poudel, Deepesh; Bertelli, Luiz; Klumpp, John A.; ...

2018-03-01

After a plutonium-contaminated wound, the role of an internal dosimetrist is to inform the patient and the physician of the dosimetric considerations. The doses averted due to medical treatments (excision or chelation) are higher if the treatments are administered early; therefore, the internal dosimetrist needs to rely on limited information on wound counts and process knowledge for advising the physician. For this study, several wound cases in the literature were reviewed to obtain estimates of the efficacies of surgical excision and chelation treatment after plutonium-contaminated wounds. The dose coefficients calculated by coupling the NCRP 156 wound model with the systemicmore » model were used to derive the decision guidelines that may indicate medical treatment based on 1) the concept of saved doses proposed by the NCRP 156 wound model, 2) the limits recommended by the CEC/DOE guidebook, and 3) the Clinical Decision Guidelines proposed in NCRP Report No. 161. These guidelines by themselves, however, are of limited use for several reasons, including 1) large uncertainties associated with wound measurements, 2) exposure to forms of radionuclides that cannot be assigned to a single category in the NCRP 156 framework, 3) inability of the NCRP 156 model to explain some of the wound cases in the literature, 4) neglect of the local doses to the wound site and the pathophysiological response of the tissue, 5) poorly understood relationship between effective doses and risks of late health effects, and 6) disregard of the psychological aspects of radionuclide intake.« less

Experimental neuropharmacology of Gelsemium sempervirens: Recent advances and debated issues.

PubMed

Bellavite, Paolo; Bonafini, Clara; Marzotto, Marta

Gelsemium sempervirens L. (Gelsemium) is traditionally used for its anxiolytic-like properties and its action mechanism in laboratory models are under scrutiny. Evidence from rodent models was reported suggesting the existence of a high sensitivity of central nervous system to anxiolytic power of Gelsemium extracts and Homeopathic dilutions. In vitro investigation of extremely low doses of this plant extract showed a modulation of gene expression of human neurocytes. These studies were criticized in a few commentaries, generated a debate in literature and were followed by further experimental studies from various laboratories. Toxic doses of Gelsemium cause neurological signs characterized by marked weakness and convulsions, while ultra-low doses or high Homeopathic dilutions counteract seizures induced by lithium and pilocarpine, decrease anxiety after stress and increases the anti-stress allopregnanolone hormone, through glycine receptors. Low (non-Homeopathic) doses of this plant or its alkaloids decrease neuropathic pain and c-Fos expression in mice brain and oxidative stress. Due to the complexity of the matter, several aspects deserve interpretation and the main controversial topics, with a focus on the issues of high dilution pharmacology, are discussed and clarified. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Dose-Response—A Challenge for Allelopathy?

PubMed Central

Belz, Regina G.; Hurle, Karl; Duke, Stephen O.

2005-01-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions. PMID:19330161

Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth.

PubMed

Anagnostou, Evdokia; Soorya, Latha; Brian, Jessica; Dupuis, Annie; Mankad, Deepali; Smile, Sharon; Jacob, Suma

2014-09-11

There is a paucity of treatments targeting core symptom domains in Autism Spectrum Disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD. Fifteen children and adolescents with verbal IQs≥70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. Among 4 doses tested, the highest dose evaluated, 0.4 IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin. This pilot study suggests that daily administration of intranasal oxytocin at 0.4 IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted. This article is part of a Special Issue entitled Oxytocin and Social Behav. Copyright © 2014 Elsevier B.V. All rights reserved.

Induction and Processing of the Radiation-Induced Gamma-H2AX Signal and Its Link to the Underlying Pattern of DSB: A Combined Experimental and Modelling Study

PubMed Central

Tommasino, Francesco; Friedrich, Thomas; Jakob, Burkhard; Meyer, Barbara; Durante, Marco; Scholz, Michael

2015-01-01

We present here an analysis of DSB induction and processing after irradiation with X-rays in an extended dose range based on the use of the γH2AX assay. The study was performed by quantitative flow cytometry measurements, since the use of foci counting would result in reasonable accuracy only in a limited dose range of a few Gy. The experimental data are complemented by a theoretical analysis based on the GLOBLE model. In fact, original aim of the study was to test GLOBLE predictions against new experimental data, in order to contribute to the validation of the model. Specifically, the γH2AX signal kinetics has been investigated up to 24 h after exposure to increasing photon doses between 2 and 500 Gy. The prolonged persistence of the signal at high doses strongly suggests dose dependence in DSB processing after low LET irradiation. Importantly, in the framework of our modelling analysis, this is related to a gradually increased fraction of DSB clustering at the micrometre scale. The parallel study of γH2AX dose response curves shows the onset of a pronounced saturation in two cell lines at a dose of about 20 Gy. This dose is much lower than expected according to model predictions based on the values usually adopted for the DSB induction yield (≈ 30 DSB/Gy) and for the γH2AX foci extension of approximately 2 Mbp around the DSB. We show and discuss how theoretical predictions and experimental findings can be in principle reconciled by combining an increased DSB induction yield with the assumption of a larger genomic extension for the single phosphorylated regions. As an alternative approach, we also considered in our model the possibility of a 3D spreading-mechanism of the H2AX phosphorylation around the induced DSB, and applied it to the analysis of both the aspects considered. Our results are found to be supportive for the basic assumptions on which GLOBLE is built. Apart from giving new insights into the H2AX phosphorylation process, experiments performed at high doses are of relevance in the context of radiation therapy, where hypo-fractionated schemes become increasingly popular. PMID:26067661

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).

PubMed

Musuamba, F T; Manolis, E; Holford, N; Cheung, Sya; Friberg, L E; Ogungbenro, K; Posch, M; Yates, Jwt; Berry, S; Thomas, N; Corriol-Rohou, S; Bornkamp, B; Bretz, F; Hooker, A C; Van der Graaf, P H; Standing, J F; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-07-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. © 2017 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Shielding from Solar Particle Event Exposures in Deep Space

NASA Technical Reports Server (NTRS)

Wilson, John W.; Cucinotta, F. A.; Shinn, J. L.; Simonsen, L. C.; Dubey, R. R.; Jordan, W. R.; Jones, T. D.; Chang, C. K.; Kim, M. Y.

1999-01-01

The physical composition and intensities of solar particle event exposures or sensitive astronaut tissues are examined under conditions approximating an astronaut in deep space. Response functions for conversion of particle fluence into dose and dose equivalent averaged over organ tissue, are used to establish significant fluence levels and the expected dose and dose rates of the most important events from past observations. The BRYNTRN transport code is used to evaluate the local environment experienced by sensitive tissues and used to evaluate bioresponse models developed for use in tactical nuclear warfare. The present results will help to the biophysical aspects of such exposure in the assessment of RBE and dose rate effects and their impact on design of protection systems for the astronauts. The use of polymers as shielding material in place of an equal mass of aluminum would prowide a large safety factor without increasing the vehicle mass. This safety factor is sufficient to provide adequate protection if a factor of two larger event than has ever been observed in fact occurs during the mission.

Evaluation of S-values and dose distributions for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re in seven lobes of the rat liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xie Tianwu; Liu Qian; Zaidi, Habib

2012-03-15

Purpose: Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver. Methods:more » The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor. Results: The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. {sup 166}Ho and {sup 188}Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues. Conclusions: The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for preclinical therapy studies, from tissue composition to organ morphology and activity distribution.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Otake, M.; Schull, W.J.

The occurrence of lenticular opacities among atomic bomb survivors in Hiroshima and Nagasaki detected in 1963-1964 has been examined in reference to their ..gamma.. and neutron doses. A lenticular opacity in this context implies an ophthalmoscopic and slit lamp biomicroscopic defect in the axial posterior aspect of the lens which may or may not interfere measureably with visual acuity. Several different dose-response models were fitted to the data after the effects of age at time of bombing (ATB) were examined. Some postulate the existence of a threshold(s), others do not. All models assume a ''background'' exists, that is, that somemore » number of posterior lenticular opacities are ascribable to events other than radiation exposure. Among these alternatives we can show that a simple linear ..gamma..-neutron relationship which assumes no threshold does not fit the data adequately under the T65 dosimetry, but does fit the recent Oak Ridge and Lawrence Livermore estimates. Other models which envisage quadratic terms in gamma and which may or may not assume a threshold are compatible with the data. The ''best'' fit, that is, the one with the smallest X/sup 2/ and largest tail probability, is with a ''linear gamma:linear neutron'' model which postulates a ..gamma.. threshold but no threshold for neutrons. It should be noted that the greatest difference in the dose-response models associated with the three different sets of doses involves the neutron component, as is, of course, to be expected. No effect of neutrons on the occurrence of lenticular opacities is demonstrable with either the Lawrence Livermore or Oak Ridge estimates.« less

Comparison of electromagnetic and hadronic models generated using Geant 4 with antiproton dose measured in CERN.

PubMed

Tavakoli, Mohammad Bagher; Reiazi, Reza; Mohammadi, Mohammad Mehdi; Jabbari, Keyvan

2015-01-01

After proposing the idea of antiproton cancer treatment in 1984 many experiments were launched to investigate different aspects of physical and radiobiological properties of antiproton, which came from its annihilation reactions. One of these experiments has been done at the European Organization for Nuclear Research known as CERN using the antiproton decelerator. The ultimate goal of this experiment was to assess the dosimetric and radiobiological properties of beams of antiprotons in order to estimate the suitability of antiprotons for radiotherapy. One difficulty on this way was the unavailability of antiproton beam in CERN for a long time, so the verification of Monte Carlo codes to simulate antiproton depth dose could be useful. Among available simulation codes, Geant4 provides acceptable flexibility and extensibility, which progressively lead to the development of novel Geant4 applications in research domains, especially modeling the biological effects of ionizing radiation at the sub-cellular scale. In this study, the depth dose corresponding to CERN antiproton beam energy by Geant4 recruiting all the standard physics lists currently available and benchmarked for other use cases were calculated. Overall, none of the standard physics lists was able to draw the antiproton percentage depth dose. Although, with some models our results were promising, the Bragg peak level remained as the point of concern for our study. It is concluded that the Bertini model with high precision neutron tracking (QGSP_BERT_HP) is the best to match the experimental data though it is also the slowest model to simulate events among the physics lists.

The 5-HT(2C) receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.

PubMed

Harvey-Lewis, Colin; Li, Zhaoxia; Higgins, Guy A; Fletcher, Paul J

2016-02-01

Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Metabolism and disposition of [14C]-methylcyclosiloxanes in rats.

PubMed

Domoradzki, Jeanne Y; Sushynski, Christopher M; Sushynski, Jacob M; McNett, Debra A; Van Landingham, Cynthia; Plotzke, Kathleen P

2017-10-20

Octamethylcyclotetrasiloxane (D 4 ) and decamethylcyclopentasiloxane (D 5 ) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates or monomers in the production of high molecular weight silicone polymers. The use of D 4 as a direct ingredient in personal care products has declined significantly over the past 20 years, although it may be present as a residual impurity in a variety of consumer products. D 5 is still used as an intentional ingredient in cosmetics, consumer products and in dry cleaning. Persons who may be exposed include occupational exposure for workers, and potential inhalation or dermal exposure for consumers and the general public. Because of the diverse use, especially of D 5 , and the potential for human exposure, a comprehensive program was undertaken to understand the kinetics, metabolism, enzyme induction and toxicity of D 4 and D 5 in rats following relevant routes of exposure. Physiologically based pharmacokinetic (PBPK) models utilizing these studies have been reported for D 4 and D 5 in the rat and human following dermal and inhalation exposures, with the oral uptake component of the model being limited in its description. Data from high dose oral studies in corn oil and simethicone vehicles and neat were used in the D 4 /D 5 harmonized PBPK model development. It was uncertain if the inability to adequately describe the oral uptake was due to unrealistic high doses or unique aspects of the chemistry of D 4 /D 5. Low dose studies were used to provide data to refine the description of oral uptake in the model by exploring the dose dependency and the impact of a more realistic food-like vehicle. Absorption, distribution, metabolism and elimination (ADME) of D 4 and D 5 was determined following a single low oral gavage dose of 14 C-D 4 and 14 C-D 5 at 30 and 100mg/kg body weight (bw), respectively, in a rodent liquid diet. Comparison of the low vs. high dose oral gavage administration of D 4 and D 5 demonstrated dose-dependent kinetic behavior. Data and modeling results suggest differences in metabolism between low and high dose administration indicating high dose administration results in or approaches non-linear saturated metabolism. These low dose data sets were used to refine the D 4 /D 5 multi-route harmonized PBPK model to allow for a better description of the disposition and toxicokinetics of D 4 /D 5 following oral exposure. With a refined oral uptake description, the model could be used in risk assessment to better define the internal dose of D 4 and D 5 following exposure to D 4 and D 5 via multiple routes. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Pharmacometrics in pregnancy: An unmet need.

PubMed

Ke, Alice Ban; Rostami-Hodjegan, Amin; Zhao, Ping; Unadkat, Jashvant D

2014-01-01

Pregnant women and their fetuses are orphan populations with respect to the safety and efficacy of drugs. Physiological and absorption, distribution, metabolism, and excretion (ADME) changes during pregnancy can significantly affect drug pharmacokinetics (PK) and may necessitate dose adjustment. Here, the specific aspects related to the design, execution, and analysis of clinical studies in pregnant women are discussed, underlining the unmet need for top-down pharmacometrics analyses and bottom-up modeling approaches. The modeling tools that support data analysis for the pregnancy population are reviewed, with a focus on physiologically based pharmacokinetics (PBPK) and population pharmacokinetics (POP-PK). By integrating physiological data, preclinical data, and clinical data (e.g., via POP-PK) to quantify anticipated changes in the PK of drugs during pregnancy, the PBPK approach allows extrapolation beyond the previously studied model drugs to other drugs with well-characterized ADME characteristics. Such a systems pharmacology approach can identify drugs whose PK may be altered during pregnancy, guide rational PK study design, and support dose adjustment for pregnant women.

Application of the Scoping of Options and Analyzing Risk Model (SOAR) in the Modeling of Radionuclide Movement and Dose Calculation for a Hypothetical Deep Geological Repository for Nuclear Fuel Wastes

NASA Astrophysics Data System (ADS)

Lei, S.; Osborne, P.

2016-12-01

The Scoping of Options and Analyzing Risk (SOAR) model was developed by the U.S. Nuclear Regulatory Commission staff to assist in their evaluation of potential high-level radioactive waste disposal options. It is a 1-D contaminant transport code that contains a biosphere module to calculate mass fluxes and radiation dose to humans. As part of the Canadian Nuclear Safety Commission (CNSC)'s Coordinated Assessment Program to assist with the review of proposals for deep geological repositories (DGR's) for nuclear fuel wastes, CNSC conducted a research project to find out whether SOAR can be used by CNSC staff as an independent scoping tool to assist review of proponents' submissions related to safety assessment for DGRs. In the research, SOAR was applied to the post-closure safety assessment for a hypothetical DGR in sedimentary rock, as described in the 5th Case Study report by the Nuclear Waste Management Organization (NWMO) of Canada (2011). The report contains, among others, modeling of transport and releases of radionuclides at various locations within the geosphere and the radiation dose to humans over a period of one million years. One aspect covered was 1-D modeling of various scenarios and sensitivity cases with both deterministic and probabilistic approaches using SYVAC3-CC4, which stands for Systems Variability Analysis Code (generation 3, Canadian Concept generation 4), developed by Atomic Energy of Canada Limited (Kitson et al., 2000). Radionuclide fluxes and radiation dose to the humans calculated using SOAR were compared with that from NWMO's modeling. Overall, the results from the two models were similar, although SOAR gave lower mass fluxes and peak dose, mainly due to differences in modeling the waste package configurations. Sensitivity analyses indicate that both models are most sensitive to the diffusion coefficient of the geological media. The research leads to the conclusion that SOAR is a robust, user friendly, and flexible scoping tool that CNSC staff may use for safety assessments; however, some improvements may be needed, such as including dose contributions from other pathways in addition to drinking water and being more flexible for modeling different waste package configurations.

Random Network Models to Predict the Long-Term Impact of HPV Vaccination on Genital Warts

PubMed Central

Díez-Domingo, Javier; Sánchez-Alonso, Víctor; Acedo, Luis; Villanueva-Oller, Javier

2017-01-01

The Human papillomaviruses (HPV) vaccine induces a herd immunity effect in genital warts when a large number of the population is vaccinated. This aspect should be taken into account when devising new vaccine strategies, like vaccination at older ages or male vaccination. Therefore, it is important to develop mathematical models with good predictive capacities. We devised a sexual contact network that was calibrated to simulate the Spanish epidemiology of different HPV genotypes. Through this model, we simulated the scenario that occurred in Australia in 2007, where 12–13 year-old girls were vaccinated with a three-dose schedule of a vaccine containing genotypes 6 and 11, which protect against genital warts, and also a catch-up program in women up to 26 years of age. Vaccine coverage were 73% in girls with three doses and with coverage rates decreasing with age until 52% for 20–26 year-olds. A fast 59% reduction in the genital warts diagnoses occurred in the model in the first years after the start of the program, similar to what was described in the literature. PMID:29035332

Random Network Models to Predict the Long-Term Impact of HPV Vaccination on Genital Warts.

PubMed

Díez-Domingo, Javier; Sánchez-Alonso, Víctor; Villanueva, Rafael-J; Acedo, Luis; Moraño, José-Antonio; Villanueva-Oller, Javier

2017-10-16

The Human papillomaviruses (HPV) vaccine induces a herd immunity effect in genital warts when a large number of the population is vaccinated. This aspect should be taken into account when devising new vaccine strategies, like vaccination at older ages or male vaccination. Therefore, it is important to develop mathematical models with good predictive capacities. We devised a sexual contact network that was calibrated to simulate the Spanish epidemiology of different HPV genotypes. Through this model, we simulated the scenario that occurred in Australia in 2007, where 12-13 year-old girls were vaccinated with a three-dose schedule of a vaccine containing genotypes 6 and 11, which protect against genital warts, and also a catch-up program in women up to 26 years of age. Vaccine coverage were 73 % in girls with three doses and with coverage rates decreasing with age until 52 % for 20-26 year-olds. A fast 59 % reduction in the genital warts diagnoses occurred in the model in the first years after the start of the program, similar to what was described in the literature.

Range Verification Methods in Particle Therapy: Underlying Physics and Monte Carlo Modeling

PubMed Central

Kraan, Aafke Christine

2015-01-01

Hadron therapy allows for highly conformal dose distributions and better sparing of organs-at-risk, thanks to the characteristic dose deposition as function of depth. However, the quality of hadron therapy treatments is closely connected with the ability to predict and achieve a given beam range in the patient. Currently, uncertainties in particle range lead to the employment of safety margins, at the expense of treatment quality. Much research in particle therapy is therefore aimed at developing methods to verify the particle range in patients. Non-invasive in vivo monitoring of the particle range can be performed by detecting secondary radiation, emitted from the patient as a result of nuclear interactions of charged hadrons with tissue, including β+ emitters, prompt photons, and charged fragments. The correctness of the dose delivery can be verified by comparing measured and pre-calculated distributions of the secondary particles. The reliability of Monte Carlo (MC) predictions is a key issue. Correctly modeling the production of secondaries is a non-trivial task, because it involves nuclear physics interactions at energies, where no rigorous theories exist to describe them. The goal of this review is to provide a comprehensive overview of various aspects in modeling the physics processes for range verification with secondary particles produced in proton, carbon, and heavier ion irradiation. We discuss electromagnetic and nuclear interactions of charged hadrons in matter, which is followed by a summary of some widely used MC codes in hadron therapy. Then, we describe selected examples of how these codes have been validated and used in three range verification techniques: PET, prompt gamma, and charged particle detection. We include research studies and clinically applied methods. For each of the techniques, we point out advantages and disadvantages, as well as clinical challenges still to be addressed, focusing on MC simulation aspects. PMID:26217586

Sci—Fri PM: Topics — 06: The influence of regional dose sensitivity on salivary loss and recovery in the parotid gland

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, H; BC Cancer Agency, Surrey, B.C.; BC Cancer Agency, Vancouver, B.C.

Purpose: The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC 2010) survey of radiation dose-volume effects on salivary gland function has called for improved understanding of intragland dose sensitivity and the effectiveness of partial sparing in salivary glands. Regional dose susceptibility of sagittally- and coronally-sub-segmented parotid gland has been studied. Specifically, we examine whether individual consideration of sub-segments leads to improved prediction of xerostomia compared with whole parotid mean dose. Methods: Data from 102 patients treated for head-and-neck cancers at the BC Cancer Agency were used in this study. Whole mouth stimulated saliva was collected before (baseline), threemore » months, and one year after cessation of radiotherapy. Organ volumes were contoured using treatment planning CT images and sub-segmented into regional portions. Both non-parametric (local regression) and parametric (mean dose exponential fitting) methods were employed. A bootstrap technique was used for reliability estimation and cross-comparison. Results: Salivary loss is described well using non-parametric and mean dose models. Parametric fits suggest a significant distinction in dose response between medial-lateral and anterior-posterior aspects of the parotid (p<0.01). Least-squares and least-median squares estimates differ significantly (p<0.00001), indicating fits may be skewed by noise or outliers. Salivary recovery exhibits a weakly arched dose response: the highest recovery is seen at intermediate doses. Conclusions: Salivary function loss is strongly dose dependent. In contrast no useful dose dependence was observed for function recovery. Regional dose dependence was observed, but may have resulted from a bias in dose distributions.« less

Re-assessing the relationship between sporozoite dose and incubation period in Plasmodium vivax malaria: a systematic re-analysis.

PubMed

Lover, Andrew A; Coker, Richard J

2014-05-01

Infections with the malaria parasite Plasmodium vivax are noteworthy for potentially very long incubation periods (6-9 months), which present a major barrier to disease elimination. Increased sporozoite challenge has been reported to be associated with both shorter incubation and pre-patent periods in a range of human challenge studies. However, this evidence base has scant empirical foundation, as these historical analyses were limited by available analytic methods, and provides no quantitative estimates of effect size. Following a comprehensive literature search, we re-analysed all identified studies using survival and/or logistic models plus contingency tables. We have found very weak evidence for dose-dependence at entomologically plausible inocula levels. These results strongly suggest that sporozoite dosage is not an important driver of long-latency. Evidence presented suggests that parasite strain and vector species have quantitatively greater impacts, and the potential existence of a dose threshold for human dose-response to sporozoites. Greater consideration of the complex interplay between these aspects of vectors and parasites are important for human challenge experiments, vaccine trials, and epidemiology towards global malaria elimination.

Comparison of image quality, myocardial perfusion, and LV function between standard imaging and single-injection ultra-low-dose imaging using a high-efficiency SPECT camera: the MILLISIEVERT study

PubMed Central

Einstein, Andrew J.; Blankstein, Ron; Andrews, Howard; Fish, Mathews; Padgett, Richard; Hayes, Sean W.; Friedman, John D.; Qureshi, Mehreen; Rakotoarivelo, Harivony; Slomka, Piotr; Nakazato, Ryo; Bokhari, Sabahat; Di Carli, Marcello; Berman, Daniel S.

2015-01-01

SPECT myocardial perfusion imaging (MPI) plays a central role in coronary artery disease diagnosis; but concerns exist regarding its radiation burden. Compared to standard Anger-SPECT (A-SPECT) cameras, new high-efficiency (HE) cameras with specialized collimators and solid-state cadmium-zinc-telluride detectors offer potential to maintain image quality (IQ), while reducing administered activity and thus radiation dose to patients. No previous study has compared IQ, interpretation, total perfusion deficit (TPD), or ejection fraction (EF) in patients receiving both ultra-low-dose (ULD) imaging on a HE-SPECT camera and standard low-dose (SLD) A-SPECT imaging. Methods We compared ULD-HE-SPECT to SLD-A-SPECT imaging by dividing the rest dose in 101 patients at 3 sites scheduled to undergo clinical A-SPECT MPI using a same day rest/stress Tc-99m protocol. Patients received HE-SPECT imaging following an initial ~130 MBq (3.5mCi) dose, and SLD-A-SPECT imaging following the remainder of the planned dose. Images were scored visually by 2 blinded readers for IQ and summed rest score (SRS). TPD and EF were assessed quantitatively. Results Mean activity was 134 MBq (3.62 mCi) for ULD-HE-SPECT (effective dose 1.15 mSv) and 278 MBq (7.50 mCi, 2.39 mSv) for SLD-A-SPECT. Overall IQ was superior for ULD-HE-SPECT (p<0.0001), with twice as many studies graded excellent quality. Extracardiac activity and overall perfusion assessment were similar. Between-method correlations were high for SRS (r=0.87), TPD (r=0.91), and EF (r=0.88). Conclusion ULD-HE-SPECT rest imaging correlates highly with SLD-A-SPECT. It has improved image quality, comparable extracardiac activity, and achieves radiation dose reduction to 1 mSv for a single injection. PMID:24982439

Affective preclinical modeling of psychiatric disorders: taking imbalanced primal emotional feelings of animals seriously in our search for novel antidepressants

PubMed Central

Panksepp, Jaak

2015-01-01

Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong—to the extent that the rewarding and punishing aspects of emotion circuit arousals reflect positive and negative affective states. During the past decade, the use of such affective neuroscience-based animal modeling has yielded three novel antidepressants (i) via the alleviation of psychic pain with low doses of buprenorphine; (ii) via the amplification of enthusiasm by direct stimulation of the medial forebrain bundle); and (iii) via the facilitation of the capacity for social joy with play facilitators such as rapastinel (GLYX13). All have progressed to successful human testing. For optimal progress, it may be useful for preclinical investigators to focus on the evolved affective foundations of psychiatrically relevant brain emotional disorders for optimal animal modeling. PMID:26869838

Preliminary post-emplacement safety analysis of the subseabed disposal of high-level nuclear waste

NASA Astrophysics Data System (ADS)

Kaplan, M. F.; Koplik, C. M.; Klett, R. D.

1984-09-01

The radiological hazard from the disposal of high-level nuclear waste within the deep ocean sediments is evaluated, on a preliminary basis, for locations in the central North Pacific and in the northwestern Atlantic. Radio-nuclide transport in the sediment and water column and by marine organisms is considered. Peak doses to an individual are approximately five orders of magnitude below background levels for both sites. Sensitivity analyses for most aspects of the post-emplacement systems models are included.

Technical aspects of the integration of three-dimensional treatment planning dose parameters (GEC-ESTRO Working Group) into pre-implant planning for LDR gynecological interstitial brachytherapy.

PubMed

Chi, A; Gao, M; Nguyen, N P; Albuquerque, K

2009-06-01

This study investigates the technical feasibility of pre-implant image-based treatment planning for LDR GYN interstitial brachytherapy(IB) based on the GEC-ESTRO guidelines. Initially, a virtual plan is generated based on the prescription dose and GEC-ESTRO defined OAR dose constraints with a pre-implant CT. After the actual implant, a regular diagnostic CT was obtained and fused with our pre-implant scan/initial treatment plan in our planning software. The Flexi-needle position changes, and treatment plan modifications were made if needed. Dose values were normalized to equivalent doses in 2 Gy fractions (LQED 2 Gy) derived from the linear-quadratic model with alpha/beta of 3 for late responding tissues and alpha/beta of 10 for early responding tissues. D(90) to the CTV, which was gross tumor (GTV) at the time of brachytherapy with a margin to count for microscopic disease, was 84.7 +/- 4.9% of the prescribed dose. The OAR doses were evaluated by D(2cc) (EBRT+IB). Mean D(2cc) values (LQED(2Gy)) for the rectum, bladder, sigmoid, and small bowel were the following: 63.7 +/- 8.4 Gy, 61.2 +/- 6.9 Gy, 48.0 +/- 3.5 Gy, and 49.9 +/- 4.2 Gy. This study confirms the feasibility of applying the GEC-ESTRO recommended dose parameters in pre-implant CT-based treatment planning in GYN IB. In the process, this pre-implant technique also demonstrates a good approximation of the target volume dose coverage, and doses to the OARs.

Benchmarking of MCNP for calculating dose rates at an interim storage facility for nuclear waste.

PubMed

Heuel-Fabianek, Burkhard; Hille, Ralf

2005-01-01

During the operation of research facilities at Research Centre Jülich, Germany, nuclear waste is stored in drums and other vessels in an interim storage building on-site, which has a concrete shielding at the side walls. Owing to the lack of a well-defined source, measured gamma spectra were unfolded to determine the photon flux on the surface of the containers. The dose rate simulation, including the effects of skyshine, using the Monte Carlo transport code MCNP is compared with the measured dosimetric data at some locations in the vicinity of the interim storage building. The MCNP data for direct radiation confirm the data calculated using a point-kernel method. However, a comparison of the modelled dose rates for direct radiation and skyshine with the measured data demonstrate the need for a more precise definition of the source. Both the measured and the modelled dose rates verified the fact that the legal limits (<1 mSv a(-1)) are met in the area outside the perimeter fence of the storage building to which members of the public have access. Using container surface data (gamma spectra) to define the source may be a useful tool for practical calculations and additionally for benchmarking of computer codes if the discussed critical aspects with respect to the source can be addressed adequately.

Using the benchmark dose (BMD) methodology to determine an appropriate reduction of certain ingredients in food products.

PubMed

Bi, Jian

2010-01-01

As the desire to promote health increases, reductions of certain ingredients, for example, sodium, sugar, and fat in food products, are widely requested. However, the reduction is not risk free in sensory and marketing aspects. Over reduction may change the taste and influence the flavor of a product and lead to a decrease in consumer's overall liking or purchase intent for the product. This article uses the benchmark dose (BMD) methodology to determine an appropriate reduction. Calculations of BMD and one-sided lower confidence limit of BMD are illustrated. The article also discusses how to calculate BMD and BMDL for over dispersed binary data in replicated testing based on a corrected beta-binomial model. USEPA Benchmark Dose Software (BMDS) were used and S-Plus programs were developed. The method discussed in the article is originally used to determine an appropriate reduction of certain ingredients, for example, sodium, sugar, and fat in food products, considering both health reason and sensory or marketing risk.

A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials

PubMed Central

2011-01-01

Background The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathological reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following intraperitoneal injection. This asbestos-like behaviour of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures. Results Carbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized reference materials and compared with three commercial samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/ml (0.38 μg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphology of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers. Conclusions Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation. PMID:21592387

Temporal aspects of tumorigenic response to individual and mixed carcinogens. [Response of mouse skin to benzo(a)pyrene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert, R.E.; Burns, F.J.

1976-02-01

Results are reported from experiments that involved either single or multiple doses of benzo(a)pyrene in mouse skin followed by prolonged observation. Preliminary results indicate linearity in dose and time and no evidence of recovery or enhancement for multiple doses of initiator given for extended periods of time. (auth)

SU-F-J-178: A Computer Simulation Model Observer for Task-Based Image Quality Assessment in Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dolly, S; Mutic, S; Anastasio, M

Purpose: Traditionally, image quality in radiation therapy is assessed subjectively or by utilizing physically-based metrics. Some model observers exist for task-based medical image quality assessment, but almost exclusively for diagnostic imaging tasks. As opposed to disease diagnosis, the task for image observers in radiation therapy is to utilize the available images to design and deliver a radiation dose which maximizes patient disease control while minimizing normal tissue damage. The purpose of this study was to design and implement a new computer simulation model observer to enable task-based image quality assessment in radiation therapy. Methods: A modular computer simulation framework wasmore » developed to resemble the radiotherapy observer by simulating an end-to-end radiation therapy treatment. Given images and the ground-truth organ boundaries from a numerical phantom as inputs, the framework simulates an external beam radiation therapy treatment and quantifies patient treatment outcomes using the previously defined therapeutic operating characteristic (TOC) curve. As a preliminary demonstration, TOC curves were calculated for various CT acquisition and reconstruction parameters, with the goal of assessing and optimizing simulation CT image quality for radiation therapy. Sources of randomness and bias within the system were analyzed. Results: The relationship between CT imaging dose and patient treatment outcome was objectively quantified in terms of a singular value, the area under the TOC (AUTOC) curve. The AUTOC decreases more rapidly for low-dose imaging protocols. AUTOC variation introduced by the dose optimization algorithm was approximately 0.02%, at the 95% confidence interval. Conclusion: A model observer has been developed and implemented to assess image quality based on radiation therapy treatment efficacy. It enables objective determination of appropriate imaging parameter values (e.g. imaging dose). Framework flexibility allows for incorporation of additional modules to include any aspect of the treatment process, and therefore has great potential for both assessment and optimization within radiation therapy.« less

A strategy to optimize CT pediatric dose with a visual discrimination model

NASA Astrophysics Data System (ADS)

Gutierrez, Daniel; Gudinchet, François; Alamo-Maestre, Leonor T.; Bochud, François O.; Verdun, Francis R.

2008-03-01

Technological developments of computed tomography (CT) have led to a drastic increase of its clinical utilization, creating concerns about patient exposure. To better control dose to patients, we propose a methodology to find an objective compromise between dose and image quality by means of a visual discrimination model. A GE LightSpeed-Ultra scanner was used to perform the acquisitions. A QRM 3D low contrast resolution phantom (QRM - Germany) was scanned using CTDI vol values in the range of 1.7 to 103 mGy. Raw data obtained with the highest CTDI vol were afterwards processed to simulate dose reductions by white noise addition. Noise realism of the simulations was verified by comparing normalized noise power spectra aspect and amplitudes (NNPS) and standard deviation measurements. Patient images were acquired using the Diagnostic Reference Levels (DRL) proposed in Switzerland. Noise reduction was then simulated, as for the QRM phantom, to obtain five different CTDI vol levels, down to 3.0 mGy. Image quality of phantom images was assessed with the Sarnoff JNDmetrix visual discrimination model and compared to an assessment made by means of the ROC methodology, taken as a reference. For patient images a similar approach was taken but using as reference the Visual Grading Analysis (VGA) method. A relationship between Sarnoff JNDmetrix and ROC results was established for low contrast detection in phantom images, demonstrating that the Sarnoff JNDmetrix can be used for qualification of images with highly correlated noise. Patient image qualification showed a threshold of conspicuity loss only for children over 35 kg.

Estimated ultraviolet radiation doses in wetlands in six national parks

USGS Publications Warehouse

Diamond, S.A.; Trenham, P.C.; Adams, Michael J.; Hossack, B.R.; Knapp, R.A.; Stark, L.; Bradford, D.; Corn, P.S.; Czarnowski, K.; Brooks, P.D.; Fagre, D.B.; Breen, B.; Dentenbeck, N.E.; Tonnessen, K.

2005-01-01

Ultraviolet-B radiation (UV-B, 280–320-nm wavelengths) doses were estimated for 1024 wetlands in six national parks: Acadia (Acadia), Glacier (Glacier), Great Smoky Mountains (Smoky), Olympic (Olympic), Rocky Mountain (Rocky), and Sequoia/Kings Canyon (Sequoia). Estimates were made using ground-based UV-B data (Brewer spectrophotometers), solar radiation models, GIS tools, field characterization of vegetative features, and quantification of DOC concentration and spectral absorbance. UV-B dose estimates were made for the summer solstice, at a depth of 1 cm in each wetland. The mean dose across all wetlands and parks was 19.3 W-h m−2 (range of 3.4–32.1 W-h m−2). The mean dose was lowest in Acadia (13.7 W-h m−2) and highest in Rocky (24.4 W-h m−2). Doses were significantly different among all parks. These wetland doses correspond to UV-B flux of 125.0 μW cm−2 (range 21.4–194.7 μW cm−2) based on a day length, averaged among all parks, of 15.5 h. Dissolved organic carbon (DOC), a key determinant of water-column UV-B flux, ranged from 0.6 (analytical detection limit) to 36.7 mg C L−1 over all wetlands and parks, and reduced potential maximal UV-B doses at 1-cm depth by 1%–87 %. DOC concentration, as well as its effect on dose, was lowest in Sequoia and highest in Acadia (DOC was equivalent in Acadia, Glacier, and Rocky). Landscape reduction of potential maximal UV-B doses ranged from zero to 77% and was lowest in Sequoia. These regional differences in UV-B wetland dose illustrate the importance of considering all aspects of exposure in evaluating the potential impact of UV-B on aquatic organisms.

Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies.

PubMed

Kesisoglou, Filippos; Chung, John; van Asperen, Judith; Heimbach, Tycho

2016-09-01

In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Web-based training course for evaluating radiological dose assessment in NRC's license termination process.

PubMed

Lepoire, D; Richmond, P; Cheng, J-J; Kamboj, S; Arnish, J; Chen, S Y; Barr, C; McKenney, C

2008-08-01

As part of the requirement for terminating the licenses of nuclear power plants or other nuclear facilities, license termination plans or decommissioning plans are submitted by the licensee to the U.S. Nuclear Regulatory Commission (NRC) for review and approval. Decommissioning plans generally refer to the decommissioning of nonreactor facilities, while license termination plans specifically refer to the decommissioning of nuclear reactor facilities. To provide a uniform and consistent review of dose modeling aspects of these plans and to address NRC-wide knowledge management issues, the NRC, in 2006, commissioned Argonne National Laboratory to develop a Web-based training course on reviewing radiological dose assessments for license termination. The course, which had first been developed in 2005 to target specific aspects of the review processes for license termination plans and decommissioning plans, evolved from a live classroom course into a Web-based training course in 2006. The objective of the Web-based training course is to train NRC staff members (who have various relevant job functions and are located at headquarters, regional offices, and site locations) to conduct an effective review of dose modeling in accordance with the latest NRC guidance, including NUREG-1757, Volumes 1 and 2. The exact size of the staff population who will receive the training has not yet been accurately determined but will depend on various factors such as the decommissioning activities at the NRC. This Web-based training course is designed to give NRC staff members modern, flexible access to training. To this end, the course is divided into 16 modules: 9 core modules that deal with basic topics, and 7 advanced modules that deal with complex issues or job-specific topics. The core and advanced modules are tailored to various NRC staff members with different job functions. The Web-based system uses the commercially available software Articulate, which incorporates audio, video, and animation in slide presentations and has glossary, document search, and Internet connectivity features. The training course has been implemented on an NRC system that allows staff members to register, select courses, track records, and self-administer quizzes.

The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

PubMed

MacVittie, Thomas J; Farese, Ann M; Jackson, William

2015-11-01

Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total body irradiation (TBI) with 250 kVp or 2 MeV x radiation, Co gamma radiation and reactor- and nuclear weapon-derived mixed gamma: neutron-radiation, delivered at various dose rates from a total body, bilateral, rotational, or unilateral exposure aspect. The DRRs established by a probit analysis vs. linear dose relationship were characterized by two main parameters or dependent variables: a slope and LD50/30. Respective LD50/30 values for studies that used 250 kVp x radiation (five primary studies combined, n = 338), 2 MeV x radiation, Co gamma radiation, and steady-state reactor-derived mixed gamma:neutron radiation for total body uniform exposures were 521 rad [498, 542], 671 rad [632, 715], 644 rad [613, 678], and 385 rad [357, 413]. The respective slopes were steep and ranged from 0.738 to 1.316. The DRR, LD50/30 values and slopes were also determined for total body, non-uniform, unilateral, pulse-rate exposures of mixed gamma:neutron radiation derived at reactor and nuclear weapon detonations. The LD50/30 values were, respectively, 395 rad [337, 432] and 412 rad [359, 460]. Secondary data sets of limited studies that did not describe a DRR were used to support the mid-to-high lethal dose range for the H-ARS and the threshold dose range for the concurrent acute GI ARS. The available evidence provided a reliable and extensive database that characterized the DRR for the H-ARS in young rhesus macaques exposed to 250 kVp uniform total body x radiation without the benefit of medical management. A less substantial but consistent database demonstrated the DRR for total body exposure of differing radiation quality, dose rate and non-uniform exposure. The DRR for the H-ARS is characterized by steep slopes and relative LD50/30 values that reflect the radiation quality, exposure aspect, and dose rate over a range in time from 1954-2012.

Modeling of Radiotherapy Linac Source Terms Using ARCHER Monte Carlo Code: Performance Comparison for GPU and MIC Parallel Computing Devices

NASA Astrophysics Data System (ADS)

Lin, Hui; Liu, Tianyu; Su, Lin; Bednarz, Bryan; Caracappa, Peter; Xu, X. George

2017-09-01

Monte Carlo (MC) simulation is well recognized as the most accurate method for radiation dose calculations. For radiotherapy applications, accurate modelling of the source term, i.e. the clinical linear accelerator is critical to the simulation. The purpose of this paper is to perform source modelling and examine the accuracy and performance of the models on Intel Many Integrated Core coprocessors (aka Xeon Phi) and Nvidia GPU using ARCHER and explore the potential optimization methods. Phase Space-based source modelling for has been implemented. Good agreements were found in a tomotherapy prostate patient case and a TrueBeam breast case. From the aspect of performance, the whole simulation for prostate plan and breast plan cost about 173s and 73s with 1% statistical error.

Cone Beam CT vs. Fan Beam CT: A Comparison of Image Quality and Dose Delivered Between Two Differing CT Imaging Modalities.

PubMed

Lechuga, Lawrence; Weidlich, Georg A

2016-09-12

A comparison of image quality and dose delivered between two differing computed tomography (CT) imaging modalities-fan beam and cone beam-was performed. A literature review of quantitative analyses for various image quality aspects such as uniformity, signal-to-noise ratio, artifact presence, spatial resolution, modulation transfer function (MTF), and low contrast resolution was generated. With these aspects quantified, cone beam computed tomography (CBCT) shows a superior spatial resolution to that of fan beam, while fan beam shows a greater ability to produce clear and anatomically correct images with better soft tissue differentiation. The results indicate that fan beam CT produces superior images to that of on-board imaging (OBI) cone beam CT systems, while providing a considerably less dose to the patient.

Cone Beam CT vs. Fan Beam CT: A Comparison of Image Quality and Dose Delivered Between Two Differing CT Imaging Modalities

PubMed Central

Weidlich, Georg A.

2016-01-01

A comparison of image quality and dose delivered between two differing computed tomography (CT) imaging modalities—fan beam and cone beam—was performed. A literature review of quantitative analyses for various image quality aspects such as uniformity, signal-to-noise ratio, artifact presence, spatial resolution, modulation transfer function (MTF), and low contrast resolution was generated. With these aspects quantified, cone beam computed tomography (CBCT) shows a superior spatial resolution to that of fan beam, while fan beam shows a greater ability to produce clear and anatomically correct images with better soft tissue differentiation. The results indicate that fan beam CT produces superior images to that of on-board imaging (OBI) cone beam CT systems, while providing a considerably less dose to the patient. PMID:27752404

Radiation Dose-Rate Effects on Gene Expression in a Mouse Biodosimetry Model

PubMed Central

Paul, Sunirmal; Smilenov, Lubomir B.; Elliston, Carl D.; Amundson, Sally A.

2015-01-01

In the event of a nuclear accident or radiological terrorist attack, there will be a pressing need for biodosimetry to triage a large, potentially exposed population and to assign individuals to appropriate treatment. Exposures from fallout are likely, resulting in protracted dose delivery that would, in turn, impact the extent of injury. Biodosimetry approaches that can distinguish such low-dose-rate (LDR) exposures from acute exposures have not yet been developed. In this study, we used the C57BL/6 mouse model in an initial investigation of the impact of low-dose-rate delivery on the transcriptomic response in blood. While a large number of the same genes responded to LDR and acute radiation exposures, for many genes the magnitude of response was lower after LDR exposures. Some genes, however, were differentially expressed (P < 0.001, false discovery rate < 5%) in mice exposed to LDR compared with mice exposed to acute radiation. We identified a set of 164 genes that correctly classified 97% of the samples in this experiment as exposed to acute or LDR radiation using a support vector machine algorithm. Gene expression is a promising approach to radiation biodosimetry, enhanced greatly by this first demonstration of its potential for distinguishing between acute and LDR exposures. Further development of this aspect of radiation biodosimetry, either as part of a complete gene expression biodosimetry test or as an adjunct to other methods, could provide vital triage information in a mass radiological casualty event. PMID:26114327

Biology of high single doses of IORT: RBE, 5 R's, and other biological aspects.

PubMed

Herskind, Carsten; Ma, Lin; Liu, Qi; Zhang, Bo; Schneider, Frank; Veldwijk, Marlon R; Wenz, Frederik

2017-01-19

Intraoperative radiotherapy differs from conventional, fractionated radiotherapy in several aspects that may influence its biological effect. The radiation quality influences the relative biologic effectiveness (RBE), and the role of the five R's of radiotherapy (reassortment, repair, reoxygenation, repopulation, radiosensitivity) is different. Furthermore, putative special biological effects and the small volume receiving a high single dose may be important. The present review focuses on RBE, repair, and repopulation, and gives an overview of the other factors that potentially contribute to the efficacy. The increased RBE should be taken into account for low-energy X-rays while evidence of RBE < 1 for high-energy electrons at higher doses is presented. Various evidence supports a hypothesis that saturation of the primary DNA double-strand break (DSB) repair mechanisms leads to increasing use of an error-prone backup repair system leading to genomic instability that may contribute to inactivate tumour cells at high single doses. Furthermore, the elimination of repopulation of residual tumour cells in the tumour bed implies that some patients are likely to have very few residual tumour cells which may be cured even by low doses to the tumour bed. The highly localised dose distribution of IORT has the potential to inactivate tumour cells while sparing normal tissue by minimising the volume exposed to high doses. Whether special effects of high single doses also contribute to the efficacy will require further experimental and clinical studies.

A critical point: the problems associated with the variety of criteria to quantify the antioxidant capacity.

PubMed

Prieto, M A; Vázquez, J A; Murado, M A

2014-06-18

The oxidant action implies interfering in an autocatalytic process, in which no less than five chemical species are present (oxygen, oxidizable substrate, radicals, antioxidants, and oxidation products); furthermore, reactions of first and second order can take place, and interactions can occur, at several levels of the process. The common and incorrect practice is to use the single-time dose-response of an established antioxidant as a calibration curve to compute the equivalent antioxidant capacity of a sample, which is only tested at one single time-dose, assuming too many false aspects as true. Its use is unreasonable, given the availability of computational applications and instrumental equipment that, combined, provide the adequate tools to work with different variables in nonlinear models. The evaluation of the dose-time dependency of the response of the β-carotene method as a case study, using the combination of strong quantification procedures and a high amount of results with lower experimental error (applying microplate readers), reveals the lack of meaning of single-time criteria. Also, it demonstrates that, in most of the reactions, the time-dependent response in the oxidation process is inherently nonlinear and should not be standardized at one single time, because it would lead to unreliable results, hiding the real aspects of the response. In food matrices, the application of single-time criteria causes deficiencies in the control of the antioxidant content. Therefore, it is logical that, in the past decade, researchers have claimed consensus to increase the determination and effectiveness of antioxidant responses.

Monte Carlo dose distribution calculation at nuclear level for Auger-emitting radionuclide energies.

PubMed

Di Maria, S; Belchior, A; Romanets, Y; Paulo, A; Vaz, P

2018-05-01

The distribution of radiopharmaceuticals in tumor cells represents a fundamental aspect for a successful molecular targeted radiotherapy. It was largely demonstrated at microscopic level that only a fraction of cells in tumoral tissues incorporate the radiolabel. In addition, the distribution of the radionuclides at sub-cellular level, namely inside each nucleus, should also be investigated for accurate dosimetry estimation. The most used method to perform cellular dosimetry is the MIRD one, where S-values are able to estimate cellular absorbed doses for several electron energies, nucleus diameters, and considering homogeneous source distributions. However the radionuclide distribution inside nuclei can be also highly non-homogeneous. The aim of this study is to show in what extent a non-accurate cellular dosimetry could lead to misinterpretations of surviving cell fraction vs dose relationship; in this context, a dosimetric case study with 99m Tc is also presented. The state-of-art MCNP6 Monte Carlo simulation was used in order to model cell structures both in MIRD geometry (MG) and MIRD modified geometries (MMG), where also entire mitotic chromosome volumes were considered (each structure was modeled as liquid water material). In order to simulate a wide energy range of Auger emitting radionuclides, four mono energetic electron emissions were considered, namely 213eV, 6keV, 11keV and 20keV. A dosimetric calculation for 99m Tc undergoing inhomogeneous nuclear internalization was also performed. After a successful validation step between MIRD and our computed S-values for three Auger-emitting radionuclides ( 99m Tc, 125 I and 64 Cu), absorbed dose results showed that the standard MG could differ from the MMG from one to three orders of magnitude. These results were also confirmed by considering the 99m Tc spectrum emission (Auger and internal conversion electrons). Moreover, considering an inhomogeneous radionuclide distribution, the average electron energy that maximizes the absorbed dose was found to be different for MG and MMG. The modeling of realistic radionuclide localization inside cells, including a inhomogeneous nuclear distribution, revealed that i) a strong bias in surviving cell fraction vs dose relationships (taking to different radiobiological models) can arise; ii) the alternative models might contribute to a more accurate prediction of the radiobiological effects inherent to more specific molecular targeted radiotherapy strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

ICRP Publication 137: Occupational Intakes of Radionuclides: Part 3.

PubMed

Paquet, F; Bailey, M R; Leggett, R W; Lipsztein, J; Marsh, J; Fell, T P; Smith, T; Nosske, D; Eckerman, K F; Berkovski, V; Blanchardon, E; Gregoratto, D; Harrison, J D

2017-12-01

The 2007 Recommendations of the International Commission on Radiological Protection (ICRP, 2007) introduced changes that affect the calculation of effective dose, and implied a revision of the dose coefficients for internal exposure, published previously in the Publication 30 series (ICRP, 1979, 1980, 1981, 1988) and Publication 68 (ICRP, 1994). In addition, new data are now available that support an update of the radionuclide-specific information given in Publications 54 and 78 (ICRP, 1988a, 1997b) for the design of monitoring programmes and retrospective assessment of occupational internal doses. Provision of new biokinetic models, dose coefficients, monitoring methods, and bioassay data was performed by Committee 2, Task Group 21 on Internal Dosimetry, and Task Group 4 on Dose Calculations. A new series, the Occupational Intakes of Radionuclides (OIR) series, will replace the Publication 30 series and Publications 54, 68, and 78. OIR Part 1 has been issued (ICRP, 2015), and describes the assessment of internal occupational exposure to radionuclides, biokinetic and dosimetric models, methods of individual and workplace monitoring, and general aspects of retrospective dose assessment. OIR Part 2 (ICRP, 2016), this current publication and upcoming publications in the OIR series (Parts 4 and 5) provide data on individual elements and their radioisotopes, including information on chemical forms encountered in the workplace; a list of principal radioisotopes and their physical half-lives and decay modes; the parameter values of the reference biokinetic model; and data on monitoring techniques for the radioisotopes encountered most commonly in workplaces. Reviews of data on inhalation, ingestion, and systemic biokinetics are also provided for most of the elements. Dosimetric data provided in the printed publications of the OIR series include tables of committed effective dose per intake (Sv Bq−1 intake) for inhalation and ingestion, tables of committed effective dose per content (Sv Bq−1 measurement) for inhalation, and graphs of retention and excretion data per Bq intake for inhalation. These data are provided for all absorption types and for the most common isotope(s) of each element. The electronic annex that accompanies the OIR series of publications contains a comprehensive set of committed effective and equivalent dose coefficients, committed effective dose per content functions, and reference bioassay functions. Data are provided for inhalation, ingestion, and direct input to blood. This third publication in the series provides the above data for the following elements: ruthenium (Ru), antimony (Sb), tellurium (Te), iodine (I), caesium (Cs), barium (Ba), iridium (Ir), lead (Pb), bismuth (Bi), polonium (Po), radon (Rn), radium (Ra), thorium (Th), and uranium (U).

ICRP Publication 134: Occupational Intakes of Radionuclides: Part 2.

PubMed

Paquet, F; Bailey, M R; Leggett, R W; Lipsztein, J; Fell, T P; Smith, T; Nosske, D; Eckerman, K F; Berkovski, V; Ansoborlo, E; Giussani, A; Bolch, W E; Harrison, J D

2016-12-01

The 2007 Recommendations of the International Commission on Radiological Protection (ICRP, 2007) introduced changes that affect the calculation of effective dose, and implied a revision of the dose coefficients for internal exposure, published previously in the Publication 30 series (ICRP, 1979, 1980, 1981, 1988b) and Publication 68 (ICRP, 1994b). In addition, new data are available that support an update of the radionuclide-specific information given in Publications 54 and 78 (ICRP, 1988a, 1997b) for the design of monitoring programmes and retrospective assessment of occupational internal doses. Provision of new biokinetic models, dose coefficients, monitoring methods, and bioassay data was performed by Committee 2, Task Group 21 on Internal Dosimetry, and Task Group 4 on Dose Calculations. A new series, the Occupational Intakes of Radionuclides (OIR) series, will replace the Publication 30 series and Publications 54, 68, and 78. Part 1 of the OIR series has been issued (ICRP, 2015), and describes the assessment of internal occupational exposure to radionuclides, biokinetic and dosimetric models, methods of individual and workplace monitoring, and general aspects of retrospective dose assessment. The following publications in the OIR series (Parts 2–5) will provide data on individual elements and their radioisotopes, including information on chemical forms encountered in the workplace; a list of principal radioisotopes and their physical half-lives and decay modes; the parameter values of the reference biokinetic model; and data on monitoring techniques for the radioisotopes encountered most commonly in workplaces. Reviews of data on inhalation, ingestion, and systemic biokinetics are also provided for most of the elements. Dosimetric data provided in the printed publications of the OIR series include tables of committed effective dose per intake (Sv per Bq intake) for inhalation and ingestion, tables of committed effective dose per content (Sv per Bq measurement) for inhalation, and graphs of retention and excretion data per Bq intake for inhalation. These data are provided for all absorption types and for the most common isotope(s) of each element. The electronic annex that accompanies the OIR series of reports contains a comprehensive set of committed effective and equivalent dose coefficients, committed effective dose per content functions, and reference bioassay functions. Data are provided for inhalation, ingestion, and direct input to blood. The present publication provides the above data for the following elements: hydrogen (H), carbon (C), phosphorus (P), sulphur (S), calcium (Ca), iron (Fe), cobalt (Co), zinc (Zn), strontium (Sr), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), and technetium (Tc).

Mouse bioassay for palytoxin. Specific symptoms and dose-response against dose-death time relationships.

PubMed

Riobó, P; Paz, B; Franco, J M; Vázquez, J A; Murado, M A; Cacho, E

2008-08-01

Nowadays, a variety of protocols are applied to quantitate palytoxin. However, there is not desirable agreement among them, the confidence intervals of the basic toxicological parameters are too wide and the formal descriptions lack the necessary generality to establish comparisons. Currently, the mouse bioassay is the most accepted one to categorize marine toxins and it must constitute the reference for other methods. In the present work, the mouse bioassay for palytoxin is deeply analyzed and carefully described showing the initial symptoms of injected mice which are presented here in the first time. These symptoms clearly differ from the more common marine toxins described up to now. Regarding to the toxicological aspects two considerations are taking into account: (i) the empiric models based in the dose-death time relationships cause serious ambiguities and (ii) the traditional moving average method contains in its regular use any inaccuracy elements. Herein is demonstrated that the logistic equation and the accumulative function of Weibull's distribution (with the modifications proposed) generate satisfactory toxicological descriptions in all the respects.

Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

PubMed

Ding, Kuan-Fu; Petricoin, Emanuel F; Finlay, Darren; Yin, Hongwei; Hendricks, William P D; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar; LoRusso, Patricia M; Vuori, Kristiina; Trent, Jeffrey M; Schork, Nicholas J

2018-01-12

Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC 50 ). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC 50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC 50 -based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.

Aspects of operational radiation protection during dismantling of nuclear facilities relevant for the estimation of internal doses.

PubMed

Labarta, T

2007-01-01

Operational radiation protection of workers during the dismantling of nuclear facilities is based on the same radiation protection principles as that applied in its exploitation period with the objective of ensuring proper implementation of the as-low-as-reasonably-achievable (ALARA) principle. These principles are: prior determination of the nature and magnitude of radiological risk; classification of workplaces and workers depending on the risks; implementation of control measures; monitoring of zones and working conditions, including, if necessary, individual monitoring. From the experiences and the lessons learned during the dismantling processes carried out in Spain, several important aspects in the practical implementation of these principles that directly influence and ensure an adequate prevention of exposures and the estimation of internal doses are pointed out, with special emphasis on the estimation of internal doses due to transuranic intakes.

Doses per vaccine vial container: An understated and underestimated driver of performance that needs more evidence.

PubMed

Heaton, Alexis; Krudwig, Kirstin; Lorenson, Tina; Burgess, Craig; Cunningham, Andrew; Steinglass, Robert

2017-04-19

The widespread use of multidose vaccine containers in low and middle income countries' immunization programs is assumed to have multiple benefits and efficiencies for health systems, yet the broader impacts on immunization coverage, costs, and safety are not well understood. To document what is known on this topic, how it has been studied, and confirm the gaps in evidence that allow us to assess the complex system interactions, the authors undertook a review of published literature that explored the relationship between doses per container and immunization systems. The relationships examined in this study are organized within a systems framework consisting of operational costs, timely coverage, safety, product costs/wastage, and policy/correct use, with the idea that a change in dose per container affects all of them, and the optimal solution will depend on what is prioritized and used to measure performance. Studies on this topic are limited and largely rely on modeling to assess the relationship between doses per container and other aspects of immunization systems. Very few studies attempt to look at how a change in doses per container affects vaccination coverage rates and other systems components simultaneously. This article summarizes the published knowledge on this topic to date and suggests areas of current and future research to ultimately improve decision making around vaccine doses per container and increase understanding of how this decision relates to other program goals. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Evaluation of the antihyperalgesic effect of tapentadol in two human evoked pain models - the TapCapMentho pilot trial.

PubMed

Förster, M; Helfert, S; Dierschke, R; Großkopf, M; Hüllemann, P; Keller, T; Baron, R; Binder, A

2016-09-01

Tapentadol is effective in the treatment of neuropathic and nociceptive pain and in acute and chronic pain conditions; two mechanisms combining opioid µ-receptor agonism and noradrenergic reuptake inhibition underlie its analgesic effect. With this single-center, placebo-controlled, double-blind, cross-over pilot-study, we investigated the antihyperalgesic effect of a single oral dose of 100 mg immediate-release tapentadol on thermal and mechanical hyperalgesia in two human models (i.e. 0.6 % topical capsaicin and 40% topical menthol) of evoked neuropathic pain signs in healthy volunteers. No significant differences regarding experimentally induced heat or cold and mechanical (pinprick) hyperalgesia, as assessed by quantitative sensory testing, could be observed between a single dose of drug and placebo (thermal pain thresholds p>0.4, mechanical pain sensitivity p>0.1). Only few mild side effects of tapentadol were reported. The discrepancy between pain models using healthy volunteers and drug trials under real acute and chronic pain conditions in patients as well as methodological aspects may have contributed to this result. The impact of these findings questions the general use of pain models as predictors for early decision making during drug development. The study was registered in ClinicalTrials.gov (NCT01615510).

On the sensitivity of TG-119 and IROC credentialing to TPS commissioning errors.

PubMed

McVicker, Drew; Yin, Fang-Fang; Adamson, Justus D

2016-01-08

We investigate the sensitivity of IMRT commissioning using the TG-119 C-shape phantom and credentialing with the IROC head and neck phantom to treatment planning system commissioning errors. We introduced errors into the various aspects of the commissioning process for a 6X photon energy modeled using the analytical anisotropic algorithm within a commercial treatment planning system. Errors were implemented into the various components of the dose calculation algorithm including primary photons, secondary photons, electron contamination, and MLC parameters. For each error we evaluated the probability that it could be committed unknowingly during the dose algorithm commissioning stage, and the probability of it being identified during the verification stage. The clinical impact of each commissioning error was evaluated using representative IMRT plans including low and intermediate risk prostate, head and neck, mesothelioma, and scalp; the sensitivity of the TG-119 and IROC phantoms was evaluated by comparing dosimetric changes to the dose planes where film measurements occur and change in point doses where dosimeter measurements occur. No commissioning errors were found to have both a low probability of detection and high clinical severity. When errors do occur, the IROC credentialing and TG 119 commissioning criteria are generally effective at detecting them; however, for the IROC phantom, OAR point-dose measurements are the most sensitive despite being currently excluded from IROC analysis. Point-dose measurements with an absolute dose constraint were the most effective at detecting errors, while film analysis using a gamma comparison and the IROC film distance to agreement criteria were less effective at detecting the specific commissioning errors implemented here.

Drug Development for Pediatric Populations: Regulatory Aspects

PubMed Central

Zisowsky, Jochen; Krause, Andreas; Dingemanse, Jasper

2010-01-01

Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted—including the regulatory basis—and examples of the use of M&S are illustrated to support pediatric drug development. PMID:27721363

A hypothetical model for predicting the toxicity of high aspect ratio nanoparticles (HARN)

NASA Astrophysics Data System (ADS)

Tran, C. L.; Tantra, R.; Donaldson, K.; Stone, V.; Hankin, S. M.; Ross, B.; Aitken, R. J.; Jones, A. D.

2011-12-01

The ability to predict nanoparticle (dimensional structures which are less than 100 nm in size) toxicity through the use of a suitable model is an important goal if nanoparticles are to be regulated in terms of exposures and toxicological effects. Recently, a model to predict toxicity of nanoparticles with high aspect ratio has been put forward by a consortium of scientists. The High aspect ratio nanoparticles (HARN) model is a platform that relates the physical dimensions of HARN (specifically length and diameter ratio) and biopersistence to their toxicity in biological environments. Potentially, this model is of great public health and economic importance, as it can be used as a tool to not only predict toxicological activity but can be used to classify the toxicity of various fibrous nanoparticles, without the need to carry out time-consuming and expensive toxicology studies. However, this model of toxicity is currently hypothetical in nature and is based solely on drawing similarities in its dimensional geometry with that of asbestos and synthetic vitreous fibres. The aim of this review is two-fold: (a) to present findings from past literature, on the physicochemical property and pathogenicity bioassay testing of HARN (b) to identify some of the challenges and future research steps crucial before the HARN model can be accepted as a predictive model. By presenting what has been done, we are able to identify scientific challenges and research directions that are needed for the HARN model to gain public acceptance. Our recommendations for future research includes the need to: (a) accurately link physicochemical data with corresponding pathogenicity assay data, through the use of suitable reference standards and standardised protocols, (b) develop better tools/techniques for physicochemical characterisation, (c) to develop better ways of monitoring HARN in the workplace, (d) to reliably measure dose exposure levels, in order to support future epidemiological studies.

[Biological mechanisms of myopia].

PubMed

Schaeffel, F

2017-01-01

Recent studies have confirmed that the prevalence of myopia has increased in most countries, that the increase must be due to environmental factors and that myopia is closely linked to the level of education. Extensive close-up work with short viewing distances, little outdoor activity and continuous exposure to low illumination are currently considered the major factors. It remains unknown how close-up work can stimulate eye growth. Animal models provide the possibility to manipulate visual experiences and to observe subsequent changes in eye growth. They have uncovered a number of unexpected aspects which have led to studies in children. When applied in low doses atropine (0.01 %) is effective against progression of myopia and shows no rebound effect after termination of the treatment, in contrast to treatment with previously used higher doses. While education cannot be limited in our society, there are now an increasing number of options to slow myopia progression so that high myopia is less frequently reached.

Medical-biological aspects of radiation effects in Daphnia magna

NASA Astrophysics Data System (ADS)

Sarapultseva, E.; Uskalova, D.; Savina, N.; Ustenko, K.

2017-01-01

We have shown that γ-irradiation at doses of 100 and 1000 mGy significantly compromised fecundity and reproductive success of the directly exposed D. magna. These effects were also observed among the non-exposed first-generation progeny of irradiated parents, thus implying the manifestation of transgenerational effects in Daphnia. We have also shown that compromised viability of irradiated D. magna can be attributed cytotoxic effects of irradiation. It would therefore appear that the compromised viability may be attributed to the cytotoxic effects resulted from epigenetic changes affecting some metabolic pathways involved in detoxification of free-radicals. Additionally we have analyzed more distant progeny of irradiated at doses of 10, 100 and 1000 mGy Daphnia. Our data demonstrated that multicellular crustacean D. magna represent a very useful experimental model for analyse of long-term effects of ionising radiation at the organismal level.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

PubMed

Teuns, Greet B A; Geys, Helena M; Geuens, Sonja M A; Stinissen, Piet; Meert, Theo F

2014-01-01

Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

NASA Technical Reports Server (NTRS)

Wotring, V. E.; Mangala, L. S.; Zhang, Y.; Wu, H.

2011-01-01

Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

Vitamin K2 alleviates type 2 diabetes in rats by induction of osteocalcin gene expression.

PubMed

Hussein, Atef G; Mohamed, Randa H; Shalaby, Sally M; Abd El Motteleb, Dalia M

2018-03-01

The biological mechanisms behind the association between vitamin K (Vit K) and glucose metabolism are uncertain. We aimed to analyze the expression of insulin 1 (Ins 1), insulin 2 (Ins 2) and cyclin D2, the expression of adiponectin and UCP-1 . In addition, we aimed to estimate the doses of Vit K2 able to affect various aspects of glucose and energy metabolism in type 2 diabetes. Thirty adult male rats were allocated equally into five groups: control group, diabetes mellitus group, and groups 3, 4, and 5, which received Vit K 2 at three daily dose levels (10, 15, and 30 mg/kg, respectively) for 8 wk. At the end of the study, blood samples were collected to quantify total osteocalcin, fasting plasma glucose, fasting insulin, and relevant variables. The expression of OC, Ins 1, Ins 2, cyclin D2, adiponectin, UCP-1 genes was analyzed by real-time polymerase chain reaction. After administration of Vit K 2 , a dose-dependent decrease in fasting plasma glucose, hemoglobin A1c and homeostatic model assessment method insulin resistance, and a dose-dependent increase in fasting insulin and homeostatic model assessment method β cell function levels, when compared with diabetes mellitus rats, were detected. There was significant upregulation of OC, Ins 1, Ins 2, or cyclin D2 gene expression in the three treated groups in a dose-dependent manner when compared with the diabetic rats. However, expression of adiponectin and UCP-1 were significantly increased at the highest dose (30 mg/kg daily) only. Vit K 2 administration could improve glycemic status in type 2 diabetic rats by induction of OC gene expression. Osteocalcin could increase β-cell proliferation, energy expenditure, and adiponectin expression. Different concentrations of Vit K 2 were required to affect glucose metabolism and insulin sensitivity. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-F-T-574: MLC Based SRS Beam Commissioning - Minimum Target Size Investigation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zakikhani, R; Able, C

2016-06-15

Purpose: To implement a MLC accelerator based SRS program using small fields down to 1 cm × 1 cm and to determine the smallest target size safe for clinical treatment. Methods: Computerized beam scanning was performed in water using a diode detector and a linac-head attached transmission ion chamber to characterize the small field dosimetric aspects of a 6 MV photon beam (Trilogy-Varian Medical Systems, Inc.). The output factors, PDD and profiles of field sizes 1, 2, 3, 4, and 10 cm{sup 2} were measured and utilized to create a new treatment planning system (TPS) model (AAA ver 11021). Staticmore » MLC SRS treatment plans were created and delivered to a homogeneous phantom (Cube 20, CIRS, Inc.) for a 1.0 cm and 1.5 cm “PTV” target. A 12 field DMLC plan was created for a 2.1 cm target. Radiochromic film (EBT3, Ashland Inc.) was used to measure the planar dose in the axial, coronal and sagittal planes. A micro ion chamber (0.007 cc) was used to measure the dose at isocenter for each treatment delivery. Results: The new TPS model was validated by using a tolerance criteria of 2% dose and 2 mm distance to agreement. For fields ≤ 3 cm{sup 2}, the max PDD, Profile and OF difference was 0.9%, 2%/2mm and 1.4% respectively. The measured radiochromic film planar dose distributions had gamma scores of 95.3% or higher using a 3%/2mm criteria. Ion chamber measurements for all 3 test plans effectively met our goal of delivering the dose accurately to within 5% when compared to the expected dose reported by the TPS (1 cm plan Δ= −5.2%, 1.5 cm plan Δ= −2.0%, 2 cm plan Δ= 1.5%). Conclusion: End to end testing confirmed that MLC defined SRS for target sizes ≥ 1.0 cm can be safely planned and delivered.« less

Human exposure and internal dose assessments of acrylamide in food.

PubMed

Dybing, E; Farmer, P B; Andersen, M; Fennell, T R; Lalljie, S P D; Müller, D J G; Olin, S; Petersen, B J; Schlatter, J; Scholz, G; Scimeca, J A; Slimani, N; Törnqvist, M; Tuijtelaars, S; Verger, P

2005-03-01

This review provides a framework contributing to the risk assessment of acrylamide in food. It is based on the outcome of the ILSI Europe FOSIE process, a risk assessment framework for chemicals in foods and adds to the overall framework by focusing especially on exposure assessment and internal dose assessment of acrylamide in food. Since the finding that acrylamide is formed in food during heat processing and preparation of food, much effort has been (and still is being) put into understanding its mechanism of formation, on developing analytical methods and determination of levels in food, and on evaluation of its toxicity and potential toxicity and potential human health consequences. Although several exposure estimations have been proposed, a systematic review of key information relevant to exposure assessment is currently lacking. The European and North American branches of the International Life Sciences Institute, ILSI, discussed critical aspects of exposure assessment, parameters influencing the outcome of exposure assessment and summarised data relevant to the acrylamide exposure assessment to aid the risk characterisation process. This paper reviews the data on acrylamide levels in food including its formation and analytical methods, the determination of human consumption patterns, dietary intake of the general population, estimation of maximum intake levels and identification of groups of potentially high intakes. Possible options and consequences of mitigation efforts to reduce exposure are discussed. Furthermore the association of intake levels with biomarkers of exposure and internal dose, considering aspects of bioavailability, is reviewed, and a physiologically-based toxicokinetic (PBTK) model is described that provides a good description of the kinetics of acrylamide in the rat. Each of the sections concludes with a summary of remaining gaps and uncertainties.

Pharmacokinetics of topically applied pilocarpine in the albino rabbit eye.

PubMed

Makoid, M C; Robinson, J R

1979-04-01

The temporal and spatial pattern of [3H]-pilocarpine nitrate distribution in the albino rabbit eye following topical administration was determined. A four-compartment caternary chain model describing this disposition corresponds to the precorneal area, the cornea, the aqueous humor, and the lens and vitreous. Simultaneous computer fitting of data from tissue corresponding to some compartments in the model supported the proposed model. Additional support was provided by the excellent correlation between predicted and observed values in multiple-dosing studies. Several important aspects of ocular drug disposition are evident from the model. The extensive parallel elimination at the absorption site gives rise to an apparent absorption rate constant that is one to two orders of magnitude larger than the true absorption rate constant. In addition, aqueous flow accounts for most of the drug removal. Thus, major effects on absorption and elimination, independent of the drug structure, suggest the possibility of similar pharmacokinetics for vastly different drugs.

Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy.

PubMed

Brazill, Jennifer M; Cruz, Beverley; Zhu, Yi; Zhai, R Grace

2018-06-12

Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of many commonly used chemotherapeutic agents, including paclitaxel. Currently, there are no neuroprotective or effective symptomatic treatments for CIPN. Lack of understanding of the in vivo mechanisms of CIPN has greatly impeded the identification of therapeutic targets. Here, we optimized a model of paclitaxel-induced peripheral neuropathy using Drosophila larvae that recapitulates aspects of chemotherapy-induced sensory dysfunction . We showed that nociceptive sensitivity is associated with disrupted organization of microtubule-associated MAP1B/Futsch and aberrant stabilization of peripheral sensory dendrites. These findings establish a robust and amenable model for studying peripheral mechanisms of CIPN. Using this model, we uncovered a critical role for nicotinamide mononucleotide adenylyltransferase (Nmnat) in maintaining the integrity and function of peripheral sensory neurons and uncovered Nmnat's therapeutic potential against diverse sensory symptoms of CIPN. © 2018. Published by The Company of Biologists Ltd.

MO-E-18C-04: Advanced Computer Simulation and Visualization Tools for Enhanced Understanding of Core Medical Physics Concepts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naqvi, S

2014-06-15

Purpose: Most medical physics programs emphasize proficiency in routine clinical calculations and QA. The formulaic aspect of these calculations and prescriptive nature of measurement protocols obviate the need to frequently apply basic physical principles, which, therefore, gradually decay away from memory. E.g. few students appreciate the role of electron transport in photon dose, making it difficult to understand key concepts such as dose buildup, electronic disequilibrium effects and Bragg-Gray theory. These conceptual deficiencies manifest when the physicist encounters a new system, requiring knowledge beyond routine activities. Methods: Two interactive computer simulation tools are developed to facilitate deeper learning of physicalmore » principles. One is a Monte Carlo code written with a strong educational aspect. The code can “label” regions and interactions to highlight specific aspects of the physics, e.g., certain regions can be designated as “starters” or “crossers,” and any interaction type can be turned on and off. Full 3D tracks with specific portions highlighted further enhance the visualization of radiation transport problems. The second code calculates and displays trajectories of a collection electrons under arbitrary space/time dependent Lorentz force using relativistic kinematics. Results: Using the Monte Carlo code, the student can interactively study photon and electron transport through visualization of dose components, particle tracks, and interaction types. The code can, for instance, be used to study kerma-dose relationship, explore electronic disequilibrium near interfaces, or visualize kernels by using interaction forcing. The electromagnetic simulator enables the student to explore accelerating mechanisms and particle optics in devices such as cyclotrons and linacs. Conclusion: The proposed tools are designed to enhance understanding of abstract concepts by highlighting various aspects of the physics. The simulations serve as virtual experiments that give deeper and long lasting understanding of core principles. The student can then make sound judgements in novel situations encountered beyond routine clinical activities.« less

Late rectal bleeding after 3D-CRT for prostate cancer: development of a neural-network-based predictive model

NASA Astrophysics Data System (ADS)

Tomatis, S.; Rancati, T.; Fiorino, C.; Vavassori, V.; Fellin, G.; Cagna, E.; Mauro, F. A.; Girelli, G.; Monti, A.; Baccolini, M.; Naldi, G.; Bianchi, C.; Menegotti, L.; Pasquino, M.; Stasi, M.; Valdagni, R.

2012-03-01

The aim of this study was to develop a model exploiting artificial neural networks (ANNs) to correlate dosimetric and clinical variables with late rectal bleeding in prostate cancer patients undergoing radical radiotherapy and to compare the ANN results with those of a standard logistic regression (LR) analysis. 718 men included in the AIROPROS 0102 trial were analyzed. This multicenter protocol was characterized by the prospective evaluation of rectal toxicity, with a minimum follow-up of 36 months. Radiotherapy doses were between 70 and 80 Gy. Information was recorded for comorbidity, previous abdominal surgery, use of drugs and hormonal therapy. For each patient, a rectal dose-volume histogram (DVH) of the whole treatment was recorded and the equivalent uniform dose (EUD) evaluated as an effective descriptor of the whole DVH. Late rectal bleeding of grade ≥ 2 was considered to define positive events in this study (52 of 718 patients). The overall population was split into training and verification sets, both of which were involved in model instruction, and a test set, used to evaluate the predictive power of the model with independent data. Fourfold cross-validation was also used to provide realistic results for the full dataset. The LR was performed on the same data. Five variables were selected to predict late rectal bleeding: EUD, abdominal surgery, presence of hemorrhoids, use of anticoagulants and androgen deprivation. Following a receiver operating characteristic analysis of the independent test set, the areas under the curves (AUCs) were 0.704 and 0.655 for ANN and LR, respectively. When evaluated with cross-validation, the AUC was 0.714 for ANN and 0.636 for LR, which differed at a significance level of p = 0.03. When a practical discrimination threshold was selected, ANN could classify data with sensitivity and specificity both equal to 68.0%, whereas these values were 61.5% for LR. These data provide reasonable evidence that results obtained with ANNs are superior to those achieved with LR when predicting late radiotherapy-related rectal bleeding. The future introduction of patient-related personal characteristics, such as gene expression profiles, might improve the predictive power of statistical classifiers. More refined morphological aspects of the dose distribution, such as dose surface mapping, might also enhance the overall performance of ANN-based predictive models.

Potential epidemiological and economical impact of two rotavirus vaccines in Colombia.

PubMed

De la Hoz, Fernando; Alvis, Nelson; Narváez, Javier; Cediel, Natalia; Gamboa, Oscar; Velandia, Martha

2010-05-14

A complete economic study was carried out to assess the economical impact of two rotavirus vaccine in Colombia. A Markov decision model was built to assess the health outcomes from birth to 24 months of age for three hypothetical cohorts: one unvaccinated, one vaccinated with 2 doses of Rotarix and the third, with 3 doses of Rotateq. Without vaccination, the annual number of medical visits by diarrhea in children under 2 years would be 1,293,159 cases, with 105,378 medical visits and 470 deaths (IC95% 295-560) related to rotavirus. Without vaccination, rotavirus disease would cost around USD$8 millions including direct and indirect costs. Assuming a cost per dose of USD$7.5, average cost-effectiveness ratio would be USD$663/DALY with Rotarix and USD$1391 with Rotateq. When price per dose falls below USD$7 both vaccines yield a similar average cost-effectiveness ratio (USD$1063/DALY). Incremental cost-effectiveness ratio of Rotateq versus Rotarix was USD$7787/DALY. Cost-effectiveness ratio was influenced mainly by vaccine cost and cost per case hospitalized. Other programmatic aspects such as number of doses to be applied, likelihood of completing vaccination schedule with shorter versus longer schedules, and storage space within the chain cold should be considered to make decisions on which vaccine should be introduced. In conclusion, vaccinating against rotavirus in Colombia with either vaccine would be very cost effective. If cost per vaccinated children falls below USD$3 per dose vaccination would be cost saving. Copyright 2010 Elsevier Ltd. All rights reserved.

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

PubMed

Camacho, Luis H; Olson, Jon; Tong, William P; Young, Charles W; Spriggs, David R; Malkin, Mark G

2007-04-01

Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

Impact of the Revised 10 CFR 835 on the Neutron Dose Rates at LLNL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radev, R

2009-01-13

In June 2007, 10 CFR 835 [1] was revised to include new radiation weighting factors for neutrons, updated dosimetric models, and dose terms consistent with the newer ICRP recommendations. A significant aspect of the revised 10 CFR 835 is the adoption of the recommendations outlined in ICRP-60 [2]. The recommended new quantities demand a review of much of the basic data used in protection against exposure to sources of ionizing radiation. The International Commission on Radiation Units and Measurements has defined a number of quantities for use in personnel and area monitoring [3,4,5] including the ambient dose equivalent H*(d) tomore » be used for area monitoring and instrument calibrations. These quantities are used in ICRP-60 and ICRP-74. This report deals only with the changes in the ambient dose equivalent and ambient dose rate equivalent for neutrons as a result of the implementation of the revised 10 CFR 835. In the report, the terms neutron dose and neutron dose rate will be used for convenience for ambient neutron dose and ambient neutron dose rate unless otherwise stated. This report provides a qualitative and quantitative estimate of how much the neutron dose rates at LLNL will change with the implementation of the revised 10 CFR 835. Neutron spectra and dose rates from selected locations at the LLNL were measured with a high resolution spectroscopic neutron dose rate system (ROSPEC) as well as with a standard neutron rem meter (a.k.a., a remball). The spectra obtained at these locations compare well with the spectra from the Radiation Calibration Laboratory's (RCL) bare californium source that is currently used to calibrate neutron dose rate instruments. The measurements obtained from the high resolution neutron spectrometer and dose meter ROSPEC and the NRD dose meter compare within the range of {+-}25%. When the new radiation weighting factors are adopted with the implementation of the revised 10 CFR 835, the measured dose rates will increase by up to 22%. The health physicists should consider this increase for any areas that have dose rates near a posting limit, such as near the 100 mrem/hr for a high radiation area, as this increase in measured dose rate may result in some changes to postings and consequent radiological controls.« less

Chasing Ghosts in Space Radiobiology Research: The Lost Focus on Non-Targeted Effects

NASA Astrophysics Data System (ADS)

Cucinotta, Francis; Saganti, Premkumar; Cacao, Eliedonna

2016-07-01

The doses and dose-rates of astronaut exposures to galactic cosmic rays (GCR) are accurately known, and lead to particle hits per cell nucleus from high charge and energy (HZE) particles of much less than one hit per cell per week. A large number of experiments have shown that additivity of biological effects is a valid assumption for space radiation exposures, while experiments at higher doses and dose-rates than occur in space continue to be a focus of the majority of space radiobiology research. Furthermore HZE particle exposures with mono-energetic particles manifest themselves as a mixed-radiation field due to the contributions of delta-rays and the random impact parameter of a particles track core to DNA and non-DNA targets in cells and tissues. The mixed-field manifestation of mono-energetic HZE particle exposures is well known from theoretical studies of microdosimetry and track structure. Additional mixed-field effects occur for single species experiments due to nuclear fragmentation in particle accelerator beam-lines and biological samples along with energy straggling. In contrast to these well known aspects of space radiobiology there are many open questions on the contribution of non-targeted effects to low dose and dose-rate exposures. Non-targeted effects (NTEs) include bystander effects and genomic instability, and have been shown to be the most important outstanding question for reducing uncertainties in space radiation cancer risk assessment. The dose-rate and radiation quality dependence of NTE's has not been established, while there is an over-arching need to develop 21st century experimental models of human cancer risk. We review possible mechanisms of NTE's and how new experiments to address these issues could be designed.

Physical models, cross sections, and numerical approximations used in MCNP and GEANT4 Monte Carlo codes for photon and electron absorbed fraction calculation.

PubMed

Yoriyaz, Hélio; Moralles, Maurício; Siqueira, Paulo de Tarso Dalledone; Guimarães, Carla da Costa; Cintra, Felipe Belonsi; dos Santos, Adimir

2009-11-01

Radiopharmaceutical applications in nuclear medicine require a detailed dosimetry estimate of the radiation energy delivered to the human tissues. Over the past years, several publications addressed the problem of internal dose estimate in volumes of several sizes considering photon and electron sources. Most of them used Monte Carlo radiation transport codes. Despite the widespread use of these codes due to the variety of resources and potentials they offered to carry out dose calculations, several aspects like physical models, cross sections, and numerical approximations used in the simulations still remain an object of study. Accurate dose estimate depends on the correct selection of a set of simulation options that should be carefully chosen. This article presents an analysis of several simulation options provided by two of the most used codes worldwide: MCNP and GEANT4. For this purpose, comparisons of absorbed fraction estimates obtained with different physical models, cross sections, and numerical approximations are presented for spheres of several sizes and composed as five different biological tissues. Considerable discrepancies have been found in some cases not only between the different codes but also between different cross sections and algorithms in the same code. Maximum differences found between the two codes are 5.0% and 10%, respectively, for photons and electrons. Even for simple problems as spheres and uniform radiation sources, the set of parameters chosen by any Monte Carlo code significantly affects the final results of a simulation, demonstrating the importance of the correct choice of parameters in the simulation.

Investigation of the practical aspects of an additional 0.1 mm copper x-ray spectral filter for cine acquisition mode imaging in a clinical care setting.

PubMed

Fetterly, Kenneth A

2010-11-01

Minimizing the x-ray radiation dose is an important aspect of patient safety during interventional fluoroscopy procedures. This work investigates the practical aspects of an additional 0.1 mm Cu x-ray beam spectral filter applied to cine acquisition mode imaging on patient dose and image quality. Measurements were acquired using clinical interventional imaging systems. Acquisition images of Solid Water phantoms (15-40 cm) were acquired using x-ray beams with the x-ray tube inherent filtration and using an additional 0.1 mm Cu x-ray beam spectral filter. The skin entrance air kerma (dose) rate was measured and the signal difference to noise ratio (SDNR) of an iodine target embedded into the phantom was calculated to assess image quality. X-ray beam parameters were recorded and analyzed and a primary x-ray beam simulation was performed to assess additional x-ray tube burden attributable to the Cu filter. For all phantom thicknesses, the 0.1 mm Cu filter resulted in a 40% reduction in the entrance air kerma rate to the phantoms and a 9% reduction in the SDNR of the iodine phantom. The expected additional tube load required by the 0.1 mm Cu filter ranged from 11% for a 120 kVp x-ray beam to 43% for a 60 kVp beam. For these clinical systems, use of the 0.1 mm Cu filter resulted in a favorable compromise between reduced skin dose rate and image quality and increased x-ray tube burden.

European Scientific Notes. Volume 35, Number 2,

DTIC Science & Technology

1981-02-28

The risk is as- however, that he did not move forward sociated with the absorbed radiation dose in a straight line from his earliest to the ... dose in latter hdbefomdoiialtoa target region rk per iici-h in a source study the fallout from atomic bombs. However as medical aspects increased in ...enables supported from the Unix systems. The the users to manipulate

Early Results from the Advanced Radiation Protection Thick GCR Shielding Project

NASA Technical Reports Server (NTRS)

Norman, Ryan B.; Clowdsley, Martha; Slaba, Tony; Heilbronn, Lawrence; Zeitlin, Cary; Kenny, Sean; Crespo, Luis; Giesy, Daniel; Warner, James; McGirl, Natalie;

Initial Efforts in Characterizing Radiation and Plasma Effects on Space Assets: Bridging the Space Environment, Engineering and User Community

NASA Astrophysics Data System (ADS)

Zheng, Y.; Ganushkina, N. Y.; Guild, T. B.; Jiggens, P.; Jun, I.; Mazur, J. E.; Meier, M. M.; Minow, J. I.; Pitchford, D. A.; O'Brien, T. P., III; Shprits, Y.; Tobiska, W. K.; Xapsos, M.; Rastaetter, L.; Jordanova, V. K.; Kellerman, A. C.; Fok, M. C. H.

2017-12-01

The Community Coordinated Modeling Center (CCMC) has been leading the community-wide model validation projects for many years. Such effort has been broadened and extended via the newly-launched International Forum for Space Weather Modeling Capabilities Assessment (https://ccmc.gsfc.nasa.gov/assessment/), Its objective is to track space weather models' progress and performance over time, which is critically needed in space weather operations. The Radiation and Plasma Effects Working Team is working on one of the many focused evaluation topics and deals with five different subtopics: Surface Charging from 10s eV to 40 keV electrons, Internal Charging due to energetic electrons from hundreds keV to several MeVs. Single Event Effects from solar energetic particles (SEPs) and galactic cosmic rays (GCRs) (several MeV to TeVs), Total Dose due to accumulation of doses from electrons (>100 KeV) and protons (> 1 MeV) in a broad energy range, and Radiation Effects from SEPs and GCRs at aviation altitudes. A unique aspect of the Radiation and Plasma Effects focus area is that it bridges the space environments, engineering and user community. This presentation will summarize the working team's progress in metrics discussion/definition and the CCMC web interface/tools to facilitate the validation efforts. As an example, tools in the areas of surface charging/internal charging will be demoed.

Performance of dry powder inhalers with single dosed capsules in preschool children and adults using improved upper airway models.

PubMed

Lindert, Sandra; Below, Antje; Breitkreutz, Joerg

2014-02-06

The pulmonary administration of pharmaceutical aerosols to patients is affected by age-dependent variations in the anatomy of the upper airways and the inhalation pattern. Considering this aspect, different upper airway models, representing the geometries of adults and preschool children, and a conventional induction port according to the European Pharmacopeia were used for in vitro testing of dry powder inhalers with single dosed capsules (Cyclohaler®, Handihaler® and Spinhaler®). Deposition measurements were performed using steady flow rates of 30 and 60 L/min for the Handihaler®/Spinhaler® and 30, 60 and 75 L/min for the Cyclohaler®. The inhalation volume was set at 1 L. For the Cyclohaler®, the in vitro testing was supplemented by a pediatric inhalation profile. Slight differences of pulmonary deposition between the idealized adult (11%-15%) and pediatric (9%-11%) upper airway model were observed for the Cyclohaler®. The applied pediatric inhalation profile resulted in a reduction of pulmonary deposition by 5% compared to steady conditions and indicated the influence of the inhalation pattern on the amount of pulmonary deposited particles. The comparison of two pediatric upper airway models showed no differences. The performance of the Handihaler® was similar to the Cyclohaler®. The Spinhaler® showed an insufficient performance and limited reproducibility in our investigations.

Iterative Reconstruction Techniques in Abdominopelvic CT: Technical Concepts and Clinical Implementation.

PubMed

Patino, Manuel; Fuentes, Jorge M; Singh, Sarabjeet; Hahn, Peter F; Sahani, Dushyant V

2015-07-01

This article discusses the clinical challenge of low-radiation-dose examinations, the commonly used approaches for dose optimization, and their effect on image quality. We emphasize practical aspects of the different iterative reconstruction techniques, along with their benefits, pitfalls, and clinical implementation. The widespread use of CT has raised concerns about potential radiation risks, motivating diverse strategies to reduce the radiation dose associated with CT. CT manufacturers have developed alternative reconstruction algorithms intended to improve image quality on dose-optimized CT studies, mainly through noise and artifact reduction. Iterative reconstruction techniques take unique approaches to noise reduction and provide distinct strength levels or settings.

EXTENDED ACCESS TO METHAMPHETAMINE SELF-ADMINISTRATION AFFECTS SENSORIMOTOR GATING IN RATS

PubMed Central

Hadamitzky, Martin; Markou, Athina; Kuczenski, Ronald

2010-01-01

Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher-dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6-h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6-h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher-dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits. PMID:21070821

Optimization of the temporal pattern of applied dose for a single fraction of radiation: Implications for radiation therapy

NASA Astrophysics Data System (ADS)

Altman, Michael B.

The increasing prevalence of intensity modulated radiation therapy (IMRT) as a treatment modality has led to a renewed interest in the potential for interaction between prolonged treatment time, as frequently associated with IMRT, and the underlying radiobiology of the irradiated tissue. A particularly relevant aspect of radiobiology is cell repair capacity, which influences cell survival, and thus directly relates to the ability to control tumors and spare normal tissues. For a single fraction of radiation, the linear quadratic (LQ) model is commonly used to relate the radiation dose to the fraction of cells surviving. The LQ model implies a dependence on two time-related factors which correlate to radiobiological effects: the duration of radiation application, and the functional form of how the dose is applied over that time (the "temporal pattern of applied dose"). Although the former has been well studied, the latter has not. Thus, the goal of this research is to investigate the impact of the temporal pattern of applied dose on the survival of human cells and to explore how the manipulation of this temporal dose pattern may be incorporated into an IMRT-based radiation therapy treatment planning scheme. The hypothesis is that the temporal pattern of applied dose in a single fraction of radiation can be optimized to maximize or minimize cell kill. Furthermore, techniques which utilize this effect could have clinical ramifications. In situations where increased cell kill is desirable, such as tumor control, or limiting the degree of cell kill is important, such as the sparing of normal tissue, temporal sequences of dose which maximize or minimize cell kill (temporally "optimized" sequences) may provide greater benefit than current clinically used radiation patterns. In the first part of this work, an LQ-based modeling analysis of effects of the temporal pattern of dose on cell kill is performed. Through this, patterns are identified for maximizing cell kill for a given radiation pattern by concentrating the highest doses in the middle of a fraction (a "Triangle" pattern), or minimizing cell kill by placing the highest doses near the beginning and end (a "V-shaped" pattern). The conditions under which temporal optimization effects are most acute are also identified: irradiation of low alpha/beta tissues, long fraction durations, and high doses/fx. An in vitro study is then performed which verifies that the temporal effects and trends predicted by the modeling study are clearly manifested in human cells. Following this a phantom which could allow similar in vitro radiobiological experiments in a 3-dimensional clinically-based environment is designed, created, and dosimetrically assessed using TLDs, film, and biological assay-based techniques. The phantom is found to be a useful and versatile tool for such experiments. A scheme for utilizing the phantom in a clinical treatment environment is then developed. This includes a demonstration of prototype methods for optimizing the temporal pattern of applied dose in clinical IMRT plans to manipulate tissue-dependent effects. Looking toward future experimental validation of such plans using the phantom, an analysis of the suitability of biological assays for use in phantom-based in vitro experiments is performed. Finally, a discussion is provided about the steps necessary to integrate temporal optimization into in vivo experiments and ultimately into a clinical radiation therapy environment. If temporal optimization is ultimately shown to have impact in vivo, the successful implementation of the methods developed in this study could enhance the efficacy and care of thousands of patients receiving radiotherapy.

Comparison of internal dose estimates obtained using organ-level, voxel S value, and Monte Carlo techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grimes, Joshua, E-mail: grimes.joshua@mayo.edu; Celler, Anna

2014-09-15

Purpose: The authors’ objective was to compare internal dose estimates obtained using the Organ Level Dose Assessment with Exponential Modeling (OLINDA/EXM) software, the voxel S value technique, and Monte Carlo simulation. Monte Carlo dose estimates were used as the reference standard to assess the impact of patient-specific anatomy on the final dose estimate. Methods: Six patients injected with{sup 99m}Tc-hydrazinonicotinamide-Tyr{sup 3}-octreotide were included in this study. A hybrid planar/SPECT imaging protocol was used to estimate {sup 99m}Tc time-integrated activity coefficients (TIACs) for kidneys, liver, spleen, and tumors. Additionally, TIACs were predicted for {sup 131}I, {sup 177}Lu, and {sup 90}Y assuming themore » same biological half-lives as the {sup 99m}Tc labeled tracer. The TIACs were used as input for OLINDA/EXM for organ-level dose calculation and voxel level dosimetry was performed using the voxel S value method and Monte Carlo simulation. Dose estimates for {sup 99m}Tc, {sup 131}I, {sup 177}Lu, and {sup 90}Y distributions were evaluated by comparing (i) organ-level S values corresponding to each method, (ii) total tumor and organ doses, (iii) differences in right and left kidney doses, and (iv) voxelized dose distributions calculated by Monte Carlo and the voxel S value technique. Results: The S values for all investigated radionuclides used by OLINDA/EXM and the corresponding patient-specific S values calculated by Monte Carlo agreed within 2.3% on average for self-irradiation, and differed by as much as 105% for cross-organ irradiation. Total organ doses calculated by OLINDA/EXM and the voxel S value technique agreed with Monte Carlo results within approximately ±7%. Differences between right and left kidney doses determined by Monte Carlo were as high as 73%. Comparison of the Monte Carlo and voxel S value dose distributions showed that each method produced similar dose volume histograms with a minimum dose covering 90% of the volume (D90) agreeing within ±3%, on average. Conclusions: Several aspects of OLINDA/EXM dose calculation were compared with patient-specific dose estimates obtained using Monte Carlo. Differences in patient anatomy led to large differences in cross-organ doses. However, total organ doses were still in good agreement since most of the deposited dose is due to self-irradiation. Comparison of voxelized doses calculated by Monte Carlo and the voxel S value technique showed that the 3D dose distributions produced by the respective methods are nearly identical.« less

A review of dosimetric and toxicity modeling of proton versus photon craniospinal irradiation for pediatrics medulloblastoma.

PubMed

Ho, Evangeline S Q; Barrett, Sarah A; Mullaney, Laura M

2017-08-01

Craniospinal irradiation (CSI) is the standard radiation therapy treatment for medulloblastoma. Conventional CSI photon therapy (Photon-CSI) delivers significant dose to surrounding normal tissue (NT). Research into pediatric CSI with proton therapy (Proton-CSI) has increased, with the aim of exploiting the potential to reduce NT dose and associated post-treatment complications. This review aims to compare treatment outcomes of pediatric medulloblastoma patients between Proton- and Photon-CSI treatments. A search and review of studies published between 1990 and 2016 comparing pediatric (2-18 years) medulloblastoma Proton- and Photon-CSI in three aspects - normal organ sparing and target coverage; normal organ dysfunction and second malignancy risks - was completed. Fifteen studies were selected for review and the results were directly compared. Proton-CSI reported improved out-of-field organ sparing while target coverage improvements were inconsistent. Normal organ dysfunction risks were predicted to be lower following Proton-CSI. Secondary malignancy risks (SMRs) were generally lower with Proton-CSI based on several different risk models. Proton-CSI conferred better treatment outcomes than Photon-CSI for pediatric medulloblastoma patients. This review serves to compare the current literature in the absence of long-term data from prospective studies.

The computation of ICRP dose coefficients for intakes of radionuclides with PLEIADES: biokinetic aspects.

PubMed

Fell, T P

2007-01-01

The ICRP has published dose coefficients for the ingestion or inhalation of radionuclides in a series of reports covering intakes by workers and members of the public including children and pregnant or lactating women. The calculation of these coefficients conveniently divides into two distinct parts--the biokinetic and dosimetric. This paper gives a brief summary of the methods used to solve the biokinetic problem in the generation of dose coefficients on behalf of the ICRP, as implemented in the Health Protection Agency's internal dosimetry code PLEIADES.

Nutritional aspects of ascorbic acid: uses and abuses.

PubMed

Vilter, R W

1980-12-01

Ascorbic acid in physiological doses is essential for the normal functioning of the human body. Larger doses are required to treat a severe deficiency of vitamin C intake, as in the case of scurvy. Occasionally, massive doses may be required to treat a metabolic defect involving ascorbic acid. There has been some mention of megadose therapy with ascorbic acid for the prevention of colds, the improved healing of wounds and even the treatment of cancer, but no acceptable scientific data have been presented. In fact, in a few instances, such therapy has proved injurious.

RADIATION PROTECTION CABIN FOR CATHETER-DIRECTED LIVER INTERVENTIONS: OPERATOR DOSE ASSESSMENT.

PubMed

Maleux, Geert; Bergans, Niki; Bosmans, Hilde; Bogaerts, Ria

2016-09-01

The number and complexity of interventional radiological procedures and in particular catheter-directed liver interventions have increased substantially. The current study investigates the reduction of personal doses when using a dedicated radiation protection cabin (RPC) for these procedures. Operator and assistant doses were assessed for 3 series of 20 chemoinfusion/chemoembolisation interventions, including an equal number of procedures with and without RPC. Whole body doses, finger doses and doses at the level of knees and eyes were evaluated with different types of TLD-100 Harshaw dosemeters. Dosemeters were also attached on the three walls of the RPC. The operator doses were significantly reduced by the RPC, but also without RPC, the doses appear to be limited as a result of thorough optimisation with existing radiation protection tools. The added value of the RPC should thus be determined by the outcome of balancing dose reduction and other aspects such as ergonomic benefits. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The effects of cysteamine in a mouse model of levodopa-induced dyskinesias.

PubMed

David, Linda S; Saint-Pierre, Martine; Lamontagne-Proulx, Jérôme; Cicchetti, Francesca

2018-01-01

Levo-dopa (L-DOPA) has shown significant and long-lasting efficacy in the treatment of motor features characteristic of Parkinson's disease (PD). However, the effects tend to wear off at a time typically when side-effects, such as L-DOPA induced dyskinesias (LIDs), start to emerge and for which the treatment options are very limited. In recent years, we have reported on the neuroprotective and neurorestorative properties of the compounds cystamine/cysteamine in ameliorating several aspects of PD. Building on these observations, we set out to further evaluate the benefits of cysteamine on LIDs. We thus treated mice displaying LIDs with single cysteamine challenges at various doses (20, 50 and 30mg/kg) or chronically for 2 weeks using cysteamine at a dose of 30mg/kg. None of the regimens nor doses ameliorated any LID-related behavioral impairments. Mice displaying LIDs did, however, respond to a single treatment of 60mg/kg of amantadine, a drug used to clinically manage LIDs. Taken together, our results suggest that cysteamine does not induce benefits on LIDs, at least at the doses and regimen tested in our study. However, the disease-modifying effects depicted by cystamine/cysteamine, which we have shown in several reports, would strongly encourage its continued evaluation in the clinical setting. Copyright © 2017 Elsevier B.V. All rights reserved.

Description of histopathological changes induced by the venom of the Persian Gulf Lionfish (Pterois russelli) in a mouse model of multiorgan toxicity.

PubMed

Memar, Bahareh; Jamili, Shahla; Shahbazzadeh, Delavar; Pooshang Bagheri, Kamran

2016-11-01

Pterois russelli is a venomous fish belongs to Scorpaenidae family. Envenomation by the Persian Gulf lionfish is associated with local pain, marked inflammation and local heat. The present study was aimed to document the histopathological changes in liver, heart, lung, kidney and alterations in release of critical enzymes such as LDH, CK. AST, ALT and ALP induced by the administration of various doses of P. russelli venom in a mouse model. LD50 of venom was determined by intravenous injection in Balb/c mice. Histopathological alterations of lung, liver, heart and kidney following injection of one LD50, 1/2 and 1/3 LD50 doses of the venom were evaluated. Simultaneously, release of LDH, CK, AST, ALT and ALP were measured in serum following administration of 1/2 and1/3 LD50 doses of the venom too. LD50 was calculated as 10.5 mg/kg. The level of all enzymes were increased after 3 h and significantly raised after 24 h and rapidly reduced after 48 h. Histological studies showed that one LD50 and 1/2 LD50 doses of the venom induced significant histological alterations in the lungs, liver, heart and kidneys including congestion, hemorrhage, necrosis, apoptosis, edema, and infiltration of inflammatory cells. The results indicate that the venom of P. russelli has nephrotoxic, hepatotoxic, cardiotoxic and pneumotoxic effects in mouse model. Among four examined vital organs, the highest critical events were seen in liver. The findings are useful to give new insight in the fish's venom studies. Gathering the data resulted from this study together will be directed us toward a good aspect concerning the toxicity of potential therapeutic molecules in the venom of lionfish. Copyright © 2016 Elsevier Ltd. All rights reserved.

Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers.

PubMed

Gouzoulis-Mayfrank, E; Heekeren, K; Neukirch, A; Stoll, M; Stock, C; Obradovic, M; Kovar, K-A

2005-11-01

Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT2A agonist DMT and the glutamate N-methyl-D-aspartate (NMDA) antagonist (S)-ketamine. Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine. The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.

The infection rate of Daphnia magna by Pasteuria ramosa conforms with the mass-action principle.

PubMed

Regoes, R R; Hottinger, J W; Sygnarski, L; Ebert, D

2003-10-01

In simple epidemiological models that describe the interaction between hosts with their parasites, the infection process is commonly assumed to be governed by the law of mass action, i.e. it is assumed that the infection rate depends linearly on the densities of the host and the parasite. The mass-action assumption, however, can be problematic if certain aspects of the host-parasite interaction are very pronounced, such as spatial compartmentalization, host immunity which may protect from infection with low doses, or host heterogeneity with regard to susceptibility to infection. As deviations from a mass-action infection rate have consequences for the dynamics of the host-parasite system, it is important to test for the appropriateness of the mass-action assumption in a given host-parasite system. In this paper, we examine the relationship between the infection rate and the parasite inoculum for the water flee Daphnia magna and its bacterial parasite Pasteuria ramosa. We measured the fraction of infected hosts after exposure to 14 different doses of the parasite. We find that the observed relationship between the fraction of infected hosts and the parasite dose is largely consistent with an infection process governed by the mass-action principle. However, we have evidence for a subtle but significant deviation from a simple mass-action infection model, which can be explained either by some antagonistic effects of the parasite spores during the infection process, or by heterogeneity in the hosts' susceptibility with regard to infection.

Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages

PubMed Central

Padmore, Trudy; Stark, Carahline; Turkevich, Leonid A.; Champion, Julie A.

2017-01-01

Background In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models. Methods Murine alveolar macrophages were exposed to long and short populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1 α, COX-2, PGE2) were measured. Results Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production. Conclusion Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data. PMID:27784615

On determining dose rate constants spectroscopically.

PubMed

Rodriguez, M; Rogers, D W O

2013-01-01

To investigate several aspects of the Chen and Nath spectroscopic method of determining the dose rate constants of (125)I and (103)Pd seeds [Z. Chen and R. Nath, Phys. Med. Biol. 55, 6089-6104 (2010)] including the accuracy of using a line or dual-point source approximation as done in their method, and the accuracy of ignoring the effects of the scattered photons in the spectra. Additionally, the authors investigate the accuracy of the literature's many different spectra for bare, i.e., unencapsulated (125)I and (103)Pd sources. Spectra generated by 14 (125)I and 6 (103)Pd seeds were calculated in vacuo at 10 cm from the source in a 2.7 × 2.7 × 0.05 cm(3) voxel using the EGSnrc BrachyDose Monte Carlo code. Calculated spectra used the initial photon spectra recommended by AAPM's TG-43U1 and NCRP (National Council of Radiation Protection and Measurements) Report 58 for the (125)I seeds, or TG-43U1 and NNDC(2000) (National Nuclear Data Center, 2000) for (103)Pd seeds. The emitted spectra were treated as coming from a line or dual-point source in a Monte Carlo simulation to calculate the dose rate constant. The TG-43U1 definition of the dose rate constant was used. These calculations were performed using the full spectrum including scattered photons or using only the main peaks in the spectrum as done experimentally. Statistical uncertainties on the air kerma/history and the dose rate/history were ≤0.2%. The dose rate constants were also calculated using Monte Carlo simulations of the full seed model. The ratio of the intensity of the 31 keV line relative to that of the main peak in (125)I spectra is, on average, 6.8% higher when calculated with the NCRP Report 58 initial spectrum vs that calculated with TG-43U1 initial spectrum. The (103)Pd spectra exhibit an average 6.2% decrease in the 22.9 keV line relative to the main peak when calculated with the TG-43U1 rather than the NNDC(2000) initial spectrum. The measured values from three different investigations are in much better agreement with the calculations using the NCRP Report 58 and NNDC(2000) initial spectra with average discrepancies of 0.9% and 1.7% for the (125)I and (103)Pd seeds, respectively. However, there are no differences in the calculated TG-43U1 brachytherapy parameters using either initial spectrum in both cases. Similarly, there were no differences outside the statistical uncertainties of 0.1% or 0.2%, in the average energy, air kerma/history, dose rate/history, and dose rate constant when calculated using either the full photon spectrum or the main-peaks-only spectrum. Our calculated dose rate constants based on using the calculated on-axis spectrum and a line or dual-point source model are in excellent agreement (0.5% on average) with the values of Chen and Nath, verifying the accuracy of their more approximate method of going from the spectrum to the dose rate constant. However, the dose rate constants based on full seed models differ by between +4.6% and -1.5% from those based on the line or dual-point source approximations. These results suggest that the main value of spectroscopic measurements is to verify full Monte Carlo models of the seeds by comparison to the calculated spectra.

Does Iterative Reconstruction Lower CT Radiation Dose: Evaluation of 15,000 Examinations

PubMed Central

Noël, Peter B.; Renger, Bernhard; Fiebich, Martin; Münzel, Daniela; Fingerle, Alexander A.; Rummeny, Ernst J.; Dobritz, Martin

2013-01-01

Purpose Evaluation of 15,000 computed tomography (CT) examinations to investigate if iterative reconstruction (IR) reduces sustainably radiation exposure. Method and Materials Information from 15,000 CT examinations was collected, including all aspects of the exams such as scan parameter, patient information, and reconstruction instructions. The examinations were acquired between January 2010 and December 2012, while after 15 months a first generation IR algorithm was installed. To collect the necessary information from PACS, RIS, MPPS and structured reports a Dose Monitoring System was developed. To harvest all possible information an optical character recognition system was integrated, for example to collect information from the screenshot CT-dose report. The tool transfers all data to a database for further processing such as the calculation of effective dose and organ doses. To evaluate if IR provides a sustainable dose reduction, the effective dose values were statistically analyzed with respect to protocol type, diagnostic indication, and patient population. Results IR has the potential to reduce radiation dose significantly. Before clinical introduction of IR the average effective dose was 10.1±7.8mSv and with IR 8.9±7.1mSv (p*=0.01). Especially in CTA, with the possibility to use kV reduction protocols, such as in aortic CTAs (before IR: average14.2±7.8mSv; median11.4mSv /with IR:average9.9±7.4mSv; median7.4mSv), or pulmonary CTAs (before IR: average9.7±6.2mSV; median7.7mSv /with IR: average6.4±4.7mSv; median4.8mSv) the dose reduction effect is significant(p*=0.01). On the contrary for unenhanced low-dose scans of the cranial (for example sinuses) the reduction is not significant (before IR:average6.6±5.8mSv; median3.9mSv/with IR:average6.0±3.1mSV; median3.2mSv). Conclusion The dose aspect remains a priority in CT research. Iterative reconstruction algorithms reduce sustainably and significantly radiation dose in the clinical routine. Our results illustrate that not only in studies with a limited number of patients but also in the clinical routine, IRs provide long-term dose saving. PMID:24303035

Does iterative reconstruction lower CT radiation dose: evaluation of 15,000 examinations.

PubMed

Noël, Peter B; Renger, Bernhard; Fiebich, Martin; Münzel, Daniela; Fingerle, Alexander A; Rummeny, Ernst J; Dobritz, Martin

2013-01-01

Evaluation of 15,000 computed tomography (CT) examinations to investigate if iterative reconstruction (IR) reduces sustainably radiation exposure. Information from 15,000 CT examinations was collected, including all aspects of the exams such as scan parameter, patient information, and reconstruction instructions. The examinations were acquired between January 2010 and December 2012, while after 15 months a first generation IR algorithm was installed. To collect the necessary information from PACS, RIS, MPPS and structured reports a Dose Monitoring System was developed. To harvest all possible information an optical character recognition system was integrated, for example to collect information from the screenshot CT-dose report. The tool transfers all data to a database for further processing such as the calculation of effective dose and organ doses. To evaluate if IR provides a sustainable dose reduction, the effective dose values were statistically analyzed with respect to protocol type, diagnostic indication, and patient population. IR has the potential to reduce radiation dose significantly. Before clinical introduction of IR the average effective dose was 10.1±7.8mSv and with IR 8.9±7.1mSv (p*=0.01). Especially in CTA, with the possibility to use kV reduction protocols, such as in aortic CTAs (before IR: average14.2±7.8mSv; median11.4mSv /with IR:average9.9±7.4mSv; median7.4mSv), or pulmonary CTAs (before IR: average9.7±6.2mSV; median7.7mSv /with IR: average6.4±4.7mSv; median4.8mSv) the dose reduction effect is significant(p*=0.01). On the contrary for unenhanced low-dose scans of the cranial (for example sinuses) the reduction is not significant (before IR:average6.6±5.8mSv; median3.9mSv/with IR:average6.0±3.1mSV; median3.2mSv). The dose aspect remains a priority in CT research. Iterative reconstruction algorithms reduce sustainably and significantly radiation dose in the clinical routine. Our results illustrate that not only in studies with a limited number of patients but also in the clinical routine, IRs provide long-term dose saving.

Single-Fraction Intraoperative Radiotherapy for Breast Cancer: Early Cosmetic Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beal, Kathryn; McCormick, Beryl; Zelefsky, Michael J.

2007-09-01

Purpose: To evaluate the cosmetic outcome of patients treated with wide local excision and intraoperative radiotherapy for early-stage breast cancer. Methods and Materials: A total of 50 women were treated on a pilot study to evaluate the feasibility of intraoperative radiotherapy at wide local excision. The eligibility criteria included age >60, tumor size {<=}2.0 cm, clinically negative lymph nodes, and biopsy-established diagnosis. After wide local excision, a custom breast applicator was placed in the excision cavity, and a dose of 20 Gy was prescribed to a depth of 1 cm. After 18 patients were treated, the dose was constrained laterallymore » to 18 Gy. The cosmetic outcome was evaluated by photographs at baseline and at 6 and 12 months postoperatively. Four examiners graded the photographs for symmetry, edema, discoloration, contour, and scarring. The grades were evaluated in relationship to the volume of irradiated tissue, tumor location, and dose at the lateral aspects of the cavity. Results: The median volume of tissue receiving 100% of the prescription dose was 47 cm{sup 3} (range, 20-97 cm{sup 3}). Patients with {<=}47 cm{sup 3} of treated tissue had better cosmetic outcomes than did the women who had >47 cm{sup 3} of treated tissue. Women who had received 18 Gy at the lateral aspects of their cavities had better cosmetic outcomes than did women who had received 20 Gy at the lateral aspects. When comparing the 6- and 12-month results, the scores remained stable for 63%, improved for 17%, and worsened for 20%. Conclusion: Intraoperative radiotherapy appears feasible for selected patients. A favorable cosmetic outcome appears to be related to a smaller treatment volume. The cosmetic outcome is acceptable, although additional follow-up is necessary.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilczek, Krzysztof; Petelenz, Barbara; Strzala, Alicja

Purpose. Biological effects of intravascular brachytherapy are very sensitive to discrepancies between the prescription and the applied dose. If brachytherapy is aimed at in-stent restenosis, shielding and shadowing effects of metallic stents may change the dose distribution relative to that produced by the bare source. The development of new generations of stents inspired us to a new experimental study in this field. The effect was studied for 14 stents which we have recently encountered in clinical practice. Methods. The model source was a continuous 20-mm column of {sup 90}Sr/{sup 90}Y solution sealed in a 1-mm-I.D. Plexiglas capillary. The dose distributionmore » in the Plexiglas phantom was mapped using GafChromic MD-55-2 film. The stent masses varied from 2.5 to 25 mg; the strut thicknesses, from 0.075 to 0.15 mm; and the atomic numbers of stent materials, from 24 (Cr) to 79 (Au). Results. Dose perturbations depend on a variety of stent features. Local reduction of the mean dose rates near the reference distance (r{sub 0} = 2 mm) varied from 11% to 47%. No simple correlation was found between these data and stent characteristics, but it seems that the atomic number of the stent material is less important than the strut thickness and mesh density. Conclusion. The results provide a warning that clinical indications for in-stent radiation therapy must always be confronted with another aspect of the patient's history: the kind of implanted stent. Intravascular brachytherapy using pure beta sources may be recommended only for patients 'wearing' light, thin-strut stents. The presence of thick-strut stents is a contraindication for this modality, due to excessive dose perturbation.« less

Symptoms and the use of wireless communication devices: A prospective cohort study in Swiss adolescents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schoeni, Anna, E-mail: anna.schoeni@unibas.ch

Background: We investigated whether radiofrequency electromagnetic fields (RF-EMF) from mobile phones and other wireless devices or by the wireless device use itself due to non-radiation related factors in that context are associated with an increase in health symptom reports of adolescents in Central Switzerland. Methods: In a prospective cohort study, 439 study participants (participation rate: 36.8%) aged 12–17 years, completed questionnaires about their mobile and cordless phone use, their self-reported symptoms and possible confounding factors at baseline (2012/2013) and one year later (2013/2014). Operator recorded mobile phone data was obtained for a subgroup of 234 adolescents. RF-EMF dose measures consideringmore » various factors affecting RF-EMF exposure were computed for the brain and the whole body. Data were analysed using a mixed-logistic cross-sectional model and a cohort approach, where we investigated whether cumulative dose over one year was related to a new onset of a symptom between baseline and follow-up. All analyses were adjusted for relevant confounders. Results: Participation rate in the follow-up was 97% (425 participants). In both analyses, cross-sectional and cohort, various symptoms tended to be mostly associated with usage measures that are only marginally related to RF-EMF exposure such as the number of text messages sent per day (e.g. tiredness: OR:1.81; 95%CI:1.20–2.74 for cross-sectional analyses and OR:1.87; 95%CI:1.04–3.38 for cohort analyses). Outcomes were generally less strongly or not associated with mobile phone call duration and RF-EMF dose measures. Conclusions: Stronger associations between symptoms of ill health and wireless communication device use than for RF-EMF dose measures were observed. Such a result pattern does not support a causal association between RF-EMF exposure and health symptoms of adolescents but rather suggests that other aspects of extensive media use are related to symptoms. - Highlights: • This is a prospective cohort study with approximately one year of follow-up. • Self-reported and operator recorded mobile phone use data were collected. • The cumulative RF-EMF dose for the brain and for the whole body was calculated. • Associations were stronger for the use of wireless devices than for RF-EMF dose. • This suggests that rather aspects of extensive media use than RF-EMF are related to symptoms.« less

Overlap of highly FDG-avid and FMISO hypoxic tumor subvolumes in patients with head and neck cancer.

PubMed

Mönnich, David; Thorwarth, Daniela; Leibfarth, Sara; Pfannenberg, Christina; Reischl, Gerald; Mauz, Paul-Stefan; Nikolaou, Konstantin; la Fougère, Christian; Zips, Daniel; Welz, Stefan

2017-11-01

PET imaging may be used to personalize radiotherapy (RT) by identifying radioresistant tumor subvolumes for RT dose escalation. Using the tracers [ 18 F]-fluorodeoxyglucose (FDG) and [ 18 F]-fluoromisonidazole (FMISO), different aspects of tumor biology can be visualized. FDG depicts various biological aspects, e.g., proliferation, glycolysis and hypoxia, while FMISO is more hypoxia specific. In this study, we analyzed size and overlap of volumes based on the two markers for head-and-neck cancer patients (HNSCC). Twenty five HNSCC patients underwent a CT scan, as well as FDG and dynamic FMISO PET/CT prior to definitive radio-chemotherapy in a prospective FMISO dose escalation study. Three PET-based subvolumes of the primary tumor (GTV prim ) were segmented: a highly FDG-avid volume V FDG , a hypoxic volume on the static FMISO image acquired four hours post tracer injection (V H ) and a retention/perfusion volume (V M ) using pharmacokinetic modeling of dynamic FMISO data. Absolute volumes, overlaps and distances to agreement (DTA) were evaluated. Sizes of PET-based volumes and the GTV prim are significantly different (GTV prim >V FDG >V H >V M ; p < .05). V H is covered by V FDG or DTAs are small (mean coverage 74.4%, mean DTA 1.4 mm). Coverage of V M is less pronounced. With respect to V FDG and V H , the mean coverage is 48.7% and 43.1% and the mean DTA is 5.3 mm and 6.3 mm, respectively. For two patients, DTAs were larger than 2 cm. Hypoxic subvolumes from static PET imaging are typically covered by or in close proximity to highly FDG-avid subvolumes. Therefore, dose escalation to FDG positive subvolumes should cover the static hypoxic subvolumes in most patients, with the disadvantage of larger volumes, resulting in a higher risk of dose-limiting toxicity. Coverage of subvolumes from dynamic FMISO PET is less pronounced. Further studies are needed to explore the relevance of mismatches in functional imaging.

Evaluation of the uncertainty in an oral reference dose for methylmercury due to interindividual variability in pharmacokinetics.

PubMed

Clewell, H J; Gearhart, J M; Gentry, P R; Covington, T R; VanLandingham, C B; Crump, K S; Shipp, A M

1999-08-01

An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 microgram/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 microgram/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 microgram/kg/day and an MRL of 0.3 microgram/kg/day.

An in vitro method to test the safety and efficacy of low-level laser therapy (LLLT) in the healing of a canine skin model.

PubMed

Gagnon, Dominique; Gibson, Thomas W G; Singh, Ameet; zur Linden, Alex R; Kazienko, Jaimie E; LaMarre, Jonathan

2016-04-08

Low-level laser therapy (LLLT) has been used clinically as a treatment modality for a variety of medical conditions including wound-healing processes. It is an attractive and emerging method to enhance wound healing and improve clinical outcomes both in human and veterinary medicine. Despite the fact that the use of LLLT continues to gain in popularity, there is no universally accepted theory that defends all its cellular effects and beneficial biological processes in tissue repair. The present study was designed to evaluate the effect of LLLT on cellular migration and proliferation of cultured canine epidermal keratinocytes (CPEK) in an in vitro wound healing model. Keratinocyte migration and proliferation were assessed using a scratch migration assay and a proliferation assay, respectively. Fifteen independent replicates were performed for each assay. Canine epidermal keratinocyte cells exposed to LLLT with 0.1, 0.2, and 1.2 J/cm(2) migrated significantly more rapidly (p < 0.03) and showed significantly higher rates of proliferation (p < 0.0001) compared to non-irradiated cells cultured in the same medium and cells exposed to the higher energy dose of 10 J/cm(2). Irradiation with 10 J/cm(2) was characterized by decreased cellular migration and proliferation. These results revealed that LLLT has a measurable, dose-dependent effect on two different aspects of keratinocyte biology in vitro. In this in vitro wound-healing model, LLLT increased cellular migration and proliferation at doses of 0.1, 0.2, and 1.2 J/cm(2) while exposure to 10 J/cm(2) decreased cellular migration and proliferation. These data suggest that the beneficial effects of LLLT in vivo may be due, in part, to effects on keratinocyte behavior.

Mathematical optimization of high dose-rate brachytherapy—derivation of a linear penalty model from a dose-volume model

NASA Astrophysics Data System (ADS)

Morén, B.; Larsson, T.; Carlsson Tedgren, Å.

2018-03-01

High dose-rate brachytherapy is a method for cancer treatment where the radiation source is placed within the body, inside or close to a tumour. For dose planning, mathematical optimization techniques are being used in practice and the most common approach is to use a linear model which penalizes deviations from specified dose limits for the tumour and for nearby organs. This linear penalty model is easy to solve, but its weakness lies in the poor correlation of its objective value and the dose-volume objectives that are used clinically to evaluate dose distributions. Furthermore, the model contains parameters that have no clear clinical interpretation. Another approach for dose planning is to solve mixed-integer optimization models with explicit dose-volume constraints which include parameters that directly correspond to dose-volume objectives, and which are therefore tangible. The two mentioned models take the overall goals for dose planning into account in fundamentally different ways. We show that there is, however, a mathematical relationship between them by deriving a linear penalty model from a dose-volume model. This relationship has not been established before and improves the understanding of the linear penalty model. In particular, the parameters of the linear penalty model can be interpreted as dual variables in the dose-volume model.

Commissioning of the tongue-and-groove modelling in treatment planning systems: from static fields to VMAT treatments

NASA Astrophysics Data System (ADS)

Hernandez, Victor; Vera-Sánchez, Juan Antonio; Vieillevigne, Laure; Saez, Jordi

2017-08-01

Adequate modelling of the multi-leaf collimator (MLC) by treatment planning systems (TPS) is essential for accurate dose calculations in intensity-modulated radiation-therapy. For this reason modern TPSs incorporate MLC characteristics such as the leaf end curvature, MLC transmission and the tongue-and-groove. However, the modelling of the tongue-and-groove is often neglected during TPS commissioning and it is not known how accurate it is. This study evaluates the dosimetric consequences of the tongue-and-groove effect for two different MLC models using both film dosimetry and ionisation chambers. A set of comprehensive tests are presented that evaluate the ability of TPSs to accurately model this effect in (a) static fields, (b) sliding window beams and (c) VMAT arcs. The tests proposed are useful for the commissioning of TPSs and for the validation of major upgrades. With the ECLIPSE TPS, relevant differences were found between calculations and measurements for beams with dynamic MLCs in the presence of the TG effect, especially for the High Definition MLC, small gap sizes and the 1 mm calculation grid. For this combination, dose differences as high as 10% and 7% were obtained for dynamic MLC gaps of 5 mm and 10 mm, respectively. These differences indicate inadequate modelling of the tongue-and-groove effect, which might not be identified without the proposed tests. In particular, the TPS tended to underestimate the calculated dose, which may require tuning of other configuration parameters in the TPS (such as the dosimetric leaf gap) in order to maximise the agreement between calculations and measurements in clinical plans. In conclusion, a need for better modelling of the MLC by TPSs is demonstrated, one of the relevant aspects being the tongue-and-groove effect. This would improve the accuracy of TPS calculations, especially for plans using small MLC gaps, such as plans with small target volumes or high complexities. Improved modelling of the MLC would also reduce the need for tuning parameters in the TPS, facilitating a more comprehensive configuration and commissioning of TPSs.

Radiation dosimetry with fiber Bragg gratings

NASA Astrophysics Data System (ADS)

Avino, S.; D'Avino, V.; Giorgini, A.; Pacelli, R.; Liuzzi, R.; Cella, L.; Gagliardi, G.; De Natale, P.

2014-05-01

The measurement and monitoring of radiation dose delivered in patient tissues is a critical aspect in radiation therapy. Various dosimeters have proven effective in measuring radiations at low doses. However, there is a growing demand for new dosimeters based on small, non-invasive and high resolution devices. Here we report on a miniature dosimeter based on an optical fiber cavity. We demonstrate an ultimate detection limit of 160 mGy with an effective interaction region of 6 x 10-4 mm3. Due to its reliability, compactness and biomedical dose level sensitivity, our system shows itself suitable for applications in radiation therapy dosimetry.

Applying risk and resilience models to predicting the effects of media violence on development.

PubMed

Prot, Sara; Gentile, Douglas A

2014-01-01

Although the effects of media violence on children and adolescents have been studied for over 50 years, they remain controversial. Much of this controversy is driven by a misunderstanding of causality that seeks the cause of atrocities such as school shootings. Luckily, several recent developments in risk and resilience theories offer a way out of this controversy. Four risk and resilience models are described, including the cascade model, dose-response gradients, pathway models, and turning-point models. Each is described and applied to the existing media effects literature. Recommendations for future research are discussed with regard to each model. In addition, we examine current developments in theorizing that stressors have sensitizing versus steeling effects and recent interest in biological and gene by environment interactions. We also discuss several of the cultural aspects that have supported the polarization and misunderstanding of the literature, and argue that applying risk and resilience models to the theories and data offers a more balanced way to understand the subtle effects of media violence on aggression within a multicausal perspective.

Modeling Rabbit Responses to Single and Multiple Aerosol ...

EPA Pesticide Factsheets

Journal Article Survival models are developed here to predict response and time-to-response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple dose dataset to predict the probability of death through specifying dose-response functions and the time between exposure and the time-to-death (TTD). Among the models developed, the best-fitting survival model (baseline model) has an exponential dose-response model with a Weibull TTD distribution. Alternative models assessed employ different underlying dose-response functions and use the assumption that, in a multiple dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this paper. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high-dose rabbit datasets. More accurate survival models depend upon future development of dose-response datasets specifically designed to assess potential multiple dose effects on response and time-to-response. The process used in this paper to dev

Electron Microscopy.

ERIC Educational Resources Information Center

Beer, Michael

1980-01-01

Reviews technical aspects of structure determination in biological electron microscopy (EM). Discusses low dose EM, low temperature microscopy, electron energy loss spectra, determination of mass or molecular weight, and EM of labeled systems. Cites 34 references. (CS)

Optimization of an experimental model for the recovery of adult Haplorchis pumilio (Heterophyidae: Digenea).

PubMed

Kay, Helle; Murrell, K Darwin; Hansen, Axel Kornerup; Madsen, Henry; Trang, Nguyen Thi Thu; Hung, Nguyen Manh; Dalsgaard, Anders

2009-06-01

Recent studies in Vietnam and other Asian countries have shown that fish-borne zoonotic intestinal trematodes (FZT) occur very frequently in humans. The dominant intestinal FZT in Vietnamese fish are species of Haplorchis, in particular H. pumilio. However, basic studies on the biology and pathology of adult H. pumilio are difficult because of the lack of a standardized experimental animal model. The objective of this study was to establish and optimize such an animal-infection model for H. pumilio. Using metacercariae isolated from naturally infected fish, experiments were conducted to identify a suitable experimental animal host species, as well as the optimum metacercariae infection dose, and to determine the post-infection interval for patency. In a series of experiments, mice (Mus musculus) and chickens (Gallus gallus dom.) were infected with different numbers of metacercariae, and worm recoveries were made at varying intervals post-infection (PI). Based on the mean number of adult flukes recovered/number of metacercariae inoculated and the percent of hosts infected, mice were significantly more susceptible to infection than were chickens. The proportion of metacercariae developing to the adult stage increased with dose size. The peak worm recovery (geometric mean) was found to be day 7, although not all recovered flukes were gravid until day 9 PI. These results describe a mouse infection model with good predictability for intestinal flukes, such as H. pumilio, results which could facilitate investigations on important biological and pathological aspects of intestinal fluke infections.

Novel test of motor and other dysfunctions in mouse neurological disease models.

PubMed

Barth, Albert M I; Mody, Istvan

2014-01-15

Just like human neurological disorders, corresponding mouse models present multiple deficiencies. Estimating disease progression or potential treatment effectiveness in such models necessitates the use of time consuming and multiple tests usually requiring a large number of scarcely available genetically modified animals. Here we present a novel and simple single camera arrangement and analysis software for detailed motor function evaluation in mice walking on a wire mesh that provides complex 3D information (instantaneous position, speed, distance traveled, foot fault depth, duration, location, relationship to speed of movement, etc.). We investigated 3 groups of mice with various neurological deficits: (1) unilateral motor cortical stroke; (2) effects of moderate ethanol doses; and (3) aging (96-99 weeks old). We show that post stroke recovery can be divided into separate stages based on strikingly different characteristics of motor function deficits, some resembling the human motor neglect syndrome. Mice treated with moderate dose of alcohol and aged mice showed specific motor and exploratory deficits. Other tests rely either partially or entirely on manual video analysis introducing a significant subjective component into the analysis, and analyze a single aspect of motor function. Our novel experimental approach provides qualitatively new, complex information about motor impairments and locomotor/exploratory activity. It should be useful for the detailed characterization of a broad range of human neurological disease models in mice, and for the more accurate assessment of disease progression or treatment effectiveness. Copyright © 2013 Elsevier B.V. All rights reserved.

Age-dependent differences in nicotine reward and withdrawal in female mice.

PubMed

Kota, D; Martin, B R; Damaj, M I

2008-06-01

Adolescent smoking is an increasing epidemic in the US. Research has shown that the commencement of smoking at a young age increases addiction and decreases the probability of successful cessation; however, limited work has focused on nicotine dependence in the female. The goal of the present study was to identify the biological and behavioral factors that may contribute to nicotine's increased abuse liability in female adolescents using animal models of nicotine dependence. Early adolescent (PND 28) and adult (PND 70) female mice were compared in various aspects of nicotine dependence using reward and withdrawal models following sub-chronic nicotine exposure. Furthermore, in vivo acute sensitivity and tolerance to nicotine were examined. In the conditioned place preference model, adolescents demonstrated a significant preference at 0.5 mg/kg nicotine, an inactive dose in adults. Adults found higher doses (0.7 and 1.0 mg/kg) of nicotine to elicit rewarding effects. Furthermore, adolescents displayed increased physical, but not affective, withdrawal signs in three models. Upon acute exposure to nicotine, adolescent mice showed increased sensitivity in an analgesic measure as well as hypothermia. After chronic nicotine exposure, both adults and adolescents displayed tolerance to nicotine with adolescents having a lower degree of tolerance to changes in body temperature. These data indicate that differences in nicotine's rewarding and aversive effects may contribute to variations in certain components of nicotine dependence between adult and adolescent female mice. Furthermore, this implies that smoking cessation therapies may not be equally effective across all ages.

The Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD) Tool

EPA Pesticide Factsheets

Providing quantal response models, which are also used in the U.S. EPA benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates.

Dose distribution for dental cone beam CT and its implication for defining a dose index

PubMed Central

Pauwels, R; Theodorakou, C; Walker, A; Bosmans, H; Jacobs, R; Horner, K; Bogaerts, R

2012-01-01

Objectives To characterize the dose distribution for a range of cone beam CT (CBCT) units, investigating different field of view sizes, central and off-axis geometries, full or partial rotations of the X-ray tube and different clinically applied beam qualities. The implications of the dose distributions on the definition and practicality of a CBCT dose index were assessed. Methods Dose measurements on CBCT devices were performed by scanning cylindrical head-size water and polymethyl methacrylate phantoms, using thermoluminescent dosemeters, a small-volume ion chamber and radiochromic films. Results It was found that the dose distribution can be asymmetrical for dental CBCT exposures throughout a homogeneous phantom, owing to an asymmetrical positioning of the isocentre and/or partial rotation of the X-ray source. Furthermore, the scatter tail along the z-axis was found to have a distinct shape, generally resulting in a strong drop (90%) in absorbed dose outside the primary beam. Conclusions There is no optimal dose index available owing to the complicated exposure geometry of CBCT and the practical aspects of quality control measurements. Practical validation of different possible dose indices is needed, as well as the definition of conversion factors to patient dose. PMID:22752320

RNA Viruses that Cause Hemorrhagic, Encephalitic, and Febrile Disease

DTIC Science & Technology

1990-01-01

doses to levels that are subopti- effective dose (ED,0) values for Rift Valley mal for cures in other bunyavirus mouse Fever ( RVF ) virus (ED,, = 80 g...serum protein and AST Etiologic Agent (SGOT) identified in the placebo group by logistic regression], utilizing a stepwise lo- RVF , an old-world...treatment of H FRS in this study. Treatment reduced mortality RVF , distributed throughout sub-Saharan and improved several important aspects of Africa

Pharmacodynamics of nicotine: implications for rational treatment of nicotine addiction.

PubMed

Benowitz, N L

1991-05-01

Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. Understanding the pharmacodynamics of nicotine and its role in the addiction process provides a basis for rational therapeutic intervention. Pharmacodynamic considerations are discussed in relation to the elements of smoking cessation therapy: setting objectives, selecting appropriate medication and dosing form, selecting the optimal doses and dosage regimens, assessing therapeutic outcome, and adjusting therapy to optimize benefits and minimize risks.

Analysis of outcomes in radiation oncology: An integrated computational platform

PubMed Central

Liu, Dezhi; Ajlouni, Munther; Jin, Jian-Yue; Ryu, Samuel; Siddiqui, Farzan; Patel, Anushka; Movsas, Benjamin; Chetty, Indrin J.

2009-01-01

Radiotherapy research and outcome analyses are essential for evaluating new methods of radiation delivery and for assessing the benefits of a given technology on locoregional control and overall survival. In this article, a computational platform is presented to facilitate radiotherapy research and outcome studies in radiation oncology. This computational platform consists of (1) an infrastructural database that stores patient diagnosis, IMRT treatment details, and follow-up information, (2) an interface tool that is used to import and export IMRT plans in DICOM RT and AAPM/RTOG formats from a wide range of planning systems to facilitate reproducible research, (3) a graphical data analysis and programming tool that visualizes all aspects of an IMRT plan including dose, contour, and image data to aid the analysis of treatment plans, and (4) a software package that calculates radiobiological models to evaluate IMRT treatment plans. Given the limited number of general-purpose computational environments for radiotherapy research and outcome studies, this computational platform represents a powerful and convenient tool that is well suited for analyzing dose distributions biologically and correlating them with the delivered radiation dose distributions and other patient-related clinical factors. In addition the database is web-based and accessible by multiple users, facilitating its convenient application and use. PMID:19544785

Consistency evaluation between EGSnrc and Geant4 charged particle transport in an equilibrium magnetic field.

PubMed

Yang, Y M; Bednarz, B

2013-02-21

Following the proposal by several groups to integrate magnetic resonance imaging (MRI) with radiation therapy, much attention has been afforded to examining the impact of strong (on the order of a Tesla) transverse magnetic fields on photon dose distributions. The effect of the magnetic field on dose distributions must be considered in order to take full advantage of the benefits of real-time intra-fraction imaging. In this investigation, we compared the handling of particle transport in magnetic fields between two Monte Carlo codes, EGSnrc and Geant4, to analyze various aspects of their electromagnetic transport algorithms; both codes are well-benchmarked for medical physics applications in the absence of magnetic fields. A water-air-water slab phantom and a water-lung-water slab phantom were used to highlight dose perturbations near high- and low-density interfaces. We have implemented a method of calculating the Lorentz force in EGSnrc based on theoretical models in literature, and show very good consistency between the two Monte Carlo codes. This investigation further demonstrates the importance of accurate dosimetry for MRI-guided radiation therapy (MRIgRT), and facilitates the integration of a ViewRay MRIgRT system in the University of Wisconsin-Madison's Radiation Oncology Department.

Consistency evaluation between EGSnrc and Geant4 charged particle transport in an equilibrium magnetic field

NASA Astrophysics Data System (ADS)

Yang, Y. M.; Bednarz, B.

2013-02-01

Following the proposal by several groups to integrate magnetic resonance imaging (MRI) with radiation therapy, much attention has been afforded to examining the impact of strong (on the order of a Tesla) transverse magnetic fields on photon dose distributions. The effect of the magnetic field on dose distributions must be considered in order to take full advantage of the benefits of real-time intra-fraction imaging. In this investigation, we compared the handling of particle transport in magnetic fields between two Monte Carlo codes, EGSnrc and Geant4, to analyze various aspects of their electromagnetic transport algorithms; both codes are well-benchmarked for medical physics applications in the absence of magnetic fields. A water-air-water slab phantom and a water-lung-water slab phantom were used to highlight dose perturbations near high- and low-density interfaces. We have implemented a method of calculating the Lorentz force in EGSnrc based on theoretical models in literature, and show very good consistency between the two Monte Carlo codes. This investigation further demonstrates the importance of accurate dosimetry for MRI-guided radiation therapy (MRIgRT), and facilitates the integration of a ViewRay MRIgRT system in the University of Wisconsin-Madison's Radiation Oncology Department.

Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology.

PubMed

Robinson, Joshua F; Theunissen, Peter T; van Dartel, Dorien A M; Pennings, Jeroen L; Faustman, Elaine M; Piersma, Aldert H

2011-09-01

Toxicogenomic evaluations may improve toxicity prediction of in vitro-based developmental models, such as whole embryo culture (WEC) and embryonic stem cells (ESC), by providing a robust mechanistic marker which can be linked with responses associated with developmental toxicity in vivo. While promising in theory, toxicogenomic comparisons between in vivo and in vitro models are complex due to inherent differences in model characteristics and experimental design. Determining factors which influence these global comparisons are critical in the identification of reliable mechanistic-based markers of developmental toxicity. In this study, we compared available toxicogenomic data assessing the impact of the known teratogen, methylmercury (MeHg) across a diverse set of in vitro and in vivo models to investigate the impact of experimental variables (i.e. model, dose, time) on our comparative assessments. We evaluated common and unique aspects at both the functional (Gene Ontology) and gene level of MeHg-induced response. At the functional level, we observed stronger similarity in MeHg-response between mouse embryos exposed in utero (2 studies), ESC, and WEC as compared to liver, brain and mouse embryonic fibroblast MeHg studies. These findings were strongly correlated to the presence of a MeHg-induced developmentally related gene signature. In addition, we identified specific MeHg-induced gene expression alterations associated with developmental signaling and heart development across WEC, ESC and in vivo systems. However, the significance of overlap between studies was highly dependent on traditional experimental variables (i.e. dose, time). In summary, we identify promising examples of unique gene expression responses which show in vitro-in vivo similarities supporting the relevance of in vitro developmental models for predicting in vivo developmental toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

Design and dosimetric characteristics of a new endocavitary contact radiotherapy system using an electronic brachytherapy source.

PubMed

Richardson, Susan; Garcia-Ramirez, Jose; Lu, Wei; Myerson, Robert J; Parikh, Parag

2012-11-01

To present design aspects and acceptance tests performed for clinical implementation of electronic brachytherapy treatment of early stage rectal adenocarcinoma. A dosimetric comparison is made between the historically used Philips RT-50 unit and the newly developed Axxent(®) Model S700 electronic brachytherapy source manufactured by Xoft (iCad, Inc.). Two proctoscope cones were manufactured by ElectroSurgical Instruments (ESI). Two custom surface applicators were manufactured by Xoft and were designed to fit and interlock with the proctoscope cones from ESI. Dose rates, half value layers (HVL), and percentage depth dose (PDD) measurements were made with the Xoft system and compared to historical RT-50 data. A description of the patient treatment approach and exposure rates during the procedure is also provided. The electronic brachytherapy system has a lower surface dose rate than the RT-50. The dose rate to water on the surface from the Xoft system is approximately 2.1 Gy∕min while the RT-50 is 10-12 Gy∕min. However, treatment times with Xoft are still reasonable. The HVLs and PDDs between the two systems were comparable resulting in similar doses to the target and to regions beyond the target. The exposure rate levels around a patient treatment were acceptable. The standard uncertainty in the dose rate to water on the surface is approximately ±5.2%. The Philips RT-50 unit is an out-of-date radiotherapy machine that is no longer manufactured with limited replacement parts. The use of a custom-designed proctoscope and Xoft surface applicators allows delivery of a well-established treatment with the ease of a modern radiotherapy device. While the dose rate is lower with the use of Xoft, the treatment times are still reasonable. Additionally, personnel may stand farther away from the Xoft radiation source, thus potentially reducing radiation exposure to the operator and other personnel.

Molecular aspect of silver nanoparticles regulated embryonic development in Zebrafish (Danio rerio) by Oct-4 expression.

PubMed

Sarkar, Biplab; Verma, Suresh K; Akhtar, Javed; Netam, Surya Prakash; Gupta, Sanjay Kr; Panda, Pritam Kumar; Mukherjee, Koel

2018-09-01

With the enhancement of commercial manifestation of silver nanoparticles, concerned has risen on their accumulation in aquatic system and consequent effects on fish development and metabolism. In this study, experiments were conducted to assess the impacts of silver nanoparticles on early life cycles of fish considering Zebrafish (Danio rerio) as experimental model. Silver nanoparticles were synthesized through chemical reduction method and characterized through UV-visible spectroscopy, dynamic light scattering (DLS), and HR-TEM. Different sub lethal doses of nanosilver were applied (13.6, 21.6, 42.4, 64, and 128 μgL -1 ) to post-fertilization phases of Zebrafish embryos and their interaction effects were monitored up to six days period. No significant morphological variations were observed at 13.6, 21.6, 42.4 μgL -1 dose of silver nanoparticles, whereas 64 and 128 μgL -1 exposure dose exhibited bending in myotome, deformity in tail region, somites, notochord and swelling in anterior and posterior region of embryos and larva. Hatching performances analysis elicited highest hatching success in 13.6 and 21.6 μgL -1 doses of silver nanoparticles followed by positive and negative control, whereas exposure dose of 64 and 128 μgL -1 exhibited comparatively lower success. Western blot analysis were conducted on developing hatchlings with Oct4 antibody and at 13.6 and 21.6 μgL -1 dose,it showed over expression elucidating stimulatory role of nanosilver in these mentioned doses. In silico analysis depicted a firm interaction of nanosilver with Oct4 revealing their key role in growth stimulation of developing embryos. The study demonstrates the function of nanosilver as a growth promoter rather only as a toxicant in fish metabolic system. Copyright © 2018 Elsevier Ltd. All rights reserved.

Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape.

PubMed

Markiewicz, Ewa; Barnard, Stephen; Haines, Jackie; Coster, Margaret; van Geel, Orry; Wu, Weiju; Richards, Shane; Ainsbury, Elizabeth; Rothkamm, Kai; Bouffler, Simon; Quinlan, Roy A

2015-04-01

Elevated cataract risk after radiation exposure was established soon after the discovery of X-rays in 1895. Today, increased cataract incidence among medical imaging practitioners and after nuclear incidents has highlighted how little is still understood about the biological responses of the lens to low-dose ionizing radiation (IR). Here, we show for the first time that in mice, lens epithelial cells (LECs) in the peripheral region repair DNA double strand breaks (DSB) after exposure to 20 and 100 mGy more slowly compared with circulating blood lymphocytes, as demonstrated by counts of γH2AX foci in cell nuclei. LECs in the central region repaired DSBs faster than either LECs in the lens periphery or lymphocytes. Although DSB markers (γH2AX, 53BP1 and RAD51) in both lens regions showed linear dose responses at the 1 h timepoint, nonlinear responses were observed in lenses for EdU (5-ethynyl-2'-deoxy-uridine) incorporation, cyclin D1 staining and cell density after 24 h at 100 and 250 mGy. After 10 months, the lens aspect ratio was also altered, an indicator of the consequences of the altered cell proliferation and cell density changes. A best-fit model demonstrated a dose-response peak at 500 mGy. These data identify specific nonlinear biological responses to low (less than 1000 mGy) dose IR-induced DNA damage in the lens epithelium.

Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape

PubMed Central

Markiewicz, Ewa; Barnard, Stephen; Haines, Jackie; Coster, Margaret; van Geel, Orry; Wu, Weiju; Richards, Shane; Ainsbury, Elizabeth; Rothkamm, Kai; Bouffler, Simon; Quinlan, Roy A.

2015-01-01

Elevated cataract risk after radiation exposure was established soon after the discovery of X-rays in 1895. Today, increased cataract incidence among medical imaging practitioners and after nuclear incidents has highlighted how little is still understood about the biological responses of the lens to low-dose ionizing radiation (IR). Here, we show for the first time that in mice, lens epithelial cells (LECs) in the peripheral region repair DNA double strand breaks (DSB) after exposure to 20 and 100 mGy more slowly compared with circulating blood lymphocytes, as demonstrated by counts of γH2AX foci in cell nuclei. LECs in the central region repaired DSBs faster than either LECs in the lens periphery or lymphocytes. Although DSB markers (γH2AX, 53BP1 and RAD51) in both lens regions showed linear dose responses at the 1 h timepoint, nonlinear responses were observed in lenses for EdU (5-ethynyl-2′-deoxy-uridine) incorporation, cyclin D1 staining and cell density after 24 h at 100 and 250 mGy. After 10 months, the lens aspect ratio was also altered, an indicator of the consequences of the altered cell proliferation and cell density changes. A best-fit model demonstrated a dose-response peak at 500 mGy. These data identify specific nonlinear biological responses to low (less than 1000 mGy) dose IR-induced DNA damage in the lens epithelium. PMID:25924630

Modified Gompertz equation for electrotherapy murine tumor growth kinetics: predictions and new hypotheses.

PubMed

Cabrales, Luis E Bergues; Nava, Juan J Godina; Aguilera, Andrés Ramírez; Joa, Javier A González; Ciria, Héctor M Camué; González, Maraelys Morales; Salas, Miriam Fariñas; Jarque, Manuel Verdecia; González, Tamara Rubio; Mateus, Miguel A O'Farril; Brooks, Soraida C Acosta; Palencia, Fabiola Suárez; Zamora, Lisset Ortiz; Quevedo, María C Céspedes; Seringe, Sarah Edward; Cuitié, Vladimir Crombet; Cabrales, Idelisa Bergues; González, Gustavo Sierra

2010-10-28

Electrotherapy effectiveness at different doses has been demonstrated in preclinical and clinical studies; however, several aspects that occur in the tumor growth kinetics before and after treatment have not yet been revealed. Mathematical modeling is a useful instrument that can reveal some of these aspects. The aim of this paper is to describe the complete growth kinetics of unperturbed and perturbed tumors through use of the modified Gompertz equation in order to generate useful insight into the mechanisms that underpin this devastating disease. The complete tumor growth kinetics for control and treated groups are obtained by interpolation and extrapolation methods with different time steps, using experimental data of fibrosarcoma Sa-37. In the modified Gompertz equation, a delay time is introduced to describe the tumor's natural history before treatment. Different graphical strategies are used in order to reveal new information in the complete kinetics of this tumor type. The first stage of complete tumor growth kinetics is highly non linear. The model, at this stage, shows different aspects that agree with those reported theoretically and experimentally. Tumor reversibility and the proportionality between regions before and after electrotherapy are demonstrated. In tumors that reach partial remission, two antagonistic post-treatment processes are induced, whereas in complete remission, two unknown antitumor mechanisms are induced. The modified Gompertz equation is likely to lead to insights within cancer research. Such insights hold promise for increasing our understanding of tumors as self-organizing systems and, the possible existence of phase transitions in tumor growth kinetics, which, in turn, may have significant impacts both on cancer research and on clinical practice.

Mineral Fiber Toxicology

EPA Science Inventory

The chemical and physical properties of different forms of mineral fibers impact biopersistence and pathology in the lung. Fiber chemistry, length, aspect ratio, surface area and dose are critical factors determining mineral fiber-associated health effects including cancer and as...

INHALATION EXPOSURE-RESPONSE METHODOLOGY

EPA Science Inventory

The Inhalation Exposure-Response Analysis Methodology Document is expected to provide guidance on the development of the basic toxicological foundations for deriving reference values for human health effects, focusing on the hazard identification and dose-response aspects of the ...

Severe hypertriglyceridemia and hypercholesterolemia accelerating renal injury: a novel model of type 1 diabetic hamsters induced by short-term high-fat / high-cholesterol diet and low-dose streptozotocin.

PubMed

He, Liang; Hao, Lili; Fu, Xin; Huang, Mingshu; Li, Rui

2015-04-11

Hyperlipidemia is thought to be a major risk factor for the progression of renal diseases in diabetes. Recent studies have shown that lipid profiles are commonly abnormal early on type 2 diabetes mellitus (T2DM) with diabetic nephropathy. However, the early effects of triglyceride and cholesterol abnormalities on renal injury in type 1 diabetes mellitus (T1DM) are not fully understood and require reliable animal models for exploration of the underlying mechanisms. Hamster models are important tools for studying lipid metabolism because of their similarity to humans in terms of lipid utilization and high susceptibility to dietary cholesterol and fat. Twenty-four male Golden Syrian hamsters (100-110 g) were rendered diabetes by intraperitoneal injections of streptozotocin (STZ) on consecutive 3 days at dose of 30 mg/kg, Ten days after STZ injections, hamsters with a plasma Glu concentration more than 12 mmol/L were selected as insulin deficient ones and divided into four groups (D-C, D-HF, D-HC, and D-HFHC), and fed with commercially available standard rodent chow, high-fat diet, high-cholesterol diet, high-fat and cholesterol diet respectively, for a period of four weeks. After an induction phase, a stable model of renal injury was established with the aspects of early T1DM kidney disease, These aspects were severe hypertriglyceridemia, hypercholesterolemia, proteinuria with mesangial matrix accumulation, upgraded creatinine clearance, significant cholesterol and triglyceride deposition, and increasing glomerular surface area, thickness of basement membrane and mesangial expansion. The mRNA levels of sterol regulatory element binding protein-1c, transforming growth factors-β, plasminogen activator inhibitor-1, tumor necrosis factor-α and interleukin-6 in the D-HFHC group were significantly up-regulated compared with control groups. This study presents a novel, non-transgenic, non-surgical method for induction of renal injury in hamsters, which is an important complement to existing diabetic models for pathophysiological studies in early acute and chronic kidney disease, especially hyperlipidemia. These data suggest that both severe hypertriglyceridemia and hypercholesterolemia can accelerate renal injury in the early development of T1DM.

Investigations on 16-Arylideno Steroids as a New Class of Neuroprotective Agents for the Treatment of Alzheimer's and Parkinson's Diseases.

PubMed

Singh, Ranjit; Bansal, Ranju

2017-01-18

Neuroinflammatory mechanisms mediated by activated glial and cytokines (TNF-α, IL-1β) might contribute to neuronal degeneration leading to Alzheimer's (AD) and Parkinson's disease (PD). Lipopolysaccharide (LPS) is an inflammogen derived from the cell wall of Gram-negative bacteria, which promotes neuroinflammation and subsequent neurodegeneration. Dehydroepiandrosterone (DHEA) and testosterone have been reported as neuroprotective steroids useful for the treatment of various neurodegenerative disorders. In the present study, several 16-arylidene steroidal derivatives have been evaluated as neuroprotective agents in LPS-treated animal models. It was observed that 16-arylidene steroidal derivatives 1a-d and 6a-h considerably improve LPS-induced learning, memory, and movement deficits in animal models. Biochemical estimations of brain serum of treated animals revealed suppression of oxidative and nitrosative stress, acetylcholinesterase activity, and reduction in TNF-α levels, which were induced through LPS mediated neuroinflammatory mechanisms leading to neurodegeneration of brain. Of all the steroidal derivatives, 16-(4-pyridylidene) steroid 1c and its 4-aza analogue 6c were found to be the most active neuroprotective agents and produced effects comparable to standard drug celecoxib at a much lower dose and better than dexamethasone at the same dose in terms of behavioral, biochemical, and molecular aspects.

Ultra-low-dose computed tomographic angiography with model-based iterative reconstruction compared with standard-dose imaging after endovascular aneurysm repair: a prospective pilot study.

PubMed

Naidu, Sailen G; Kriegshauser, J Scott; Paden, Robert G; He, Miao; Wu, Qing; Hara, Amy K

2014-12-01

An ultra-low-dose radiation protocol reconstructed with model-based iterative reconstruction was compared with our standard-dose protocol. This prospective study evaluated 20 men undergoing surveillance-enhanced computed tomography after endovascular aneurysm repair. All patients underwent standard-dose and ultra-low-dose venous phase imaging; images were compared after reconstruction with filtered back projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction. Objective measures of aortic contrast attenuation and image noise were averaged. Images were subjectively assessed (1 = worst, 5 = best) for diagnostic confidence, image noise, and vessel sharpness. Aneurysm sac diameter and endoleak detection were compared. Quantitative image noise was 26% less with ultra-low-dose model-based iterative reconstruction than with standard-dose adaptive statistical iterative reconstruction and 58% less than with ultra-low-dose adaptive statistical iterative reconstruction. Average subjective noise scores were not different between ultra-low-dose model-based iterative reconstruction and standard-dose adaptive statistical iterative reconstruction (3.8 vs. 4.0, P = .25). Subjective scores for diagnostic confidence were better with standard-dose adaptive statistical iterative reconstruction than with ultra-low-dose model-based iterative reconstruction (4.4 vs. 4.0, P = .002). Vessel sharpness was decreased with ultra-low-dose model-based iterative reconstruction compared with standard-dose adaptive statistical iterative reconstruction (3.3 vs. 4.1, P < .0001). Ultra-low-dose model-based iterative reconstruction and standard-dose adaptive statistical iterative reconstruction aneurysm sac diameters were not significantly different (4.9 vs. 4.9 cm); concordance for the presence of endoleak was 100% (P < .001). Compared with a standard-dose technique, an ultra-low-dose model-based iterative reconstruction protocol provides comparable image quality and diagnostic assessment at a 73% lower radiation dose.

Biological PET-guided adaptive radiotherapy for dose escalation in head and neck cancer: a systematic review.

PubMed

Hamming-Vrieze, Olga; Navran, Arash; Al-Mamgani, Abrahim; Vogel, Wouter V

2018-06-04

In recent years, the possibility of adapting radiotherapy to changes in biological tissue parameters has emerged. It is hypothesized that early identification of radio-resistant parts of the tumor during treatment provides the possibility to adjust the radiotherapy plan to improve outcome. The aim of this systematic literature review was to evaluate the current state of the art of biological PET-guided adaptive radiotherapy, focusing on dose escalation to radio-resistant tumor. A structured literature search was done to select clinical trials including patients with head and neck cancer of the oral cavity, oropharynx, hypopharynx or larynx, with a PET performed during treatment used to develop biological adaptive radiotherapy by i) delineation of sub-volumes suitable for adaptive re-planning, ii) in silico adaptive treatment planning or iii) treatment of patients with PET based dose escalated adaptive radiotherapy. Nineteen articles were selected, 12 articles analyzing molecular imaging signal during treatment and 7 articles focused on biological adaptive treatment planning, of which two were clinical trials. Studied biological pathways include metabolism (FDG), hypoxia (MISO, FAZA and HX4) and proliferation (FLT). In the development of biological dose adaptation in radiotherapy for head-neck tumors, many aspects of the procedure remain ambiguous. Patient selection, tracer selection for detection of the radio-resistant sub-volumes, timing of adaptive radiotherapy, workflow and treatment planning aspects are discussed in a clinical context.

A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Houweling, Antonetta C., E-mail: A.Houweling@umcutrecht.n; Philippens, Marielle E.P.; Dijkema, Tim

2010-03-15

Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulatedmore » salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.« less

The effects of small field dosimetry on the biological models used in evaluating IMRT dose distributions

NASA Astrophysics Data System (ADS)

Cardarelli, Gene A.

The primary goal in radiation oncology is to deliver lethal radiation doses to tumors, while minimizing dose to normal tissue. IMRT has the capability to increase the dose to the targets and decrease the dose to normal tissue, increasing local control, decrease toxicity and allow for effective dose escalation. This advanced technology does present complex dose distributions that are not easily verified. Furthermore, the dose inhomogeneity caused by non-uniform dose distributions seen in IMRT treatments has caused the development of biological models attempting to characterize the dose-volume effect in the response of organized tissues to radiation. Dosimetry of small fields can be quite challenging when measuring dose distributions for high-energy X-ray beams used in IMRT. The proper modeling of these small field distributions is essential in reproducing accurate dose for IMRT. This evaluation was conducted to quantify the effects of small field dosimetry on IMRT plan dose distributions and the effects on four biological model parameters. The four biological models evaluated were: (1) the generalized Equivalent Uniform Dose (gEUD), (2) the Tumor Control Probability (TCP), (3) the Normal Tissue Complication Probability (NTCP) and (4) the Probability of uncomplicated Tumor Control (P+). These models are used to estimate local control, survival, complications and uncomplicated tumor control. This investigation compares three distinct small field dose algorithms. Dose algorithms were created using film, small ion chamber, and a combination of ion chamber measurements and small field fitting parameters. Due to the nature of uncertainties in small field dosimetry and the dependence of biological models on dose volume information, this examination quantifies the effects of small field dosimetry techniques on radiobiological models and recommends pathways to reduce the errors in using these models to evaluate IMRT dose distributions. This study demonstrates the importance of valid physical dose modeling prior to the use of biological modeling. The success of using biological function data, such as hypoxia, in clinical IMRT planning will greatly benefit from the results of this study.

Eye lens monitoring for interventional radiology personnel: dosemeters, calibration and practical aspects of H p (3) monitoring. A 2015 review.

PubMed

Carinou, Eleftheria; Ferrari, Paolo; Bjelac, Olivera Ciraj; Gingaume, Merce; Merce, Marta Sans; O'Connor, Una

2015-09-01

A thorough literature review about the current situation on the implementation of eye lens monitoring has been performed in order to provide recommendations regarding dosemeter types, calibration procedures and practical aspects of eye lens monitoring for interventional radiology personnel. Most relevant data and recommendations from about 100 papers have been analysed and classified in the following topics: challenges of today in eye lens monitoring; conversion coefficients, phantoms and calibration procedures for eye lens dose evaluation; correction factors and dosemeters for eye lens dose measurements; dosemeter position and influence of protective devices. The major findings of the review can be summarised as follows: the recommended operational quantity for the eye lens monitoring is H p (3). At present, several dosemeters are available for eye lens monitoring and calibration procedures are being developed. However, in practice, very often, alternative methods are used to assess the dose to the eye lens. A summary of correction factors found in the literature for the assessment of the eye lens dose is provided. These factors can give an estimation of the eye lens dose when alternative methods, such as the use of a whole body dosemeter, are used. A wide range of values is found, thus indicating the large uncertainty associated with these simplified methods. Reduction factors from most common protective devices obtained experimentally and using Monte Carlo calculations are presented. The paper concludes that the use of a dosemeter placed at collar level outside the lead apron can provide a useful first estimate of the eye lens exposure. However, for workplaces with estimated annual equivalent dose to the eye lens close to the dose limit, specific eye lens monitoring should be performed. Finally, training of the involved medical staff on the risks of ionising radiation for the eye lens and on the correct use of protective systems is strongly recommended.

Fluoxetine potentiation of omega-3 fatty acid antidepressant effect: evaluating pharmacokinetic and brain fatty acid-related aspects in rodents.

PubMed

Laino, Carlos Horacio; Garcia, Pilar; Podestá, María Fernanda; Höcht, Christian; Slobodianik, Nora; Reinés, Analía

2014-10-01

We previously reported that combined fluoxetine administration at antidepressant doses renders additive antidepressant effects, whereas non-antidepressant doses potentiate the omega-3 fatty acid antidepressant effect. In the present study, we aimed to evaluate putative pharmacokinetic and brain omega-3 fatty acid-related aspects for fluoxetine potentiation of omega-3 fatty acid antidepressant effect in rats. Coadministration of omega-3 fatty acids with a non-antidepressant dose of fluoxetine (1 mg/kg day) failed to affect both brain fluoxetine concentration and norfluoxetine plasma concentration profile. Fluoxetine plasma concentrations remained below the sensitivity limit of the detection method. Either antidepressant (10 mg/kg day) or non-antidepressant (1 mg/kg day) doses of fluoxetine in combination with omega-3 fatty acids increased hippocampal docosapentaenoic acid (DPA, 22:5 omega-3) levels. Although individual treatments had no effects on DPA concentration, DPA increase was higher when omega-3 were combined with the non-antidepressant dose of fluoxetine. Chronic DPA administration exerted antidepressant-like effects in the forced swimming test while increasing hippocampal docosahexaenoic (22:6 omega-3) and DPA levels. Our results suggest no pharmacokinetic interaction and reveal specific hippocampal DPA changes after fluoxetine and omega-3 combined treatments in our experimental conditions. The DPA role in the synergistic effect of fluoxetine and omega-3 combined treatments will be for sure the focus of future studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3316-3325, 2014. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Developmental Exposure to Low Levels of Ethinylestradiol Affects Play Behavior in Juvenile Female Rats.

PubMed

Zaccaroni, Marco; Massolo, Alessandro; Della Seta, Daniele; Farabollini, Francesca; Giannelli, Giulietta; Fusani, Leonida; Dessì-Fulgheri, Francesco

2018-05-01

Juvenile social play contributes to the development of adult social and emotional skills in humans and non-human animals, and is therefore a useful endpoint to study the effects of endocrine disrupters on behavior in animal models. Ethinylestradiol (EE 2 ) is a widely produced, powerful synthetic estrogen that is widespread in the environment mainly because is a component of the contraceptive pill. In addition, fetuses may be exposed to EE2 when pregnancy is undetected during contraceptive treatment. To understand whether exposure to EE 2 during gestation or lactation affects social play, we exposed 72 female Sprague-Dawley rats to EE 2 or vehicle either during gestation (gestation day (GD) 5 through GD 20) or during lactation (from postnatal day (PND) 1 through PND 21). Two doses of EE 2 were used to treat the dams: a lower dose in the range of possible environmental exposure (4 ng/kg/day) and a higher dose equivalent to that received during contraceptive treatment (400 ng/kg/day). Behavioral testing was carried out between PND 40 and 45. A principal component analysis of frequencies of behavioral items observed during play sessions identified three main components: defensive-like play, aggressive-like play, and exploration. Aggressive-like play was significantly increased by both doses of EE 2 , and the gestational administration was in general more effective than the lactational one. Defensive-like play and exploration were not significantly affected by treatment. This research showed that low and very low doses of EE 2 that mimic clinical or environmental exposure during development can affect important aspects of social behavior even during restricted time windows.

A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer.

PubMed

Wang, F; Yeung, K L; Chan, W C; Kwok, C C H; Leung, S L; Wu, C; Chan, E Y Y; Yu, I T S; Yang, X R; Tse, L A

2013-11-01

This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose-response meta-analysis approach. We systematicly searched all cohort and case-control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose-response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies. Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between 'ever exposed to night shift work' and breast cancer was 1.19 [95% confidence interval (CI) 1.05-1.35]. Further meta-analyses on dose-response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01-1.05; Pheterogeneity < 0.001). Our meta-analysis also suggested that an increase in 500-night shifts would result in a 13% (RR = 1.13, 95% CI 1.07-1.21; Pheterogeneity = 0.06) increase in breast cancer risk. This systematic review updated the evidence that a positive dose-response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work.

Customized vaginal vault brachytherapy with computed tomography imaging-derived applicator prototyping.

PubMed

Wiebe, Ericka; Easton, Harry; Thomas, Gillian; Barbera, Lisa; D'Alimonte, Laura; Ravi, Ananth

2015-01-01

A novel customized vaginal brachytherapy mould technique has been developed for clinical use. This image-guided technique provides a brachytherapy applicator solution for irregular vaginal vault configuration and/or a wide vaginal apex relative to the vaginal introitus that would be sub-optimally treated with standard cylinders. The customized vaginal applicator is generated by the following process: CT images are obtained with contrast-soaked vaginal packing in situ to highlight unique anatomical detail. A 3-dimensional digital model is developed from the images and subsequently converted into a custom applicator with the use of stereolithography, which is an additive manufacturing technique whereby layers 50-100 μm thick of resin are deposited and polymerized using a laser to create intricate 3-dimensional objects. The density of the applicator and the dose delivered using the custom applicator were both measured to ensure accurate dosimetry. The CT-based densities of a clinical vaginal cylinder and the cylinder generated using stereolithography were 1.29 ± 0.06 g/cm(3) vs 1.28 ± 0.01 g/cm(3), respectively. The mean measured dose from a representative stereolithographed applicator normalized to dose measured for a single plastic catheter was 99.8 ± 4.2%. In patient dosimetric results indicate improved coverage of the lateral aspect of vaginal vault with the custom cylinder relative to the standard cylinder; 700 cGy vs 328 cGy, respectively, at a representative lateral vaginal dose point, while simultaneously achieving relatively narrow dose distribution in the anterior/posterior direction. Stereolithographic applicator production was available within a clinically acceptable timeframe, and its clinical feasibility and utility has been demonstrated. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice.

PubMed

Payandemehr, Borna; Rahimian, Reza; Gooshe, Maziar; Bahremand, Arash; Gholizadeh, Ramtin; Berijani, Sina; Ahmadi-Dastgerdi, Mohammad; Aminizade, Mehdi; Sarreshte-Dari, Ali; Dianati, Vahid; Amanlou, Massoud; Dehpour, Ahmad Reza

2014-05-01

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature. Copyright © 2014 Elsevier Inc. All rights reserved.

Dose Adjustment for Normal Eating: A Role for the Expert Patient?

PubMed Central

2014-01-01

The Dose Adjustment for Normal Eating (DAFNE) programme of intensive insulin therapy for type 1 diabetes provides a structured educational intervention to improve glycemic control, reduce hypoglycemia and improve quality of life. Enhancement of self-management skills is a key element of DAFNE and patients acquire detailed skills in insulin dose adjustment. Following DAFNE training, patients report improved confidence in their ability to manage their own insulin dosing, but generally still seek and require the assistance of health professionals when making substantial changes to their insulin regimens. Some DAFNE trained patients may be able to assist their peers in aspects of diabetes management within a group environment, but widespread introduction of the expert patient/peer educator role in the self-management of type 1 diabetes, in particular related to insulin dose management, would require formal and detailed evaluation, preferably in randomized controlled clinical trials, before being introduced into routine clinical practice. PMID:24851201

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Radiation protection aspects of the cosmic radiation exposure of aircraft crew.

PubMed

Bartlett, D T

2004-01-01

Aircraft crew and frequent flyers are exposed to elevated levels of cosmic radiation of galactic and solar origin and secondary radiation produced in the atmosphere, the aircraft structure and its contents. Following recommendations of the International Commission on Radiological Protection in Publication 60, the European Union introduced a revised Basic Safety Standards Directive, which included exposure to natural sources of ionising radiation, including cosmic radiation, as occupational exposure. The revised Directive has been incorporated into laws and regulations in the European Union Member States. Where the assessment of the occupational exposure of aircraft crew is necessary, the preferred approach to monitoring is by the recording of staff flying times and calculated route doses. Route doses are to be validated by measurements. This paper gives the general background, and considers the radiation protection aspects of the cosmic radiation exposure of aircraft crew, with the focus on the situation in Europe.

Modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit.

PubMed

Gutting, Bradford W; Marchette, David; Sherwood, Robert; Andrews, George A; Director-Myska, Alison; Channel, Stephen R; Wolfe, Daniel; Berger, Alan E; Mackie, Ryan S; Watson, Brent J; Rukhin, Andrey

2013-07-21

There is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. Combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. The objective of the current work was to apply and advance the competing risks (CR) computational model of inhalational anthrax where data was collected from NZW rabbits exposed to aerosols of Ames strain Bacillus anthracis. An initial aim was to parameterize the CR model using high-dose rabbit data and then conduct a low-dose extrapolation. The CR low-dose attack rate was then compared against known low-dose rabbit data as well as the low-dose curve obtained when the entire rabbit dose-response data set was fitted to an exponential dose-response (EDR) model. The CR model predictions demonstrated excellent agreement with actual low-dose rabbit data. We next used a modified CR model (MCR) to examine disease incubation period (the time to reach a fever >40 °C). The MCR model predicted a germination period of 14.5h following exposure to a low spore dose, which was confirmed by monitoring spore germination in the rabbit lung using PCR, and predicted a low-dose disease incubation period in the rabbit between 14.7 and 16.8 days. Overall, the CR and MCR model appeared to describe rabbit inhalational anthrax well. These results are discussed in the context of conducting laboratory studies in other relevant animal models, combining the CR/MCR model with other computation models of inhalational anthrax, and using the resulting information towards extrapolating a low-dose response prediction for man. Published by Elsevier Ltd.

Cholinesterase inhibitors do not alter the length of stay in nursing homes among patients with Alzheimer's disease: a prospective, observational study of factors affecting survival time from admission to death.

PubMed

Wattmo, Carina; Londos, Elisabet; Minthon, Lennart

2016-08-31

The survival time in nursing homes (NHs) in Alzheimer's disease (AD) might be affected by sociodemographic/clinical characteristics, rate of disease progression, and use of specific medications and community-based services. Whether different aspects of cholinesterase inhibitor (ChEI) therapy modify time spent in NHs is unclear. Therefore, we examined the relationship between these potential predictors and survival time in NHs. This prospective, multicenter study of ChEI treatment in clinical practice included 220 deceased patients clinically diagnosed with mild-to-moderate AD who were admitted to NHs during the study. Cognitive and activities of daily living (ADL) performance, ChEI dose, and amount of services used/week were evaluated every 6 months over 3 years. Dates of nursing-home placement (NHP) and death were recorded. Variables that determined survival time in NHs were analyzed using general linear models. The mean survival time in NHs was 4.06 years (men, 2.78 years; women, 4.53 years; P < 0.001). The multivariate model showed that a shorter stay in NHs was associated with the interaction term male living with a family member, use of antihypertensive/cardiac therapy or anxiolytics/sedatives/hypnotics, and worse basic ADL at NHP, but not with age or cognitive and instrumental ADL capacities. Increased community-based care did not reduce the survival time in NHs among individuals with AD. Men living with family spent significantly less time in NHs compared with the corresponding women, which suggests that the situation of female spouses of AD patients may need attention and possibly support. There was no indication that different aspects of ChEI therapy, e.g., drug type, dose, or duration, alter survival time in NHs.

COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

PubMed Central

Wood, Suzanne C.; Fay, Jonathon; Sage, Jennifer R.; Anagnostaras, Stephan G.

2007-01-01

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning. PMID:17098299

Radiation dose optimization in the decommissioning plan for Loviisa NPP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holmberg, R.; Eurajoki, T.

1995-03-01

Finnish rules for nuclear power require a detailed decommissioning plan to be made and kept up to date already during plant operation. The main reasons for this {open_quotes}premature{close_quotes} plan, is, firstly, the need to demonstrate the feasibility of decommissioning, and, secondly, to make realistic cost estimates in order to fund money for this future operation. The decomissioning for Lovissa Nuclear Power Plant (NPP) (2{times}445 MW, PWR) was issued in 1987. It must be updated about every five years. One important aspect of the plant is an estimate of radiation doses to the decomissioning workers. The doses were recently re-estimated becausemore » of a need to decrease the total collective dose estimate in the original plan, 23 manSv. In the update, the dose was reduced by one-third. Part of the reduction was due to changes in the protection and procedures, in which ALARA considerations were taken into account, and partly because of re-estimation of the doses.« less

Treatment regimens of classical and newer taxanes.

PubMed

Joerger, Markus

2016-02-01

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing.

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

Wood, Suzanne C; Fay, Jonathan; Sage, Jennifer R; Anagnostaras, Stephan G

2007-01-25

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice.

PubMed

McGovern, Robin; Luderman, Lauryn; Knecht, Kelly; Griffin, William C

2014-12-01

Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily×14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2 mg/kg) or a higher dose (4 mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that previous exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination.

Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.

PubMed

Liedert, B; Bassus, S; Schneider, C K; Kalinke, U; Löwer, J

2007-01-01

This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.

The Importance of Conducting Life Sciences Experiments on the Deep Space Gateway Platform

NASA Technical Reports Server (NTRS)

Bhattacharya, S.

2018-01-01

Over the last several decades important information has been gathered by conducting life science experiments on the Space Shuttle and on the International Space Station. It is now time to leverage that scientific knowledge, as well as aspects of the hardware that have been developed to support the biological model systems, to NASA's next frontier - the Deep Space Gateway. In order to facilitate long duration deep space exploration for humans, it is critical for NASA to understand the effects of long duration, low dose, deep space radiation on biological systems. While carefully controlled ground experiments on Earth-based radiation facilities have provided valuable preliminary information, we still have a significant knowledge gap on the biological responses of organisms to chronic low doses of the highly ionizing particles encountered beyond low Earth orbit. Furthermore, the combined effects of altered gravity and radiation have the potential to cause greater biological changes than either of these parameters alone. Therefore a thorough investigation of the biological effects of a cis-lunar environment will facilitate long term human exploration of deep space.

Immunotoxins: magic bullets or misguided missiles?

PubMed

Vitetta, E S; Thorpe, P E; Uhr, J W

1993-05-01

Thirteen years have passed since specific in vitro and in vivo killing of tumour cells by immunotoxins was first described. Why, then, has it taken so long to determine whether these drugs will have a major impact on the treatment of cancer, AIDS and autoimmune disease? The answer is that the transfer of basic discoveries to the clinic is a slow, multistep, interdisciplinary process. Thus, immunotoxin molecules must be designed and redesigned by the basic scientist depending on the efficacy and toxicity shown in vitro and in relevant experimental models. Next, each version must be evaluated by clinicians in humans through a lengthy process (1-3 years) in which the dose regimen is optimized and in which new problems and issues frequently emerge. These problems must again be modelled and studied in animals before additional clinical trials are initiated. In this article, Ellen Vitetta and colleagues discuss both basic and clinical aspects of the development of immunotoxin therapy.

Building up a QSAR model for toxicity toward Tetrahymena pyriformis by the Monte Carlo method: A case of benzene derivatives.

PubMed

Toropova, Alla P; Schultz, Terry W; Toropov, Andrey A

2016-03-01

Data on toxicity toward Tetrahymena pyriformis is indicator of applicability of a substance in ecologic and pharmaceutical aspects. Quantitative structure-activity relationships (QSARs) between the molecular structure of benzene derivatives and toxicity toward T. pyriformis (expressed as the negative logarithms of the population growth inhibition dose, mmol/L) are established. The available data were randomly distributed three times into the visible training and calibration sets, and invisible validation sets. The statistical characteristics for the validation set are the following: r(2)=0.8179 and s=0.338 (first distribution); r(2)=0.8682 and s=0.341 (second distribution); r(2)=0.8435 and s=0.323 (third distribution). These models are built up using only information on the molecular structure: no data on physicochemical parameters, 3D features of the molecular structure and quantum mechanics descriptors are involved in the modeling process. Copyright © 2016 Elsevier B.V. All rights reserved.

[Protection and bidirectional effect of rhubarb anthraquinone and tannins for rats' liver].

PubMed

Qin, Lu-shan; Zhao, Hai-ping; Zhao, Yan-ling; Ma, Zhi-jiel; Zeng, Ling-na; Zhang, Ya-ming; Zhang, Ping; Yan, Dan; Bai, Zhao-fang; Li, Yue; Hao, Qing-xiu; Zhao, Kui-jun; Wang, Jia-bo; Xiao, Xiao-he

2014-06-01

To compare the bidirectional effect of rhubarb total anthraquinone (TA) and total tannins (TT) on rats' liver. One hundred rats were randomly divided into 10 groups, i.e., the blank group, the model group, the blank + high dose TA group, the blank +low dose TA group, the blank + high dose TT group, the blank + low dose TT group, the model + high dose TA group, the model + low dose TA group, the model +high dose TT group, and the model + low dose TT group, 10 in each group. The carbon tetrachloride (CCI4) was used to prepare the acute liver injury rat model. TA and TT of rhubarb (at 5.40 g crude drugs/kg and 14.69 g crude drugs/kg) were intragastrically administrated to rats in all groups except the blank group and the model group, once daily for 6 successive days.The general state of rats, biochemical indices such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), laminin (LN), hyaluronic acid (HA), transforming growth factor beta1 (TGF-beta1), as well pathological results of rat liver tissues. Finally the protection laws of TA and TT for rats' liver were analyzed using factor analysis. Compared with the blank control group, all biochemical indices increased in the blank group (P < 0.05, P < 0.01). HA also increased in the blank + high dose TA group; AST, ALT, and HA also increased in the blank +high dose TT group (P < 0.05). Compared with the model group, AST, ALT, ALP, HA, and TGF-beta1 significantly decreased in the model + low dose TA group, the model + high dose TA group, the model + low dose TT group (P < 0.05, P < 0.01). Serum AST, ALT, and ALP also decreased in the model + high dose TT group (P < 0.05, P < 0.01). Pathological results showed that mild swollen liver cells in the model + high dose TA group. Fatty degeneration and fragmental necrosis around the central veins occurred in the blank + high dose TA group. The pathological injury was inproved in the model +low dose TA group. Two common factors, liver fibrosis and liver cell injury, were extracted by using factor analysis. TA showed stronger improvement of the two common factors than TT. Rhubarb TA and TT showed protective and harmful effects on rats' liver. At an equivalent dosage, TA had better liver protection than TT. High dose TT played a role in liver injury to some extent.

Granuloma Encapsulation Is a Key Factor for Containing Tuberculosis Infection in Minipigs

PubMed Central

Vilaplana, Cristina; Tapia, Gustavo; Díaz, Jorge; Fort, María; Cáceres, Neus; Pinto, Sergio; Caylà, Joan; Corner, Leigh; Domingo, Mariano; Cardona, Pere-Joan

2010-01-01

A transthoracic infection involving a low dose of Mycobacterium tuberculosis has been used to establish a new model of infection in minipigs. The 20-week monitoring period showed a marked Th1 response and poor humoral response for the whole infection. A detailed histopathological analysis was performed after slicing the formalin-fixed whole lungs of each animal. All lesions were recorded and classified according to their microscopic aspect, their relationship with the intralobular connective network and their degree of maturity in order to obtain a dissemination ratio (DR) between recent and old lesions. CFU counts and evolution of the DR with time showed that the proposed model correlated with a contained infection, decreasing from week 9 onwards. These findings suggest that the infection induces an initial Th1 response, which is followed by local fibrosis and encapsulation of the granulomas, thereby decreasing the onset of new lesions. Two therapeutic strategies were applied in order to understand how they could influence the model. Thus, chemotherapy with isoniazid alone helped to decrease the total number of lesions, despite the increase in DR after week 9, with similar kinetics to those of the control group, whereas addition of a therapeutic M. tuberculosis fragment-based vaccine after chemotherapy increased the Th1 and humoral responses, as well as the number of lesions, but decreased the DR. By providing a local pulmonary structure similar to that in humans, the mini-pig model highlights new aspects that could be key to a better understanding tuberculosis infection control in humans. PMID:20386605

Granuloma encapsulation is a key factor for containing tuberculosis infection in minipigs.

PubMed

Gil, Olga; Díaz, Ivan; Vilaplana, Cristina; Tapia, Gustavo; Díaz, Jorge; Fort, María; Cáceres, Neus; Pinto, Sergio; Caylà, Joan; Corner, Leigh; Domingo, Mariano; Cardona, Pere-Joan

2010-04-06

A transthoracic infection involving a low dose of Mycobacterium tuberculosis has been used to establish a new model of infection in minipigs. The 20-week monitoring period showed a marked Th1 response and poor humoral response for the whole infection. A detailed histopathological analysis was performed after slicing the formalin-fixed whole lungs of each animal. All lesions were recorded and classified according to their microscopic aspect, their relationship with the intralobular connective network and their degree of maturity in order to obtain a dissemination ratio (DR) between recent and old lesions. CFU counts and evolution of the DR with time showed that the proposed model correlated with a contained infection, decreasing from week 9 onwards. These findings suggest that the infection induces an initial Th1 response, which is followed by local fibrosis and encapsulation of the granulomas, thereby decreasing the onset of new lesions. Two therapeutic strategies were applied in order to understand how they could influence the model. Thus, chemotherapy with isoniazid alone helped to decrease the total number of lesions, despite the increase in DR after week 9, with similar kinetics to those of the control group, whereas addition of a therapeutic M. tuberculosis fragment-based vaccine after chemotherapy increased the Th1 and humoral responses, as well as the number of lesions, but decreased the DR. By providing a local pulmonary structure similar to that in humans, the mini-pig model highlights new aspects that could be key to a better understanding tuberculosis infection control in humans.

Three-dimensional transgenic cell model to quantify genotoxic effects of space environment

NASA Astrophysics Data System (ADS)

Gonda, S. R.; Wu, H.; Pingerelli, P. L.; Glickman, B. W.

In this paper we describe a three-dimensional, multicellular tissue-equivalent model, produced in NASA-designed, rotating wall bioreactors using mammalian cells engineered for genomic containment of multiple copies of defined target genes for genotoxic assessment. Rat 2λ fibroblasts, genetically engineered to contain high-density target genes for mutagenesis (Stratagene, Inc., Austin, TX), were cocultured with human epithelial cells on Cytodex beads in the High Aspect Ratio Bioreactor (Synthecon, Inc, Houston, TX). Multi-bead aggregates were formed by day 5 following the complete covering of the beads by fibroblasts. Cellular retraction occurred 8-14 days after coculture initiation culminating in spheroids retaining few or no beads. Analysis of the resulting tissue assemblies revealed: multicellular spheroids, fibroblasts synthesized collagen, and cell viability was retained for the 30-day test period after removal from the bioreactor. Quantification of mutation at the LacI gene in Rat 2λ fibroblasts in spheroids exposed to 0-2 Gy neon using the Big Blue color assay (Stratagene, Inc.), revealed a linear dose-response for mutation induction. Limited sequencing analysis of mutant clones from 0.25 or 1 Gy exposures revealed a higher frequency of deletions and multiple base sequencing changes with increasing dose. These results suggest that the three-dimensional, multicellular tissue assembly model produced in NASA bioreactors are applicable to a wide variety of studies involving the quantification and identification of genotocity including measurement of the inherent damage incurred in Space.

On determining dose rate constants spectroscopically

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodriguez, M.; Rogers, D. W. O.

2013-01-15

Purpose: To investigate several aspects of the Chen and Nath spectroscopic method of determining the dose rate constants of {sup 125}I and {sup 103}Pd seeds [Z. Chen and R. Nath, Phys. Med. Biol. 55, 6089-6104 (2010)] including the accuracy of using a line or dual-point source approximation as done in their method, and the accuracy of ignoring the effects of the scattered photons in the spectra. Additionally, the authors investigate the accuracy of the literature's many different spectra for bare, i.e., unencapsulated {sup 125}I and {sup 103}Pd sources. Methods: Spectra generated by 14 {sup 125}I and 6 {sup 103}Pd seedsmore » were calculated in vacuo at 10 cm from the source in a 2.7 Multiplication-Sign 2.7 Multiplication-Sign 0.05 cm{sup 3} voxel using the EGSnrc BrachyDose Monte Carlo code. Calculated spectra used the initial photon spectra recommended by AAPM's TG-43U1 and NCRP (National Council of Radiation Protection and Measurements) Report 58 for the {sup 125}I seeds, or TG-43U1 and NNDC(2000) (National Nuclear Data Center, 2000) for {sup 103}Pd seeds. The emitted spectra were treated as coming from a line or dual-point source in a Monte Carlo simulation to calculate the dose rate constant. The TG-43U1 definition of the dose rate constant was used. These calculations were performed using the full spectrum including scattered photons or using only the main peaks in the spectrum as done experimentally. Statistical uncertainties on the air kerma/history and the dose rate/history were Less-Than-Or-Slanted-Equal-To 0.2%. The dose rate constants were also calculated using Monte Carlo simulations of the full seed model. Results: The ratio of the intensity of the 31 keV line relative to that of the main peak in {sup 125}I spectra is, on average, 6.8% higher when calculated with the NCRP Report 58 initial spectrum vs that calculated with TG-43U1 initial spectrum. The {sup 103}Pd spectra exhibit an average 6.2% decrease in the 22.9 keV line relative to the main peak when calculated with the TG-43U1 rather than the NNDC(2000) initial spectrum. The measured values from three different investigations are in much better agreement with the calculations using the NCRP Report 58 and NNDC(2000) initial spectra with average discrepancies of 0.9% and 1.7% for the {sup 125}I and {sup 103}Pd seeds, respectively. However, there are no differences in the calculated TG-43U1 brachytherapy parameters using either initial spectrum in both cases. Similarly, there were no differences outside the statistical uncertainties of 0.1% or 0.2%, in the average energy, air kerma/history, dose rate/history, and dose rate constant when calculated using either the full photon spectrum or the main-peaks-only spectrum. Conclusions: Our calculated dose rate constants based on using the calculated on-axis spectrum and a line or dual-point source model are in excellent agreement (0.5% on average) with the values of Chen and Nath, verifying the accuracy of their more approximate method of going from the spectrum to the dose rate constant. However, the dose rate constants based on full seed models differ by between +4.6% and -1.5% from those based on the line or dual-point source approximations. These results suggest that the main value of spectroscopic measurements is to verify full Monte Carlo models of the seeds by comparison to the calculated spectra.« less

Isl1 Is required for multiple aspects of motor neuron development

PubMed Central

Liang, Xingqun; Song, Mi-Ryoung; Xu, ZengGuang; Lanuza, Guillermo M.; Liu, Yali; Zhuang, Tao; Chen, Yihan; Pfaff, Samuel L.; Evans, Sylvia M.; Sun, Yunfu

2011-01-01

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. PMID:21569850

Commissioning dose computation models for spot scanning proton beams in water for a commercially available treatment planning system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, X. R.; Poenisch, F.; Lii, M.

2013-04-15

Purpose: To present our method and experience in commissioning dose models in water for spot scanning proton therapy in a commercial treatment planning system (TPS). Methods: The input data required by the TPS included in-air transverse profiles and integral depth doses (IDDs). All input data were obtained from Monte Carlo (MC) simulations that had been validated by measurements. MC-generated IDDs were converted to units of Gy mm{sup 2}/MU using the measured IDDs at a depth of 2 cm employing the largest commercially available parallel-plate ionization chamber. The sensitive area of the chamber was insufficient to fully encompass the entire lateralmore » dose deposited at depth by a pencil beam (spot). To correct for the detector size, correction factors as a function of proton energy were defined and determined using MC. The fluence of individual spots was initially modeled as a single Gaussian (SG) function and later as a double Gaussian (DG) function. The DG fluence model was introduced to account for the spot fluence due to contributions of large angle scattering from the devices within the scanning nozzle, especially from the spot profile monitor. To validate the DG fluence model, we compared calculations and measurements, including doses at the center of spread out Bragg peaks (SOBPs) as a function of nominal field size, range, and SOBP width, lateral dose profiles, and depth doses for different widths of SOBP. Dose models were validated extensively with patient treatment field-specific measurements. Results: We demonstrated that the DG fluence model is necessary for predicting the field size dependence of dose distributions. With this model, the calculated doses at the center of SOBPs as a function of nominal field size, range, and SOBP width, lateral dose profiles and depth doses for rectangular target volumes agreed well with respective measured values. With the DG fluence model for our scanning proton beam line, we successfully treated more than 500 patients from March 2010 through June 2012 with acceptable agreement between TPS calculated and measured dose distributions. However, the current dose model still has limitations in predicting field size dependence of doses at some intermediate depths of proton beams with high energies. Conclusions: We have commissioned a DG fluence model for clinical use. It is demonstrated that the DG fluence model is significantly more accurate than the SG fluence model. However, some deficiencies in modeling the low-dose envelope in the current dose algorithm still exist. Further improvements to the current dose algorithm are needed. The method presented here should be useful for commissioning pencil beam dose algorithms in new versions of TPS in the future.« less

Commissioning dose computation models for spot scanning proton beams in water for a commercially available treatment planning system

PubMed Central

Zhu, X. R.; Poenisch, F.; Lii, M.; Sawakuchi, G. O.; Titt, U.; Bues, M.; Song, X.; Zhang, X.; Li, Y.; Ciangaru, G.; Li, H.; Taylor, M. B.; Suzuki, K.; Mohan, R.; Gillin, M. T.; Sahoo, N.

2013-01-01

Purpose: To present our method and experience in commissioning dose models in water for spot scanning proton therapy in a commercial treatment planning system (TPS). Methods: The input data required by the TPS included in-air transverse profiles and integral depth doses (IDDs). All input data were obtained from Monte Carlo (MC) simulations that had been validated by measurements. MC-generated IDDs were converted to units of Gy mm2/MU using the measured IDDs at a depth of 2 cm employing the largest commercially available parallel-plate ionization chamber. The sensitive area of the chamber was insufficient to fully encompass the entire lateral dose deposited at depth by a pencil beam (spot). To correct for the detector size, correction factors as a function of proton energy were defined and determined using MC. The fluence of individual spots was initially modeled as a single Gaussian (SG) function and later as a double Gaussian (DG) function. The DG fluence model was introduced to account for the spot fluence due to contributions of large angle scattering from the devices within the scanning nozzle, especially from the spot profile monitor. To validate the DG fluence model, we compared calculations and measurements, including doses at the center of spread out Bragg peaks (SOBPs) as a function of nominal field size, range, and SOBP width, lateral dose profiles, and depth doses for different widths of SOBP. Dose models were validated extensively with patient treatment field-specific measurements. Results: We demonstrated that the DG fluence model is necessary for predicting the field size dependence of dose distributions. With this model, the calculated doses at the center of SOBPs as a function of nominal field size, range, and SOBP width, lateral dose profiles and depth doses for rectangular target volumes agreed well with respective measured values. With the DG fluence model for our scanning proton beam line, we successfully treated more than 500 patients from March 2010 through June 2012 with acceptable agreement between TPS calculated and measured dose distributions. However, the current dose model still has limitations in predicting field size dependence of doses at some intermediate depths of proton beams with high energies. Conclusions: We have commissioned a DG fluence model for clinical use. It is demonstrated that the DG fluence model is significantly more accurate than the SG fluence model. However, some deficiencies in modeling the low-dose envelope in the current dose algorithm still exist. Further improvements to the current dose algorithm are needed. The method presented here should be useful for commissioning pencil beam dose algorithms in new versions of TPS in the future. PMID:23556893

Commissioning dose computation models for spot scanning proton beams in water for a commercially available treatment planning system.

PubMed

Zhu, X R; Poenisch, F; Lii, M; Sawakuchi, G O; Titt, U; Bues, M; Song, X; Zhang, X; Li, Y; Ciangaru, G; Li, H; Taylor, M B; Suzuki, K; Mohan, R; Gillin, M T; Sahoo, N

2013-04-01

To present our method and experience in commissioning dose models in water for spot scanning proton therapy in a commercial treatment planning system (TPS). The input data required by the TPS included in-air transverse profiles and integral depth doses (IDDs). All input data were obtained from Monte Carlo (MC) simulations that had been validated by measurements. MC-generated IDDs were converted to units of Gy mm(2)/MU using the measured IDDs at a depth of 2 cm employing the largest commercially available parallel-plate ionization chamber. The sensitive area of the chamber was insufficient to fully encompass the entire lateral dose deposited at depth by a pencil beam (spot). To correct for the detector size, correction factors as a function of proton energy were defined and determined using MC. The fluence of individual spots was initially modeled as a single Gaussian (SG) function and later as a double Gaussian (DG) function. The DG fluence model was introduced to account for the spot fluence due to contributions of large angle scattering from the devices within the scanning nozzle, especially from the spot profile monitor. To validate the DG fluence model, we compared calculations and measurements, including doses at the center of spread out Bragg peaks (SOBPs) as a function of nominal field size, range, and SOBP width, lateral dose profiles, and depth doses for different widths of SOBP. Dose models were validated extensively with patient treatment field-specific measurements. We demonstrated that the DG fluence model is necessary for predicting the field size dependence of dose distributions. With this model, the calculated doses at the center of SOBPs as a function of nominal field size, range, and SOBP width, lateral dose profiles and depth doses for rectangular target volumes agreed well with respective measured values. With the DG fluence model for our scanning proton beam line, we successfully treated more than 500 patients from March 2010 through June 2012 with acceptable agreement between TPS calculated and measured dose distributions. However, the current dose model still has limitations in predicting field size dependence of doses at some intermediate depths of proton beams with high energies. We have commissioned a DG fluence model for clinical use. It is demonstrated that the DG fluence model is significantly more accurate than the SG fluence model. However, some deficiencies in modeling the low-dose envelope in the current dose algorithm still exist. Further improvements to the current dose algorithm are needed. The method presented here should be useful for commissioning pencil beam dose algorithms in new versions of TPS in the future.

Patient perspectives on care received at community acupuncture clinics: a qualitative thematic analysis.

PubMed

Tippens, Kimberly M; Chao, Maria T; Connelly, Erin; Locke, Adrianna

2013-10-29

Community acupuncture is a recent innovation in acupuncture service delivery in the U.S. that aims to improve access to care through low-cost treatments in group-based settings. Patients at community acupuncture clinics represent a broader socioeconomic spectrum and receive more frequent treatments compared to acupuncture users nationwide. As a relatively new model of acupuncture in the U.S., little is known about the experiences of patients at community acupuncture clinics and whether quality of care is compromised through this high-volume model. The aim of this study was to assess patients' perspectives on the care received through community acupuncture clinics. The investigators conducted qualitative, thematic analysis of written comments from an observational, cross-sectional survey of clients of the Working Class Acupuncture clinics in Portland, Oregon. The survey included an open-ended question for respondents to share comments about their experiences with community acupuncture. Comments were received from 265 community acupuncture patients. Qualitative analysis of written comments identified two primary themes that elucidate patients' perspectives on quality of care: 1) aspects of health care delivery unique to community acupuncture, and 2) patient engagement in health care. Patients identified unique aspects of community acupuncture, including structures that facilitate access, processes that make treatments more comfortable and effective and holistic outcomes including physical improvements, enhanced quality of life, and empowerment. The group setting, community-based locations, and low cost were highlighted as aspects of this model that allow patients to access acupuncture. Patients' perspectives on the values and experiences unique to community acupuncture offer insights on the quality of care received in these settings. The group setting, community-based locations, and low cost of this model potentially reduce access barriers for those who might not otherwise consider using acupuncture. In addition, the community acupuncture model may offer individuals the opportunity for increased frequency of treatments, which raises pertinent questions about the dose-response relationship of acupuncture and health outcomes. This study provides preliminary data for future evaluations of the quality and effectiveness of community acupuncture. Future studies should include the perspectives of patients who initiated, and subsequently, discontinued community acupuncture treatment.

Simulation of enhanced deposition due to magnetic field alignment of ellipsoidal particles in a lung bifurcation.

PubMed

Martinez, R C; Roshchenko, A; Minev, P; Finlay, W H

2013-02-01

Aerosolized chemotherapy has been recognized as a potential treatment for lung cancer. The challenge of providing sufficient therapeutic effects without reaching dose-limiting toxicity levels hinders the development of aerosolized chemotherapy. This could be mitigated by increasing drug-delivery efficiency with a noninvasive drug-targeting delivery method. The purpose of this study is to use direct numerical simulations to study the resulting local enhancement of deposition due to magnetic field alignment of high aspect ratio particles. High aspect ratio particles were approximated by a rigid ellipsoid with a minor diameter of 0.5 μm and fluid particle density ratio of 1,000. Particle trajectories were calculated by solving the coupled fluid particle equations using an in-house micro-macro grid finite element algorithm based on a previously developed fictitious domain approach. Particle trajectories were simulated in a morphologically realistic geometry modeling a symmetrical terminal bronchiole bifurcation. Flow conditions were steady inspiratory air flow due to typical breathing at 18 L/min. Deposition efficiency was estimated for two different cases: [1] particles aligned with the streamlines and [2] particles with fixed angular orientation simulating the magnetic field alignment of our previous in vitro study. The local enhancement factor defined as the ratio between deposition efficiency of Case [1] and Case [2] was found to be 1.43 and 3.46 for particles with an aspect ratio of 6 and 20, respectively. Results indicate that externally forcing local alignment of high aspect ratio particles can increase local deposition considerably.

CT dose reduction in children.

PubMed

Vock, Peter

2005-11-01

World wide, the number of CT studies in children and the radiation exposure by CT increases. The same energy dose has a greater biological impact in children than in adults, and scan parameters have to be adapted to the smaller diameter of the juvenile body. Based on seven rules, a practical approach to paediatric CT is shown: Justification and patient preparation are important steps before scanning, and they differ from the preparation of adult patients. The subsequent choice of scan parameters aims at obtaining the minimal signal-to-noise ratio and volume coverage needed in a specific medical situation; exposure can be divided in two aspects: the CT dose index determining energy deposition per rotation and the dose-length product (DLP) determining the volume dose. DLP closely parallels the effective dose, the best parameter of the biological impact. Modern scanners offer dose modulation to locally minimise exposure while maintaining image quality. Beyond the selection of the physical parameters, the dose can be kept low by scanning the minimal length of the body and by avoiding any non-qualified repeated scanning of parts of the body. Following these rules, paediatric CT examinations of good quality can be obtained at a reasonable cost of radiation exposure.

Histopathological effects and evolution of transvenous β-radiation applications in right and left atria: an animal study.

PubMed

Franceschi, Frédéric; Bonan, Raoul; Khairy, Paul; Dubuc, Marc; Thibault, Bernard; Macle, Laurent; Talajic, Mario; Roy, Denis; Koutbi, Linda; Virmani, Renu; Guerra, Peter G

2012-05-01

β-radiation is a novel potential energy source for the creation of myocardial lesions. While the feasibility of delivering β-radiation via a deflectable transvenous catheter has been described, dose effects and the time course of histopathological changes have not been previously assessed. The purpose of this study was to characterize pathological aspects of cardiac lesions induced by β-radiation in an animal model at various stages of evolution and in response to different dose exposures. Nine dogs and one pig were studied. The cavotricuspid isthmus, antrum of pulmonary veins (PVs), and mitral isthmus were irradiated (25, 50, 75, or 100 Gy) with strontium-yttrium-90, delivered via a deflectable catheter (cavotricuspid isthmus and mitral isthmus) or a double-loop catheter (antrum of PVs). Eighteen lesions were created. Animals were sacrificed at 2 weeks, 1 month, 3 months, or 6 months. Lesions were processed for morphometric histopathological analyses. Over the first month, lesions were characterized by inflammation, haemorrhage, and myocyte necrosis. Thereafter, fibrotic replacement was predominant. Transmurality of lesions was observed in 50% of cases, with no dose-response effect (P = 0.976). Surface fibrin thrombus was present in 50% of cases and was essentially limited to lesions assessed within the first month. No neighbouring injury or pulmonary venous stenosis was observed. Atrial lesions created by β-radiation are characterized by an inflammatory phase with surface fibrin thrombosis during the first month and replacement fibrosis thereafter. No appreciable dose-response effect was noted within the 25-100 Gy range tested.

Monte Carlo simulation of electron beams from an accelerator head using PENELOPE.

PubMed

Sempau, J; Sánchez-Reyes, A; Salvat, F; ben Tahar, H O; Jiang, S B; Fernández-Varea, J M

2001-04-01

The Monte Carlo code PENELOPE has been used to simulate electron beams from a Siemens Mevatron KDS linac with nominal energies of 6, 12 and 18 MeV. Owing to its accuracy, which stems from that of the underlying physical interaction models, PENELOPE is suitable for simulating problems of interest to the medical physics community. It includes a geometry package that allows the definition of complex quadric geometries, such as those of irradiation instruments, in a straightforward manner. Dose distributions in water simulated with PENELOPE agree well with experimental measurements using a silicon detector and a monitoring ionization chamber. Insertion of a lead slab in the incident beam at the surface of the water phantom produces sharp variations in the dose distributions, which are correctly reproduced by the simulation code. Results from PENELOPE are also compared with those of equivalent simulations with the EGS4-based user codes BEAM and DOSXYZ. Angular and energy distributions of electrons and photons in the phase-space plane (at the downstream end of the applicator) obtained from both simulation codes are similar, although significant differences do appear in some cases. These differences, however, are shown to have a negligible effect on the calculated dose distributions. Various practical aspects of the simulations, such as the calculation of statistical uncertainties and the effect of the 'latent' variance in the phase-space file, are discussed in detail.

Dose-response studies and 'no-effect-levels' of N-nitroso compounds: some general aspects.

PubMed

Preussmann, R

1980-01-01

One major problem in the evaluation of potential carcinogenic food additives and contaminants is that of thresholds or, better, of 'no-adverse-effect-levels'. Arguments in favor of the postulated 'irreversibility' of carcinogenic effects are based on dose-response studies, single dose and multigeneration experiments as well as on the concept of somatic mutation as the first step in carcinogenesis with subsequent transmittance of induced defects during cell replication. The problem of extrapolation of results of animal experiments using high doses to low exposure and low incidences in man is not yet solved satisfactorily. Possible practical consequences include zero tolerance, acceptable thresholds at low risk and safety factors. Acceptable intakes should never be considered constants but should be changeable as soon as new facts in regard to the safety evaluation are available.

Quantifying annual internal effective 137Cesium dose utilizing direct body-burden measurement and ecological dose modeling.

PubMed

Jelin, Benjamin A; Sun, Wenjie; Kravets, Alexandra; Naboka, Maryna; Stepanova, Eugenia I; Vdovenko, Vitaliy Y; Karmaus, Wilfried J; Lichosherstov, Alex; Svendsen, Erik R

2016-11-01

The Chernobyl Nuclear Power Plant (CNPP) accident represents one of the most significant civilian releases of 137 Cesium ( 137 Cs, radiocesium) in human history. In the Chernobyl-affected region, radiocesium is considered to be the greatest on-going environmental hazard to human health by radiobiologists and public health scientists. The goal of this study was to characterize dosimetric patterns and predictive factors for whole-body count (WBC)-derived radiocesium internal dose estimations in a CNPP-affected children's cohort, and cross-validate these estimations with a soil-based ecological dose estimation model. WBC data were used to estimate the internal effective dose using the International Commission on Radiological Protection (ICRP) 67 dose conversion coefficient for 137 Cs and MONDAL Version 3.01 software. Geometric mean dose estimates from each model were compared utilizing paired t-tests and intra-class correlation coefficients. Additionally, we developed predictive models for WBC-derived dose estimation in order to determine the appropriateness of EMARC to estimate dose for this population. The two WBC-derived dose predictive models identified 137 Cs soil concentration (P<0.0001) as the strongest predictor of annual internal effective dose from radiocesium validating the use of the soil-based EMARC model. The geometric mean internal effective dose estimate of the EMARC model (0.183 mSv/y) was the highest followed by the ICRP 67 dose estimates (0.165 mSv/y) and the MONDAL model estimates (0.149 mSv/y). All three models yielded significantly different geometric mean dose (P<0.05) estimates for this cohort when stratified by sex, age at time of exam and season of exam, except for the mean MONDAL and EMARC estimates for 15- and 16-year olds and mean ICRP and MONDAL estimates for children examined in Winter. Further prospective and retrospective radio-epidemiological studies utilizing refined WBC measurements and ecological model dose estimations, in conjunction with findings from animal toxicological studies, should help elucidate possible deterministic radiogenic health effects associated with chronic low-dose internal exposure to 137 Cs.

Aripiprazole Lauroxil

PubMed Central

Hard, Marjie L.; Mills, Richard J.; Sadler, Brian M.; Turncliff, Ryan Z.; Citrome, Leslie

2017-01-01

Abstract Background Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Methods Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. Findings The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441–882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. Conclusions This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice. PMID:28350572

Modified Gompertz equation for electrotherapy murine tumor growth kinetics: predictions and new hypotheses

PubMed Central

2010-01-01

Background Electrotherapy effectiveness at different doses has been demonstrated in preclinical and clinical studies; however, several aspects that occur in the tumor growth kinetics before and after treatment have not yet been revealed. Mathematical modeling is a useful instrument that can reveal some of these aspects. The aim of this paper is to describe the complete growth kinetics of unperturbed and perturbed tumors through use of the modified Gompertz equation in order to generate useful insight into the mechanisms that underpin this devastating disease. Methods The complete tumor growth kinetics for control and treated groups are obtained by interpolation and extrapolation methods with different time steps, using experimental data of fibrosarcoma Sa-37. In the modified Gompertz equation, a delay time is introduced to describe the tumor's natural history before treatment. Different graphical strategies are used in order to reveal new information in the complete kinetics of this tumor type. Results The first stage of complete tumor growth kinetics is highly non linear. The model, at this stage, shows different aspects that agree with those reported theoretically and experimentally. Tumor reversibility and the proportionality between regions before and after electrotherapy are demonstrated. In tumors that reach partial remission, two antagonistic post-treatment processes are induced, whereas in complete remission, two unknown antitumor mechanisms are induced. Conclusion The modified Gompertz equation is likely to lead to insights within cancer research. Such insights hold promise for increasing our understanding of tumors as self-organizing systems and, the possible existence of phase transitions in tumor growth kinetics, which, in turn, may have significant impacts both on cancer research and on clinical practice. PMID:21029411

TU-H-207A-08: Estimating Radiation Dose From Low-Dose Lung Cancer Screening CT Exams Using Tube Current Modulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardy, A; Bostani, M; McMillan, K

Purpose: The purpose of this work is to estimate effective and lung doses from a low-dose lung cancer screening CT protocol using Tube Current Modulation (TCM) across patient models of different sizes. Methods: Monte Carlo simulation methods were used to estimate effective and lung doses from a low-dose lung cancer screening protocol for a 64-slice CT (Sensation 64, Siemens Healthcare) that used TCM. Scanning parameters were from the AAPM protocols. Ten GSF voxelized patient models were used and had all radiosensitive organs identified to facilitate estimating both organ and effective doses. Predicted TCM schemes for each patient model were generatedmore » using a validated method wherein tissue attenuation characteristics and scanner limitations were used to determine the TCM output as a function of table position and source angle. The water equivalent diameter (WED) was determined by estimating the attenuation at the center of the scan volume for each patient model. Monte Carlo simulations were performed using the unique TCM scheme for each patient model. Lung doses were tallied and effective doses were estimated using ICRP 103 tissue weighting factors. Effective and lung dose values were normalized by scanspecific 32 cm CTDIvol values based upon the average tube current across the entire simulated scan. Absolute and normalized doses were reported as a function of WED for each patient. Results: For all ten patients modeled, the effective dose using TCM protocols was below 1.5 mSv. Smaller sized patient models experienced lower absolute doses compared to larger sized patients. Normalized effective and lung doses showed some dependence on patient size (R2 = 0.77 and 0.78, respectively). Conclusion: Effective doses for a low-dose lung screening protocol using TCM were below 1.5 mSv for all patient models used in this study. Institutional research agreement, Siemens Healthcare; Past recipient, research grant support, Siemens Healthcare; Consultant, Toshiba America Medical Systems; Consultant, Samsung Electronics.« less

Model-based dose calculations for COMS eye plaque brachytherapy using an anatomically realistic eye phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lesperance, Marielle; Inglis-Whalen, M.; Thomson, R. M., E-mail: rthomson@physics.carleton.ca

Purpose : To investigate the effects of the composition and geometry of ocular media and tissues surrounding the eye on dose distributions for COMS eye plaque brachytherapy with{sup 125}I, {sup 103}Pd, or {sup 131}Cs seeds, and to investigate doses to ocular structures. Methods : An anatomically and compositionally realistic voxelized eye model with a medial tumor is developed based on a literature review. Mass energy absorption and attenuation coefficients for ocular media are calculated. Radiation transport and dose deposition are simulated using the EGSnrc Monte Carlo user-code BrachyDose for a fully loaded COMS eye plaque within a water phantom andmore » our full eye model for the three radionuclides. A TG-43 simulation with the same seed configuration in a water phantom neglecting the plaque and interseed effects is also performed. The impact on dose distributions of varying tumor position, as well as tumor and surrounding tissue media is investigated. Each simulation and radionuclide is compared using isodose contours, dose volume histograms for the lens and tumor, maximum, minimum, and average doses to structures of interest, and doses to voxels of interest within the eye. Results : Mass energy absorption and attenuation coefficients of the ocular media differ from those of water by as much as 12% within the 20–30 keV photon energy range. For all radionuclides studied, average doses to the tumor and lens regions in the full eye model differ from those for the plaque in water by 8%–10% and 13%–14%, respectively; the average doses to the tumor and lens regions differ between the full eye model and the TG-43 simulation by 2%–17% and 29%–34%, respectively. Replacing the surrounding tissues in the eye model with water increases the maximum and average doses to the lens by 2% and 3%, respectively. Substituting the tumor medium in the eye model for water, soft tissue, or an alternate melanoma composition affects tumor dose compared to the default eye model simulation by up to 16%. In the full eye model simulations, the average dose to the lens is larger by 7%–9% than the dose to the center of the lens, and the maximum dose to the optic nerve is 17%–22% higher than the dose to the optic disk for all radionuclides. In general, when normalized to the same prescription dose at the tumor apex, doses delivered to all structures of interest in the full eye model are lowest for{sup 103}Pd and highest for {sup 131}Cs, except for the tumor where the average dose is highest for {sup 103}Pd and lowest for {sup 131}Cs. Conclusions : The eye is not radiologically water-equivalent, as doses from simulations of the plaque in the full eye model differ considerably from doses for the plaque in a water phantom and from simulated TG-43 calculated doses. This demonstrates the importance of model-based dose calculations for eye plaque brachytherapy, for which accurate elemental compositions of ocular media are necessary.« less

Animal Models of Fibrotic Lung Disease

PubMed Central

Lawson, William E.; Oury, Tim D.; Sisson, Thomas H.; Raghavendran, Krishnan; Hogaboam, Cory M.

2013-01-01

Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell–cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease. PMID:23526222

Modification and validation of an analytical source model for external beam radiotherapy Monte Carlo dose calculations.

PubMed

Davidson, Scott E; Cui, Jing; Kry, Stephen; Deasy, Joseph O; Ibbott, Geoffrey S; Vicic, Milos; White, R Allen; Followill, David S

2016-08-01

A dose calculation tool, which combines the accuracy of the dose planning method (DPM) Monte Carlo code and the versatility of a practical analytical multisource model, which was previously reported has been improved and validated for the Varian 6 and 10 MV linear accelerators (linacs). The calculation tool can be used to calculate doses in advanced clinical application studies. One shortcoming of current clinical trials that report dose from patient plans is the lack of a standardized dose calculation methodology. Because commercial treatment planning systems (TPSs) have their own dose calculation algorithms and the clinical trial participant who uses these systems is responsible for commissioning the beam model, variation exists in the reported calculated dose distributions. Today's modern linac is manufactured to tight specifications so that variability within a linac model is quite low. The expectation is that a single dose calculation tool for a specific linac model can be used to accurately recalculate dose from patient plans that have been submitted to the clinical trial community from any institution. The calculation tool would provide for a more meaningful outcome analysis. The analytical source model was described by a primary point source, a secondary extra-focal source, and a contaminant electron source. Off-axis energy softening and fluence effects were also included. The additions of hyperbolic functions have been incorporated into the model to correct for the changes in output and in electron contamination with field size. A multileaf collimator (MLC) model is included to facilitate phantom and patient dose calculations. An offset to the MLC leaf positions was used to correct for the rudimentary assumed primary point source. Dose calculations of the depth dose and profiles for field sizes 4 × 4 to 40 × 40 cm agree with measurement within 2% of the maximum dose or 2 mm distance to agreement (DTA) for 95% of the data points tested. The model was capable of predicting the depth of the maximum dose within 1 mm. Anthropomorphic phantom benchmark testing of modulated and patterned MLCs treatment plans showed agreement to measurement within 3% in target regions using thermoluminescent dosimeters (TLD). Using radiochromic film normalized to TLD, a gamma criteria of 3% of maximum dose and 2 mm DTA was applied with a pass rate of least 85% in the high dose, high gradient, and low dose regions. Finally, recalculations of patient plans using DPM showed good agreement relative to a commercial TPS when comparing dose volume histograms and 2D dose distributions. A unique analytical source model coupled to the dose planning method Monte Carlo dose calculation code has been modified and validated using basic beam data and anthropomorphic phantom measurement. While this tool can be applied in general use for a particular linac model, specifically it was developed to provide a singular methodology to independently assess treatment plan dose distributions from those clinical institutions participating in National Cancer Institute trials.

Application of computational models to estimate organ radiation dose in rainbow trout from uptake of molybdenum-99 with comparison to iodine-131.

PubMed

Martinez, N E; Johnson, T E; Pinder, J E

2016-01-01

This study compares three anatomical phantoms for rainbow trout (Oncorhynchus mykiss) for the purpose of estimating organ radiation dose and dose rates from molybdenum-99 ((99)Mo) uptake in the liver and GI tract. Model comparison and refinement is important to the process of determining accurate doses and dose rates to the whole body and the various organs. Accurate and consistent dosimetry is crucial to the determination of appropriate dose-effect relationships for use in environmental risk assessment. The computational phantoms considered are (1) a geometrically defined model employing anatomically relevant organ size and location, (2) voxel reconstruction of internal anatomy obtained from CT imaging, and (3) a new model utilizing NURBS surfaces to refine the model in (2). Dose Conversion Factors (DCFs) for whole body as well as selected organs of O. mykiss were computed using Monte Carlo modeling and combined with empirical models for predicting activity concentration to estimate dose rates and ultimately determine cumulative radiation dose (μGy) to selected organs after several half-lives of (99)Mo. The computational models provided similar results, especially for organs that were both the source and target of radiation (less than 30% difference between all models). Values in the empirical model as well as the 14 day cumulative organ doses determined from (99)Mo uptake are compared to similar models developed previously for (131)I. Finally, consideration is given to treating the GI tract as a solid organ compared to partitioning it into gut contents and GI wall, which resulted in an order of magnitude difference in estimated dose for most organs. Copyright © 2015 Elsevier Ltd. All rights reserved.

SU-E-T-430: Modeling MLC Leaf End in 2D for Sliding Window IMRT and Arc Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, X; Zhu, T

2014-06-01

Purpose: To develop a 2D geometric model for MLC accounting for leaf end dose leakage for dynamic IMRT and Rapidarc therapy. Methods: Leaf-end dose leakage is one of the problems for MLC dose calculation and modeling. Dosimetric leaf gap used to model the MLC and to count for leakage in dose calculation, but may not be accurate for smaller leaf gaps. We propose another geometric modeling method to compensate for the MLC round-shape leaf ends dose leakage, and improve the accuracy of dose calculation and dose verification. A triangular function is used to geometrically model the MLC leaf end leakagemore » in the leaf motion direction, and a step function is used in the perpendicular direction. Dose measurements with different leaf gap, different window width, and different window height were conducted, and the results were used to fit the analytical model to get the model parameters. Results: Analytical models have been obtained for stop-and-shoot and dynamic modes for MLC motion. Parameters a=0.4, lw'=5.0 mm for 6X and a=0.54, lw'=4.1 mm for 15x were obtained from the fitting process. The proposed MLC leaf end model improves the dose profile at the two ends of the sliding window opening. This improvement is especially significant for smaller sliding window openings, which are commonly used for highly modulated IMRT plans and arc therapy plans. Conclusion: This work models the MLC round leaf end shape and movement pattern for IMRT dose calculation. The theory, as well as the results in this work provides a useful tool for photon beam IMRT dose calculation and verification.« less

Mobile-Dose: A Dose-Meter Designed for Use in Automatic Machineries for Dose Manipulation in Nuclear Medicine

NASA Astrophysics Data System (ADS)

de Asmundis, Riccardo; Boiano, Alfonso; Ramaglia, Antonio

2008-06-01

Mobile-Dose has been designed for a very innovative use: the integration in a robotic machinery for automatic preparation of radioactive doses, to be injected to patients in Nuclear Medicine Departments, with real time measurement of the activity under preparation. Mobile-Dose gives a constant measurement of the dose during the filling of vials or syringes, triggering the end of the filling process based on a predefined dose limit. Several applications of Mobile-Dose have been delivered worldwide, from Italian hospitals and clinics to European and Japanese ones. The design of such an instrument and its integration in robotic machineries, was required by an Italian company specialised in radiation protection tools for nuclear applications, in the period 2001-2003. At the time of its design, apparently no commercial instruments with a suitable interfacing capability to the external world existed: we designed it in order to satisfy all the strict requirements coming from the medical aspects (precision within 10%, repeatability, stability, time response) and from the industrial conceiving principles that are mandatory to ensure a good reliability in such a complicated environment. The instrument is suitable to be used in standalone mode too, thanks to its portability and compactness and to the intelligent operator panel programmed for this purpose.

Model-based decision making in early clinical development: minimizing the impact of a blood pressure adverse event.

PubMed

Stroh, Mark; Addy, Carol; Wu, Yunhui; Stoch, S Aubrey; Pourkavoos, Nazaneen; Groff, Michelle; Xu, Yang; Wagner, John; Gottesdiener, Keith; Shadle, Craig; Wang, Hong; Manser, Kimberly; Winchell, Gregory A; Stone, Julie A

2009-03-01

We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic-pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.

Temporal aspects of tumorigenic response to individual and mixed carcinogens. Comprehensive progress report, June 1, 1975--May 31, 1978. [Mouse skin, rats, hamsters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert, R.E.; Burns, F.J.; Altshuler, B.

1978-02-01

The research proposed here is designed to obtain a better understanding of the temporal kinetics of tumor induction when one or more carcinogens are present simultaneously or sequentially for prolonged periods of time. Studies done to date under this contract have shown that carcinogenesis in mouse skin by polycyclic aromatic hydrocarbon carcinogens is consistent with the induction of dependent and autonomous cell transformations by the carcinogen followed by the conversion of autonomous tumor cells into malignancies at a rate which is determined by the level of carcinogen exposure. Dependent cell transformations remain latent in the skin unless expressed by amore » promoting agent. Dependent neoplasia appears to follow one-hit kinetics while malignancy is a multihit endpoint. Dose-related and time-related aspects of tumor induction are separable in the initiation-promotion system of mouse skin which along with rat skin and hamster lung is being used as a model for testing hypotheses. Results to date provide the basis for a new interpretation of the linear non-threshold extrapolation model. The broad aim of the study is to provide a basis or rationale for estimating risks associated with prolonged exposures to carcinogens found in the environment and to predict how different tissues and species respond to the same carcinogens.« less

An Engineering Tool for the Prediction of Internal Dielectric Charging

NASA Astrophysics Data System (ADS)

Rodgers, D. J.; Ryden, K. A.; Wrenn, G. L.; Latham, P. M.; Sorensen, J.; Levy, L.

1998-11-01

A practical internal charging tool has been developed. It provides an easy-to-use means for satellite engineers to predict whether on-board dielectrics are vulnerable to electrostatic discharge in the outer radiation belt. The tool is designed to simulate irradiation of single-dielectric planar or cylindrical structures with or without shielding. Analytical equations are used to describe current deposition in the dielectric. This is fast and gives charging currents to sufficient accuracy given the uncertainties in other aspects of the problem - particularly material characteristics. Time-dependent internal electric fields are calculated, taking into account the effect on conductivity of electric field, dose rate and temperature. A worst-case model of electron fluxes in the outer belt has been created specifically for the internal charging problem and is built into the code. For output, the tool gives a YES or NO decision on the susceptibility of the structure to internal electrostatic breakdown and if necessary, calculates the required changes to bring the system below the breakdown threshold. A complementary programme of laboratory irradiations has been carried out to validate the tool. The results for Epoxy-fibreglass samples show that the code models electric field realistically for a wide variety of shields, dielectric thicknesses and electron spectra. Results for Teflon samples indicate that some further experimentation is required and the radiation-induced conductivity aspects of the code have not been validated.

Urinary symptoms following external beam radiotherapy of the prostate: Dose-symptom correlates with multiple-event and event-count models.

PubMed

Yahya, Noorazrul; Ebert, Martin A; Bulsara, Max; House, Michael J; Kennedy, Angel; Joseph, David J; Denham, James W

2015-11-01

This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations. For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Evaluation of the radiological risks associated with the routine transport of radioactive material within Michigan

NASA Astrophysics Data System (ADS)

Steinman, Rebecca Lee

Radioactive materials play an important role in modern society. In addition to providing electrical power and supporting national defense, radioisotopes play significant roles in the fields of medicine, research, manufacturing, and industry. Since most of these materials are not manufactured or disposed of at the site where they are used, they must be transported between various processing, use, storage, and disposal facilities. This dissertation examines the mathematical model used to predict the collective dose to the population that resides along a potential transport route, commonly called the off-link dose. The currently accepted RADTRAN and RISKIND transient dose models are reviewed. Then three new individual transient dose models are derived by assuming that a point, line, or surface cylinder can approximate the actual transport package. Groundscatter effects were investigated using a Monte Carlo simulation of the surface cylinder model and found to contribute no more than 12% to the total individual dose from a passing shipment of radioactive material, thus not warranting explicit inclusion in the newly derived transient dose models. All five of the individual transient dose models were evaluated for representative shipments of spent nuclear fuel and low-level waste within the State of Michigan and compared to experimentally measured doses. The individual dose for the Michigan shipment scenarios was found to be on the order of 1 murem. Comparison to the experimental measurements revealed that RISKIND consistently predicts the best estimate of the measured dose, followed closely by the surface cylinder model. RADTRAN consistently over predicted the measured dose by at least a factor of two. Finally, the line dose model is integrated over strips of uniform population along the transport route to arrive at the collective off-link population dose. This off-link dose model was incorporated into an ArcView application using the Avenue scripting language. Then this script was used to investigate the off-link dose to Michigan residents for the previously mentioned representative transport scenarios. The off-link dose was found to be less than 3 person-rem for all of the scenarios investigated.

A general model for stray dose calculation of static and intensity-modulated photon radiation.

PubMed

Hauri, Pascal; Hälg, Roger A; Besserer, Jürgen; Schneider, Uwe

2016-04-01

There is an increasing number of cancer survivors who are at risk of developing late effects caused by ionizing radiation such as induction of second tumors. Hence, the determination of out-of-field dose for a particular treatment plan in the patient's anatomy is of great importance. The purpose of this study was to analytically model the stray dose according to its three major components. For patient scatter, a mechanistic model was developed. For collimator scatter and head leakage, an empirical approach was used. The models utilize a nominal beam energy of 6 MeV to describe two linear accelerator types of a single vendor. The parameters of the models were adjusted using ionization chamber measurements registering total absorbed dose in simple geometries. Whole-body dose measurements using thermoluminescent dosimeters in an anthropomorphic phantom for static and intensity-modulated treatment plans were compared to the 3D out-of-field dose distributions calculated by a combined model. The absolute mean difference between the whole-body predicted and the measured out-of-field dose of four different plans was 11% with a maximum difference below 44%. Computation time of 36 000 dose points for one field was around 30 s. By combining the model-calculated stray dose with the treatment planning system dose, the whole-body dose distribution can be viewed in the treatment planning system. The results suggest that the model is accurate, fast and can be used for a wide range of treatment modalities to calculate the whole-body dose distribution for clinical analysis. For similar energy spectra, the mechanistic patient scatter model can be used independently of treatment machine or beam orientation.

The Effect of Ongoing Exposure Dynamics in Dose Response Relationships

PubMed Central

Pujol, Josep M.; Eisenberg, Joseph E.; Haas, Charles N.; Koopman, James S.

2009-01-01

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. PMID:19503605

Analysis of α-particle-induced chromosomal aberrations by chemically-induced PCC. Elaboration of dose-effect curves.

PubMed

Puig, Roser; Pujol, Mònica; Barrios, Leonardo; Caballín, María Rosa; Barquinero, Joan-Francesc

2016-09-01

In a similar way to high-dose exposures to low-LET radiations, cells show difficulties reaching mitosis after high-LET radiation exposure. For this reason, techniques have been proposed that are able to analyze chromosome aberrations in interphase by prematurely condensing the chromosomes (PCC-techniques). Few dose-effect curves for high-LET radiation types have been reported, and none for α-particles. The aim of this study was to evaluate, by chemically-induced PCC, the chromosome aberrations induced by several doses of α-particles. Monolayers of peripheral lymphocytes were exposed to an α-source of Americium-241 with a mean energy entering the cells of 2.7 MeV. Lymphocytes were exposed to 10 doses, from 0-2.5 Gy, and then cultured for 48 h. Colcemid and Calyculin-A were added at 24 and 1 h before harvesting, respectively. During microscope analysis, chromosome rings and extra chromosome pieces were scored in G2/M-PCC and M cells, while dicentric chromosomes were only scored in M cells. As the dose increased, fewer cells were able to reach mitosis and the proportion of G2/M-PCC cells increased. Chromosome rings were hardly observed in M cells when compared to G2/M-PCC cells. Extra fragments were more frequent than rings in both G2/M-PCC and M cells, but with lower frequencies than in G2/M-PCC cells. The distribution of dicentrics and extra fragments showed a clear overdispersion; this was not so evident for rings. The dose-effect curves obtained fitted very well to a linear model. Damaged cells after α-particle irradiation show more difficulties in reaching mitosis than cells exposed to γ-rays. After α-particle irradiation the frequency of all the chromosome aberrations considered increased linearly with the dose, and α-particles clearly produced more dicentrics and extra chromosome pieces with respect to γ-rays. After α-particle exposure, the existence of extra chromosome fragments in PCC cells seems to be a good candidate for use as a biomarker for dose assessment. However, the observed frequencies of different types of chromosomal aberrations could be influenced by some methodological aspects; for this reason, and in order to avoid possible methodological bias, standardization of the technique will be desirable.

Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

PubMed Central

Vaiserman, Alexander M.

2010-01-01

Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure. PMID:20585444

Quantification of dose uncertainties for the bladder in prostate cancer radiotherapy based on dominant eigenmodes

NASA Astrophysics Data System (ADS)

Rios, Richard; Acosta, Oscar; Lafond, Caroline; Espinosa, Jairo; de Crevoisier, Renaud

2017-11-01

In radiotherapy for prostate cancer the dose at the treatment planning for the bladder may be a bad surrogate of the actual delivered dose as the bladder presents the largest inter-fraction shape variations during treatment. This paper presents PCA models as a virtual tool to estimate dosimetric uncertainties for the bladder produced by motion and deformation between fractions. Our goal is to propose a methodology to determine the minimum number of modes required to quantify dose uncertainties of the bladder for motion/deformation models based on PCA. We trained individual PCA models using the bladder contours available from three patients with a planning computed tomography (CT) and on-treatment cone-beam CTs (CBCTs). Based on the above models and via deformable image registration (DIR), we estimated two accumulated doses: firstly, an accumulated dose obtained by integrating the planning dose over the Gaussian probability distribution of the PCA model; and secondly, an accumulated dose obtained by simulating treatment courses via a Monte Carlo approach. We also computed a reference accumulated dose for each patient using his available images via DIR. Finally, we compared the planning dose with the three accumulated doses, and we calculated local dose variability and dose-volume histogram uncertainties.

Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

PubMed

Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Turncliff, Ryan Z; Citrome, Leslie

2017-06-01

Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Study of a chemically amplified resist for X-ray lithography by Fourier transform infrared spectroscopy.

PubMed

Tan, T L; Wong, D; Lee, P; Rawat, R S; Patran, A

2004-11-01

Future applications of microelectromechanical systems (MEMS) require lithographic performance of very high aspect ratio. Chemically amplified resists (CARs) such as the negative tone commercial SU-8 provide critical advantages in sensitivity, resolution, and process efficiency in deep ultraviolet, electron-beam, and X-ray lithographies (XRLs), which result in a very high aspect ratio. In this investigation, an SU-8 resist was characterized and optimized for X-ray lithographic applications by studying the cross-linking process of the resist under different conditions of resist thickness and X-ray exposure dose. The exposure dose of soft X-ray (SXR) irradiation at the average weighted wavelength of 1.20 nm from a plasma focus device ranges from 100 to 1600 mJ/cm(2) on the resist surface. Resist thickness varies from 3.5 to 15 mum. The cross-linking process of the resist during post-exposure bake (PEB) was accurately monitored using Fourier transform infrared (FT-IR) spectroscopy. The infrared absorption peaks at 862, 914, 972, and 1128 cm(-1) in the spectrum of the SU-8 resist were found to be useful indicators for the completion of cross-linking in the resist. Results of the experiments showed that the cross-linking of SU-8 was optimized at the exposure dose of 800 mJ/cm(2) for resist thicknesses of 3.5, 9.5, and 15 microm. PEB temperature was set at 95 degrees C and time at 3 min. The resist thickness was measured using interference patterns in the FT-IR spectra of the resist. Test structures with an aspect ratio 3:1 on 10 microm thick SU-8 resist film were obtained using scanning electron microscopy (SEM).

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

PubMed Central

Lu, Yanhui; Bliven-Sizemore, Erin; Weiner, Marc; Nuermberger, Eric; Burman, William; Dorman, Susan E.; Dooley, Kelly E.

2014-01-01

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h−1, respectively, after a single dose to 2.2 and 5.0 liters · h−1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) PMID:24614383

Can we use the equivalent sphere model to approximate organ doses in space radiation environments?

NASA Astrophysics Data System (ADS)

Lin, Zi-Wei

For space radiation protection one often calculates the dose or dose equivalent in blood forming organs (BFO). It has been customary to use a 5cm equivalent sphere to approximate the BFO dose. However, previous studies have concluded that a 5cm sphere gives a very different dose from the exact BFO dose. One study concludes that a 9cm sphere is a reasonable approximation for the BFO dose in solar particle event (SPE) environments. In this study we investigate the reason behind these observations and extend earlier studies by studying whether BFO, eyes or the skin can be approximated by the equivalent sphere model in different space radiation environments such as solar particle events and galactic cosmic ray (GCR) environments. We take the thickness distribution functions of the organs from the CAM (Computerized Anatomical Man) model, then use a deterministic radiation transport to calculate organ doses in different space radiation environments. The organ doses have been evaluated with a water or aluminum shielding from 0 to 20 g/cm2. We then compare these exact doses with results from the equivalent sphere model and determine in which cases and at what radius parameters the equivalent sphere model is a reasonable approximation. Furthermore, we propose to use a modified equivalent sphere model with two radius parameters to represent the skin or eyes. For solar particle events, we find that the radius parameters for the organ dose equivalent increase significantly with the shielding thickness, and the model works marginally for BFO but is unacceptable for eyes or the skin. For galactic cosmic rays environments, the equivalent sphere model with one organ-specific radius parameter works well for the BFO dose equivalent, marginally well for the BFO dose and the dose equivalent of eyes or the skin, but is unacceptable for the dose of eyes or the skin. The BFO radius parameters are found to be significantly larger than 5 cm in all cases, consistent with the conclusion of an earlier study. The radius parameters for the dose equivalent in GCR environments are approximately between 10 and 11 cm for the BFO, 3.7 to 4.8 cm for eyes, and 3.5 to 5.6 cm for the skin; while the radius parameters are between 10 and 13 cm for the BFO dose. In the proposed modified equivalent sphere model, the range of each of the two radius parameters for the skin (or eyes) is much tighter than that in the equivalent sphere model with one radius parameter. Our results thus show that the equivalent sphere model works better in galactic cosmic rays environments than in solar particle events. The model works well or marginally well for BFO but usually does not work for eyes or the skin. A modified model with two radius parameters works much better in approximating the dose and dose equivalent in eyes or the skin.

The physics of proton therapy.

PubMed

Newhauser, Wayne D; Zhang, Rui

2015-04-21

The physics of proton therapy has advanced considerably since it was proposed in 1946. Today analytical equations and numerical simulation methods are available to predict and characterize many aspects of proton therapy. This article reviews the basic aspects of the physics of proton therapy, including proton interaction mechanisms, proton transport calculations, the determination of dose from therapeutic and stray radiations, and shielding design. The article discusses underlying processes as well as selected practical experimental and theoretical methods. We conclude by briefly speculating on possible future areas of research of relevance to the physics of proton therapy.

The physics of proton therapy

PubMed Central

Newhauser, Wayne D; Zhang, Rui

2015-01-01

The physics of proton therapy has advanced considerably since it was proposed in 1946. Today analytical equations and numerical simulation methods are available to predict and characterize many aspects of proton therapy. This article reviews the basic aspects of the physics of proton therapy, including proton interaction mechanisms, proton transport calculations, the determination of dose from therapeutic and stray radiations, and shielding design. The article discusses underlying processes as well as selected practical experimental and theoretical methods. We conclude by briefly speculating on possible future areas of research of relevance to the physics of proton therapy. PMID:25803097

Gamma-ray dose from an overhead plume

DOE PAGES

McNaughton, Michael W.; Gillis, Jessica McDonnel; Ruedig, Elizabeth; ...

2017-05-01

Standard plume models can underestimate the gamma-ray dose when most of the radioactive material is above the heads of the receptors. Typically, a model is used to calculate the air concentration at the height of the receptor, and the dose is calculated by multiplying the air concentration by a concentration-to-dose conversion factor. Models indicate that if the plume is emitted from a stack during stable atmospheric conditions, the lower edges of the plume may not reach the ground, in which case both the ground-level concentration and the dose are usually reported as zero. However, in such cases, the dose frommore » overhead gamma-emitting radionuclides may be substantial. Such underestimates could impact decision making in emergency situations. The Monte Carlo N-Particle code, MCNP, was used to calculate the overhead shine dose and to compare with standard plume models. At long distances and during unstable atmospheric conditions, the MCNP results agree with the standard models. As a result, at short distances, where many models calculate zero, the true dose (as modeled by MCNP) can be estimated with simple equations.« less

Antiplatelet Drugs

PubMed Central

Hirsh, Jack; Spencer, Frederick A.; Baglin, Trevor P.; Weitz, Jeffrey I.

2012-01-01

The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment. PMID:22315278

Towards aspect-oriented functional--structural plant modelling.

PubMed

Cieslak, Mikolaj; Seleznyova, Alla N; Prusinkiewicz, Przemyslaw; Hanan, Jim

2011-10-01

Functional-structural plant models (FSPMs) are used to integrate knowledge and test hypotheses of plant behaviour, and to aid in the development of decision support systems. A significant amount of effort is being put into providing a sound methodology for building them. Standard techniques, such as procedural or object-oriented programming, are not suited for clearly separating aspects of plant function that criss-cross between different components of plant structure, which makes it difficult to reuse and share their implementations. The aim of this paper is to present an aspect-oriented programming approach that helps to overcome this difficulty. The L-system-based plant modelling language L+C was used to develop an aspect-oriented approach to plant modelling based on multi-modules. Each element of the plant structure was represented by a sequence of L-system modules (rather than a single module), with each module representing an aspect of the element's function. Separate sets of productions were used for modelling each aspect, with context-sensitive rules facilitated by local lists of modules to consider/ignore. Aspect weaving or communication between aspects was made possible through the use of pseudo-L-systems, where the strict-predecessor of a production rule was specified as a multi-module. The new approach was used to integrate previously modelled aspects of carbon dynamics, apical dominance and biomechanics with a model of a developing kiwifruit shoot. These aspects were specified independently and their implementation was based on source code provided by the original authors without major changes. This new aspect-oriented approach to plant modelling is well suited for studying complex phenomena in plant science, because it can be used to integrate separate models of individual aspects of plant development and function, both previously constructed and new, into clearly organized, comprehensive FSPMs. In a future work, this approach could be further extended into an aspect-oriented programming language for FSPMs.

Towards aspect-oriented functional–structural plant modelling

PubMed Central

Cieslak, Mikolaj; Seleznyova, Alla N.; Prusinkiewicz, Przemyslaw; Hanan, Jim

2011-01-01

Background and Aims Functional–structural plant models (FSPMs) are used to integrate knowledge and test hypotheses of plant behaviour, and to aid in the development of decision support systems. A significant amount of effort is being put into providing a sound methodology for building them. Standard techniques, such as procedural or object-oriented programming, are not suited for clearly separating aspects of plant function that criss-cross between different components of plant structure, which makes it difficult to reuse and share their implementations. The aim of this paper is to present an aspect-oriented programming approach that helps to overcome this difficulty. Methods The L-system-based plant modelling language L+C was used to develop an aspect-oriented approach to plant modelling based on multi-modules. Each element of the plant structure was represented by a sequence of L-system modules (rather than a single module), with each module representing an aspect of the element's function. Separate sets of productions were used for modelling each aspect, with context-sensitive rules facilitated by local lists of modules to consider/ignore. Aspect weaving or communication between aspects was made possible through the use of pseudo-L-systems, where the strict-predecessor of a production rule was specified as a multi-module. Key Results The new approach was used to integrate previously modelled aspects of carbon dynamics, apical dominance and biomechanics with a model of a developing kiwifruit shoot. These aspects were specified independently and their implementation was based on source code provided by the original authors without major changes. Conclusions This new aspect-oriented approach to plant modelling is well suited for studying complex phenomena in plant science, because it can be used to integrate separate models of individual aspects of plant development and function, both previously constructed and new, into clearly organized, comprehensive FSPMs. In a future work, this approach could be further extended into an aspect-oriented programming language for FSPMs. PMID:21724653

Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice

PubMed Central

Lei, Kelly; Wegner, Scott A.; Yu, Ji-Hwan; Hopf, F. Woodward

2016-01-01

Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption. However, the critical mechanisms that drive compulsive-like drinking are only beginning to be identified. The neuropeptide orexin has been linked to high motivation for cocaine, preferred foods, and alcohol. Thus, we investigated the role of orexin receptors in compulsive-like alcohol drinking, where C57BL/6 mice had 2-hr daily access to 15% alcohol with or without quinine (100 µM). We found that systemic administration of the widely used selective orexin-1 receptor (OX1R) blocker, SB-334867 (SB), significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB, in particular, suppressed only compulsive-like drinking. Furthermore, SB did not reduce concurrent water intake during the alcohol drinking sessions, and did not alter saccharin+quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, our results suggest that OX1R signaling is particularly important for promoting compulsive-like alcohol drinking, and that OX1Rs might represent a novel therapy to counteract compulsive aspects of human AUDs. PMID:27523303

Potential implications of the bystander effect on TCP and EUD when considering target volume dose heterogeneity.

PubMed

Balderson, Michael J; Kirkby, Charles

2015-01-01

In light of in vitro evidence suggesting that radiation-induced bystander effects may enhance non-local cell killing, there is potential for impact on radiotherapy treatment planning paradigms such as the goal of delivering a uniform dose throughout the clinical target volume (CTV). This work applies a bystander effect model to calculate equivalent uniform dose (EUD) and tumor control probability (TCP) for external beam prostate treatment and compares the results with a more common model where local response is dictated exclusively by local absorbed dose. The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. EUD and TCP of a prostate cancer target volume under conditions of increasing dose heterogeneity were calculated using two models: One incorporating bystander effects derived from previously published in vitro bystander data ( McMahon et al. 2012 , 2013a); and one using a common linear-quadratic (LQ) response that relies exclusively on local absorbed dose. Dose through the CTV was modelled as a normal distribution, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). Also, a representative clinical dose distribution was examined as cold (low dose) sub-volumes were systematically introduced. The bystander model suggests a moderate degree of dose heterogeneity throughout a target volume will yield as good or better outcome compared to a uniform dose in terms of EUD and TCP. For a typical intermediate risk prostate prescription of 78 Gy over 39 fractions maxima in EUD and TCP as a function of increasing SD occurred at SD ∼ 5 Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. Small, but potentially significant differences in the outcome metrics between the models were identified in the clinically-derived dose distribution as cold sub-volumes were introduced. In terms of EUD and TCP, the bystander model demonstrates the potential to deviate from the common local LQ model predictions as dose heterogeneity through a prostate CTV varies. The results suggest, at least in a limiting sense, the potential for allowing some degree of dose heterogeneity within a CTV, although further investigation of the assumptions of the bystander model are warranted.

Comparison of TG-43 and TG-186 in breast irradiation using a low energy electronic brachytherapy source.

PubMed

White, Shane A; Landry, Guillaume; Fonseca, Gabriel Paiva; Holt, Randy; Rusch, Thomas; Beaulieu, Luc; Verhaegen, Frank; Reniers, Brigitte

2014-06-01

The recently updated guidelines for dosimetry in brachytherapy in TG-186 have recommended the use of model-based dosimetry calculations as a replacement for TG-43. TG-186 highlights shortcomings in the water-based approach in TG-43, particularly for low energy brachytherapy sources. The Xoft Axxent is a low energy (<50 kV) brachytherapy system used in accelerated partial breast irradiation (APBI). Breast tissue is a heterogeneous tissue in terms of density and composition. Dosimetric calculations of seven APBI patients treated with Axxent were made using a model-based Monte Carlo platform for a number of tissue models and dose reporting methods and compared to TG-43 based plans. A model of the Axxent source, the S700, was created and validated against experimental data. CT scans of the patients were used to create realistic multi-tissue/heterogeneous models with breast tissue segmented using a published technique. Alternative water models were used to isolate the influence of tissue heterogeneity and backscatter on the dose distribution. Dose calculations were performed using Geant4 according to the original treatment parameters. The effect of the Axxent balloon applicator used in APBI which could not be modeled in the CT-based model, was modeled using a novel technique that utilizes CAD-based geometries. These techniques were validated experimentally. Results were calculated using two dose reporting methods, dose to water (Dw,m) and dose to medium (Dm,m), for the heterogeneous simulations. All results were compared against TG-43-based dose distributions and evaluated using dose ratio maps and DVH metrics. Changes in skin and PTV dose were highlighted. All simulated heterogeneous models showed a reduced dose to the DVH metrics that is dependent on the method of dose reporting and patient geometry. Based on a prescription dose of 34 Gy, the average D90 to PTV was reduced by between ~4% and ~40%, depending on the scoring method, compared to the TG-43 result. Peak skin dose is also reduced by 10%-15% due to the absence of backscatter not accounted for in TG-43. The balloon applicator also contributed to the reduced dose. Other ROIs showed a difference depending on the method of dose reporting. TG-186-based calculations produce results that are different from TG-43 for the Axxent source. The differences depend strongly on the method of dose reporting. This study highlights the importance of backscatter to peak skin dose. Tissue heterogeneities, applicator, and patient geometries demonstrate the need for a more robust dose calculation method for low energy brachytherapy sources.

Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation

PubMed Central

Angle, Brittany M.; Do, Rylee Phuong; Ponzi, Davide; Stahlhut, Richard W.; Drury, Bertram E.; Nagel, Susan C.; Welshons, Wade V.; Besch-Williford, Cynthia L; Palanza, Paola; Parmigiani, Stefano; vom Saal, Frederick S.; Taylor, Julia A.

2013-01-01

Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000 μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0–24h),we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose–response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes. PMID:23892310

Multicentre dose audit for clinical trials of radiation therapy in Asia

PubMed Central

Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C.R. Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-01-01

Abstract A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. PMID:27864507

Isl1 is required for multiple aspects of motor neuron development.

PubMed

Liang, Xingqun; Song, Mi-Ryoung; Xu, ZengGuang; Lanuza, Guillermo M; Liu, Yali; Zhuang, Tao; Chen, Yihan; Pfaff, Samuel L; Evans, Sylvia M; Sun, Yunfu

2011-07-01

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

Improving Low-Dose Blood-Brain Barrier Permeability Quantification Using Sparse High-Dose Induced Prior for Patlak Model

PubMed Central

Fang, Ruogu; Karlsson, Kolbeinn; Chen, Tsuhan; Sanelli, Pina C.

2014-01-01

Blood-brain-barrier permeability (BBBP) measurements extracted from the perfusion computed tomography (PCT) using the Patlak model can be a valuable indicator to predict hemorrhagic transformation in patients with acute stroke. Unfortunately, the standard Patlak model based PCT requires excessive radiation exposure, which raised attention on radiation safety. Minimizing radiation dose is of high value in clinical practice but can degrade the image quality due to the introduced severe noise. The purpose of this work is to construct high quality BBBP maps from low-dose PCT data by using the brain structural similarity between different individuals and the relations between the high- and low-dose maps. The proposed sparse high-dose induced (shd-Patlak) model performs by building a high-dose induced prior for the Patlak model with a set of location adaptive dictionaries, followed by an optimized estimation of BBBP map with the prior regularized Patlak model. Evaluation with the simulated low-dose clinical brain PCT datasets clearly demonstrate that the shd-Patlak model can achieve more significant gains than the standard Patlak model with improved visual quality, higher fidelity to the gold standard and more accurate details for clinical analysis. PMID:24200529

Estimating organ doses from tube current modulated CT examinations using a generalized linear model.

PubMed

Bostani, Maryam; McMillan, Kyle; Lu, Peiyun; Kim, Grace Hyun J; Cody, Dianna; Arbique, Gary; Greenberg, S Bruce; DeMarco, John J; Cagnon, Chris H; McNitt-Gray, Michael F

2017-04-01

Currently, available Computed Tomography dose metrics are mostly based on fixed tube current Monte Carlo (MC) simulations and/or physical measurements such as the size specific dose estimate (SSDE). In addition to not being able to account for Tube Current Modulation (TCM), these dose metrics do not represent actual patient dose. The purpose of this study was to generate and evaluate a dose estimation model based on the Generalized Linear Model (GLM), which extends the ability to estimate organ dose from tube current modulated examinations by incorporating regional descriptors of patient size, scanner output, and other scan-specific variables as needed. The collection of a total of 332 patient CT scans at four different institutions was approved by each institution's IRB and used to generate and test organ dose estimation models. The patient population consisted of pediatric and adult patients and included thoracic and abdomen/pelvis scans. The scans were performed on three different CT scanner systems. Manual segmentation of organs, depending on the examined anatomy, was performed on each patient's image series. In addition to the collected images, detailed TCM data were collected for all patients scanned on Siemens CT scanners, while for all GE and Toshiba patients, data representing z-axis-only TCM, extracted from the DICOM header of the images, were used for TCM simulations. A validated MC dosimetry package was used to perform detailed simulation of CT examinations on all 332 patient models to estimate dose to each segmented organ (lungs, breasts, liver, spleen, and kidneys), denoted as reference organ dose values. Approximately 60% of the data were used to train a dose estimation model, while the remaining 40% was used to evaluate performance. Two different methodologies were explored using GLM to generate a dose estimation model: (a) using the conventional exponential relationship between normalized organ dose and size with regional water equivalent diameter (WED) and regional CTDI vol as variables and (b) using the same exponential relationship with the addition of categorical variables such as scanner model and organ to provide a more complete estimate of factors that may affect organ dose. Finally, estimates from generated models were compared to those obtained from SSDE and ImPACT. The Generalized Linear Model yielded organ dose estimates that were significantly closer to the MC reference organ dose values than were organ doses estimated via SSDE or ImPACT. Moreover, the GLM estimates were better than those of SSDE or ImPACT irrespective of whether or not categorical variables were used in the model. While the improvement associated with a categorical variable was substantial in estimating breast dose, the improvement was minor for other organs. The GLM approach extends the current CT dose estimation methods by allowing the use of additional variables to more accurately estimate organ dose from TCM scans. Thus, this approach may be able to overcome the limitations of current CT dose metrics to provide more accurate estimates of patient dose, in particular, dose to organs with considerable variability across the population. © 2017 American Association of Physicists in Medicine.

Modification and validation of an analytical source model for external beam radiotherapy Monte Carlo dose calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davidson, Scott E., E-mail: sedavids@utmb.edu

Purpose: A dose calculation tool, which combines the accuracy of the dose planning method (DPM) Monte Carlo code and the versatility of a practical analytical multisource model, which was previously reported has been improved and validated for the Varian 6 and 10 MV linear accelerators (linacs). The calculation tool can be used to calculate doses in advanced clinical application studies. One shortcoming of current clinical trials that report dose from patient plans is the lack of a standardized dose calculation methodology. Because commercial treatment planning systems (TPSs) have their own dose calculation algorithms and the clinical trial participant who usesmore » these systems is responsible for commissioning the beam model, variation exists in the reported calculated dose distributions. Today’s modern linac is manufactured to tight specifications so that variability within a linac model is quite low. The expectation is that a single dose calculation tool for a specific linac model can be used to accurately recalculate dose from patient plans that have been submitted to the clinical trial community from any institution. The calculation tool would provide for a more meaningful outcome analysis. Methods: The analytical source model was described by a primary point source, a secondary extra-focal source, and a contaminant electron source. Off-axis energy softening and fluence effects were also included. The additions of hyperbolic functions have been incorporated into the model to correct for the changes in output and in electron contamination with field size. A multileaf collimator (MLC) model is included to facilitate phantom and patient dose calculations. An offset to the MLC leaf positions was used to correct for the rudimentary assumed primary point source. Results: Dose calculations of the depth dose and profiles for field sizes 4 × 4 to 40 × 40 cm agree with measurement within 2% of the maximum dose or 2 mm distance to agreement (DTA) for 95% of the data points tested. The model was capable of predicting the depth of the maximum dose within 1 mm. Anthropomorphic phantom benchmark testing of modulated and patterned MLCs treatment plans showed agreement to measurement within 3% in target regions using thermoluminescent dosimeters (TLD). Using radiochromic film normalized to TLD, a gamma criteria of 3% of maximum dose and 2 mm DTA was applied with a pass rate of least 85% in the high dose, high gradient, and low dose regions. Finally, recalculations of patient plans using DPM showed good agreement relative to a commercial TPS when comparing dose volume histograms and 2D dose distributions. Conclusions: A unique analytical source model coupled to the dose planning method Monte Carlo dose calculation code has been modified and validated using basic beam data and anthropomorphic phantom measurement. While this tool can be applied in general use for a particular linac model, specifically it was developed to provide a singular methodology to independently assess treatment plan dose distributions from those clinical institutions participating in National Cancer Institute trials.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lesperance, Marielle; Inglis-Whalen, M.; Thomson, R. M., E-mail: rthomson@physics.carleton.ca

Purpose : To investigate the effects of the composition and geometry of ocular media and tissues surrounding the eye on dose distributions for COMS eye plaque brachytherapy with{sup 125}I, {sup 103}Pd, or {sup 131}Cs seeds, and to investigate doses to ocular structures. Methods : An anatomically and compositionally realistic voxelized eye model with a medial tumor is developed based on a literature review. Mass energy absorption and attenuation coefficients for ocular media are calculated. Radiation transport and dose deposition are simulated using the EGSnrc Monte Carlo user-code BrachyDose for a fully loaded COMS eye plaque within a water phantom andmore » our full eye model for the three radionuclides. A TG-43 simulation with the same seed configuration in a water phantom neglecting the plaque and interseed effects is also performed. The impact on dose distributions of varying tumor position, as well as tumor and surrounding tissue media is investigated. Each simulation and radionuclide is compared using isodose contours, dose volume histograms for the lens and tumor, maximum, minimum, and average doses to structures of interest, and doses to voxels of interest within the eye. Results : Mass energy absorption and attenuation coefficients of the ocular media differ from those of water by as much as 12% within the 20–30 keV photon energy range. For all radionuclides studied, average doses to the tumor and lens regions in the full eye model differ from those for the plaque in water by 8%–10% and 13%–14%, respectively; the average doses to the tumor and lens regions differ between the full eye model and the TG-43 simulation by 2%–17% and 29%–34%, respectively. Replacing the surrounding tissues in the eye model with water increases the maximum and average doses to the lens by 2% and 3%, respectively. Substituting the tumor medium in the eye model for water, soft tissue, or an alternate melanoma composition affects tumor dose compared to the default eye model simulation by up to 16%. In the full eye model simulations, the average dose to the lens is larger by 7%–9% than the dose to the center of the lens, and the maximum dose to the optic nerve is 17%–22% higher than the dose to the optic disk for all radionuclides. In general, when normalized to the same prescription dose at the tumor apex, doses delivered to all structures of interest in the full eye model are lowest for{sup 103}Pd and highest for {sup 131}Cs, except for the tumor where the average dose is highest for {sup 103}Pd and lowest for {sup 131}Cs. Conclusions : The eye is not radiologically water-equivalent, as doses from simulations of the plaque in the full eye model differ considerably from doses for the plaque in a water phantom and from simulated TG-43 calculated doses. This demonstrates the importance of model-based dose calculations for eye plaque brachytherapy, for which accurate elemental compositions of ocular media are necessary.« less

Monte Carlo Simulation of a 12 MeV Cargo Container Inspection System

NASA Astrophysics Data System (ADS)

Ozcan, Ibrahim; Chandler, Katherine; Spaulding, Randy; Farfan, Eduardo

2007-05-01

After the terrorist events of 9/11, border security has become one of the most important issues in national security due to the large number of cargo containers entering the country. Screening of all cargo containers for nuclear materials should be performed during border inspections. The technical aspects of inspecting cargo containers using electron accelerators have been studied previously. However, the radiological protection aspects involved in these studies have not been fully considered. This screening process may accidentally harm operators, workers, and bystanders; as well as stowaways hiding inside the containers. In this research project, external doses were estimated at various locations near the inspection system. A 12-MeV linear accelerator (LINAC) was used in the experiment. The relationship between the various locations and doses were determined in this simulation. The simulation was performed using MCNPX. To cite this abstract, use the following reference: http://meetings.aps.org/link/BAPS.2007.NWS07.B2.8

Comparison of the dose distribution obtained from dosimetric systems with intensity modulated radiotherapy planning system in the treatment of prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gökçe, M., E-mail: mgokce@adu.edu.tr; Uslu, D. Koçyiğit; Ertunç, C.

The aim of this study is to compare Intensity Modulated Radiation Therapy (IMRT) plan of prostate cancer patients with different dose verification systems in dosimetric aspects and to compare these systems with each other in terms of reliability, applicability and application time. Dosimetric control processes of IMRT plan of three prostate cancer patients were carried out using thermoluminescent dosimeter (TLD), ion chamber (IC) and 2D Array detector systems. The difference between the dose values obtained from the dosimetric systems and treatment planning system (TPS) were found to be about % 5. For the measured (TLD) and calculated (TPS) doses %3more » percentage differences were obtained for the points close to center while percentage differences increased at the field edges. It was found that TLD and IC measurements will increase the precision and reliability of the results of 2D Array.« less

Influenza vaccine strategies for solid organ transplant recipients.

PubMed

Hirzel, Cédric; Kumar, Deepali

2018-05-15

The aim of this study was to highlight recent evidence on important aspects of influenza vaccination in solid organ transplant recipients. Influenza vaccine is the most evaluated vaccine in transplant recipients. The immunogenicity of the vaccine is suboptimal after transplantation. Newer formulations such as inactivated unadjuvanted high-dose influenza vaccine and the administration of a booster dose within the same season have shown to increase response rates. Intradermal vaccination and adjuvanted vaccines did not show clear benefit over standard influenza vaccines. Recent studies in transplant recipients do not suggest a higher risk for allograft rejection, neither after vaccination with a standard influenza vaccine nor after the administration of nonstandard formulation (high-dose, adjuvanted vaccines), routes (intradermally) or a booster dose. Nevertheless, influenza vaccine coverage in transplant recipients is still unsatisfactory low, potentially due to misinterpretation of risks and benefits. Annual influenza vaccination is well tolerated and is an important part of long-term care of solid organ transplant recipients.

Dosimetry in MARS spectral CT: TOPAS Monte Carlo simulations and ion chamber measurements.

PubMed

Lu, Gray; Marsh, Steven; Damet, Jerome; Carbonez, Pierre; Laban, John; Bateman, Christopher; Butler, Anthony; Butler, Phil

2017-06-01

Spectral computed tomography (CT) is an up and coming imaging modality which shows great promise in revealing unique diagnostic information. Because this imaging modality is based on X-ray CT, it is of utmost importance to study the radiation dose aspects of its use. This study reports on the implementation and evaluation of a Monte Carlo simulation tool using TOPAS for estimating dose in a pre-clinical spectral CT scanner known as the MARS scanner. Simulated estimates were compared with measurements from an ionization chamber. For a typical MARS scan, TOPAS estimated for a 30 mm diameter cylindrical phantom a CT dose index (CTDI) of 29.7 mGy; CTDI was measured by ion chamber to within 3% of TOPAS estimates. Although further development is required, our investigation of TOPAS for estimating MARS scan dosimetry has shown its potential for further study of spectral scanning protocols and dose to scanned objects.

Properties of model-averaged BMDLs: a study of model averaging in dichotomous response risk estimation.

PubMed

Wheeler, Matthew W; Bailer, A John

2007-06-01

Model averaging (MA) has been proposed as a method of accounting for model uncertainty in benchmark dose (BMD) estimation. The technique has been used to average BMD dose estimates derived from dichotomous dose-response experiments, microbial dose-response experiments, as well as observational epidemiological studies. While MA is a promising tool for the risk assessor, a previous study suggested that the simple strategy of averaging individual models' BMD lower limits did not yield interval estimators that met nominal coverage levels in certain situations, and this performance was very sensitive to the underlying model space chosen. We present a different, more computationally intensive, approach in which the BMD is estimated using the average dose-response model and the corresponding benchmark dose lower bound (BMDL) is computed by bootstrapping. This method is illustrated with TiO(2) dose-response rat lung cancer data, and then systematically studied through an extensive Monte Carlo simulation. The results of this study suggest that the MA-BMD, estimated using this technique, performs better, in terms of bias and coverage, than the previous MA methodology. Further, the MA-BMDL achieves nominal coverage in most cases, and is superior to picking the "best fitting model" when estimating the benchmark dose. Although these results show utility of MA for benchmark dose risk estimation, they continue to highlight the importance of choosing an adequate model space as well as proper model fit diagnostics.

Comprehensive Aspectual UML approach to support AspectJ.

PubMed

Magableh, Aws; Shukur, Zarina; Ali, Noorazean Mohd

2014-01-01

Unified Modeling Language is the most popular and widely used Object-Oriented modelling language in the IT industry. This study focuses on investigating the ability to expand UML to some extent to model crosscutting concerns (Aspects) to support AspectJ. Through a comprehensive literature review, we identify and extensively examine all the available Aspect-Oriented UML modelling approaches and find that the existing Aspect-Oriented Design Modelling approaches using UML cannot be considered to provide a framework for a comprehensive Aspectual UML modelling approach and also that there is a lack of adequate Aspect-Oriented tool support. This study also proposes a set of Aspectual UML semantic rules and attempts to generate AspectJ pseudocode from UML diagrams. The proposed Aspectual UML modelling approach is formally evaluated using a focus group to test six hypotheses regarding performance; a "good design" criteria-based evaluation to assess the quality of the design; and an AspectJ-based evaluation as a reference measurement-based evaluation. The results of the focus group evaluation confirm all the hypotheses put forward regarding the proposed approach. The proposed approach provides a comprehensive set of Aspectual UML structural and behavioral diagrams, which are designed and implemented based on a comprehensive and detailed set of AspectJ programming constructs.

Comprehensive Aspectual UML Approach to Support AspectJ

PubMed Central

Magableh, Aws; Shukur, Zarina; Mohd. Ali, Noorazean

2014-01-01

Unified Modeling Language is the most popular and widely used Object-Oriented modelling language in the IT industry. This study focuses on investigating the ability to expand UML to some extent to model crosscutting concerns (Aspects) to support AspectJ. Through a comprehensive literature review, we identify and extensively examine all the available Aspect-Oriented UML modelling approaches and find that the existing Aspect-Oriented Design Modelling approaches using UML cannot be considered to provide a framework for a comprehensive Aspectual UML modelling approach and also that there is a lack of adequate Aspect-Oriented tool support. This study also proposes a set of Aspectual UML semantic rules and attempts to generate AspectJ pseudocode from UML diagrams. The proposed Aspectual UML modelling approach is formally evaluated using a focus group to test six hypotheses regarding performance; a “good design” criteria-based evaluation to assess the quality of the design; and an AspectJ-based evaluation as a reference measurement-based evaluation. The results of the focus group evaluation confirm all the hypotheses put forward regarding the proposed approach. The proposed approach provides a comprehensive set of Aspectual UML structural and behavioral diagrams, which are designed and implemented based on a comprehensive and detailed set of AspectJ programming constructs. PMID:25136656

Sci—Fri PM: Topics — 04: What if bystander effects influence cell kill within a target volume? Potential consequences of dose heterogeneity on TCP and EUD on intermediate risk prostate patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balderson, M.J.; Kirkby, C.; Department of Medical Physics, Tom Baker Cancer Centre, Calgary, Alberta

In vitro evidence has suggested that radiation induced bystander effects may enhance non-local cell killing which may influence radiotherapy treatment planning paradigms. This work applies a bystander effect model, which has been derived from published in vitro data, to calculate equivalent uniform dose (EUD) and tumour control probability (TCP) and compare them with predictions from standard linear quadratic (LQ) models that assume a response due only to local absorbed dose. Comparisons between the models were made under increasing dose heterogeneity scenarios. Dose throughout the CTV was modeled with normal distributions, where the degree of heterogeneity was then dictated by changingmore » the standard deviation (SD). The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. The bystander model suggests a moderate degree of dose heterogeneity yields as good or better outcome compared to a uniform dose in terms of EUD and TCP. Intermediate risk prostate prescriptions of 78 Gy over 39 fractions had maximum EUD and TCP values at SD of around 5Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. The bystander model demonstrates the potential to deviate from the common local LQ model predictions as dose heterogeneity through a prostate CTV is varies. The results suggest the potential for allowing some degree of dose heterogeneity within a CTV, although further investigations of the assumptions of the bystander model are warranted.« less

Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950-2003.

PubMed

Schöllnberger, Helmut; Eidemüller, Markus; Cullings, Harry M; Simonetto, Cristoforo; Neff, Frauke; Kaiser, Jan Christian

2018-03-01

The scientific community faces important discussions on the validity of the linear no-threshold (LNT) model for radiation-associated cardiovascular diseases at low and moderate doses. In the present study, mortalities from cerebrovascular diseases (CeVD) and heart diseases from the latest data on atomic bomb survivors were analyzed. The analysis was performed with several radio-biologically motivated linear and nonlinear dose-response models. For each detrimental health outcome one set of models was identified that all fitted the data about equally well. This set was used for multi-model inference (MMI), a statistical method of superposing different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. MMI provides a more accurate determination of the dose response and a more comprehensive characterization of uncertainties. It was found that for CeVD, the dose-response curve from MMI is located below the linear no-threshold model at low and medium doses (0-1.4 Gy). At higher doses MMI predicts a higher risk compared to the LNT model. A sublinear dose-response was also found for heart diseases (0-3 Gy). The analyses provide no conclusive answer to the question whether there is a radiation risk below 0.75 Gy for CeVD and 2.6 Gy for heart diseases. MMI suggests that the dose-response curves for CeVD and heart diseases in the Lifespan Study are sublinear at low and moderate doses. This has relevance for radiotherapy treatment planning and for international radiation protection practices in general.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorissen, BL; Giantsoudi, D; Unkelbach, J

Purpose: Cell survival experiments suggest that the relative biological effectiveness (RBE) of proton beams depends on linear energy transfer (LET), leading to higher RBE near the end of range. With intensity-modulated proton therapy (IMPT), multiple treatment plans that differ in the dose contribution per field may yield a similar physical dose distribution, but the RBE-weighted dose distribution may be disparate. RBE models currently do not have the required predictive power to be included in an optimization model due to the variations in experimental data. We propose an LET-based planning method that guides IMPT optimization models towards plans with reduced RBE-weightedmore » dose in surrounding organs at risk (OARs) compared to inverse planning based on physical dose alone. Methods: Optimization models for physical dose are extended with a term for dose times LET (doseLET). Monte Carlo code is used to generate the physical dose and doseLET distribution of each individual pencil beam. The method is demonstrated for an atypical meningioma patient where the target volume abuts the brainstem and partially overlaps with the optic nerve. Results: A reference plan optimized based on physical dose alone yields high doseLET values in parts of the brainstem and optic nerve. Minimizing doseLET in these critical structures as an additional planning goal reduces the risk of high RBE-weighted dose. The resulting treatment plan avoids the distal fall-off of the Bragg peaks for shaping the dose distribution in front of critical stuctures. The maximum dose in the OARs evaluated with RBE models from literature is reduced by 8–14\\% with our method compared to conventional planning. Conclusion: LET-based inverse planning for IMPT offers the ability to reduce the RBE-weighted dose in OARs without sacrificing target dose. This project was in part supported by NCI - U19 CA 21239.« less

WE-G-16A-01: Evolution of Radiation Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rothenberg, L; Mohan, R; Van Dyk, J

Welcome and Introduction - Lawrence N. Rothenberg This symposium is one a continuing series of presentations at AAPM Annual Meetings on the historical aspects of medical physics, radiology, and radiation oncology that have been organized by the AAPM History Committee. Information on previous presentations including “Early Developments in Teletherapy” (Indianapolis 2013), “Historical Aspects of Cross-Sectional Imaging” (Charlotte 2012), “Historical Aspects of Brachytherapy” (Vancouver 2011), “50 Years of Women in Medical Physics” (Houston 2008), and “Roentgen's Early Investigations” (Minneapolis 2007) can be found in the Education Section of the AAPM Website. The Austin 2014 History Symposium will be on “Evolution ofmore » Radiation Treatment Planning.” Overview - Radhe Mohan Treatment planning is one of the most critical components in the chain of radiation therapy of cancers. Treatment plans of today contain a wide variety of sophisticated information conveying the potential clinical effectiveness of the designed treatment to practitioners. Examples of such information include dose distributions superimposed on three- or even four-dimensional anatomic images; dose volume histograms, dose, dose-volume and dose-response indices for anatomic structures of interest; etc. These data are used for evaluating treatment plans and for making treatment decisions. The current state-of-the-art has evolved from the 1940s era when the dose to the tumor and normal tissues was estimated approximately by manual means. However, the symposium will cover the history of the field from the late-1950's, when computers were first introduced for treatment planning, to the present state involving the use of high performance computing and advanced multi-dimensional anatomic, functional and biological imaging, focusing only on external beam treatment planning. The symposium will start with a general overview of the treatment planning process including imaging, structure delineation, assignment of dose requirements, consideration of uncertainties, selection of beam configurations and shaping of beams, and calculations, optimization and evaluation of dose distributions. This will be followed by three presentations covering the evolution of treatment planning, which parallels the evolution of computers, availability of advanced volumetric imaging and the development of novel technologies such as dynamic multi-leaf collimators and online image guidance. This evolution will be divided over three distinct periods - prior to 1970's, the 2D era; from 1980 to the mid-1990's, the 3D era; and from the mid 1990's to today, the IMRT era. When the World was Flat: The Two-Dimensional Radiation Therapy Era” - Jacob Van Dyk In the 2D era, anatomy was defined with the aid of solder wires, special contouring devices and projection x-rays. Dose distributions were calculated manually from single field, flat surface isodoses on transparencies. Precalculated atlases of generic dose distributions were produced by the International Atomic Energy Agency. Massive time-shared main frames and mini-computers were used to compute doses at individual points or dose distributions in a single plane. Beam shapes were generally rectangular, with wedges, missing tissue compensators and occasional blocks to shield critical structures. Dose calculations were measurement-based or they used primary and scatter calculations based on scatter-air ratio methodologies. Dose distributions were displayed on line printers as alpha-numeric character maps or isodose patterns made with pen plotters. More than Pretty Pictures: 3D Treatment Planning and Conformal Therapy - Benedick A. Fraass The introduction of computed tomography allowed the delineation of anatomy three-dimensionally and, supported partly by contracts from the National Cancer Institute, made possible the introduction and clinical use of 3D treatment planning, leading to development and use of 3D conformal therapy in the 1980's. 3D computer graphics and 3D anatomical structure definitions made possible Beam's Eye View (BEV) displays, making conformal beam shaping and much more sophisticated beam arrangements possible. These conformal plans significantly improved target dose coverage as well as normal tissue sparing. The use of dose volume histograms, gross/clinical/planning target volumes, MRI and PET imaging, multileaf collimators, and computer-controlled treatment delivery made sophisticated planning approaches practical. The significant improvements in dose distributions and analysis achievable with 3D conformal therapy made possible formal dose escalation and normal tissue tolerance clinical studies that set new and improved expectations for improved local control and decreasing complications in many clinical sites. From the Art to the State of the Art: Inverse Planning and IMRT - Thomas R. Bortfeld While the potential of intensity modulation was recognized in the mid- 1980's, intensity-modulated radiotherapy (IMRT) did not become a reality until the mid-1990's. Broad beams of photons could be sub-divided into narrow beamlets whose intensities could be determined using sophisticated optimization algorithms to appropriately balance tumor dose with normal tissue sparing. The development of dynamic multi-leaf collimators (on conventional linear accelerators as well as in helical delivery devices) enabled the efficient delivery of IMRT. The evolution of IMRT planning is continuing in the form of Volumetric Modulated Arc Therapy (VMAT) and through advanced optimization tools, such as multi-criteria optimization, automated IMRT planning, and robust optimization to protect dose distributions against uncertainties. IMRT also facilitates “dose painting” in which different sub-volumes of the target are prescribed different doses. Clearly, these advancements are being made possible by the increasing power and lower cost of computers and developments in other fields such as imaging and operations research. Summary - Radhe Mohan The history does not end here. The advancement of treatment planning is expected to continue, leading to further automation and improvements in conformality and robustness of dose distributions, particularly in the area of particle therapy. Radiobiological modeling will gain emphasis as part of the planning process. Learning Objectives: The scope of changes in technology and the capabilities of radiation treatment planning The impact of these changes in the quality of treatment plans and optimality of dose distributions The impact of development in other fields (imaging, computers, operations research, etc.) on the evolution of radiation treatment planning.« less

A diversity index for model space selection in the estimation of benchmark and infectious doses via model averaging.

PubMed

Kim, Steven B; Kodell, Ralph L; Moon, Hojin

2014-03-01

In chemical and microbial risk assessments, risk assessors fit dose-response models to high-dose data and extrapolate downward to risk levels in the range of 1-10%. Although multiple dose-response models may be able to fit the data adequately in the experimental range, the estimated effective dose (ED) corresponding to an extremely small risk can be substantially different from model to model. In this respect, model averaging (MA) provides more robustness than a single dose-response model in the point and interval estimation of an ED. In MA, accounting for both data uncertainty and model uncertainty is crucial, but addressing model uncertainty is not achieved simply by increasing the number of models in a model space. A plausible set of models for MA can be characterized by goodness of fit and diversity surrounding the truth. We propose a diversity index (DI) to balance between these two characteristics in model space selection. It addresses a collective property of a model space rather than individual performance of each model. Tuning parameters in the DI control the size of the model space for MA. © 2013 Society for Risk Analysis.

Rates of Change in Naturalistic Psychotherapy: Contrasting Dose-Effect and Good-Enough Level Models of Change

ERIC Educational Resources Information Center

Baldwin, Scott A.; Berkeljon, Arjan; Atkins, David C.; Olsen, Joseph A.; Nielsen, Stevan L.

2009-01-01

Most research on the dose-effect model of change has combined data across patients who vary in their total dose of treatment and has implicitly assumed that the rate of change during therapy is constant across doses. In contrast, the good-enough level model predicts that rate of change will be related to total dose of therapy. In this study, the…

A distributed lag approach to fitting non-linear dose-response models in particulate matter air pollution time series investigations.

PubMed

Roberts, Steven; Martin, Michael A

2007-06-01

The majority of studies that have investigated the relationship between particulate matter (PM) air pollution and mortality have assumed a linear dose-response relationship and have used either a single-day's PM or a 2- or 3-day moving average of PM as the measure of PM exposure. Both of these modeling choices have come under scrutiny in the literature, the linear assumption because it does not allow for non-linearities in the dose-response relationship, and the use of the single- or multi-day moving average PM measure because it does not allow for differential PM-mortality effects spread over time. These two problems have been dealt with on a piecemeal basis with non-linear dose-response models used in some studies and distributed lag models (DLMs) used in others. In this paper, we propose a method for investigating the shape of the PM-mortality dose-response relationship that combines a non-linear dose-response model with a DLM. This combined model will be shown to produce satisfactory estimates of the PM-mortality dose-response relationship in situations where non-linear dose response models and DLMs alone do not; that is, the combined model did not systemically underestimate or overestimate the effect of PM on mortality. The combined model is applied to ten cities in the US and a pooled dose-response model formed. When fitted with a change-point value of 60 microg/m(3), the pooled model provides evidence for a positive association between PM and mortality. The combined model produced larger estimates for the effect of PM on mortality than when using a non-linear dose-response model or a DLM in isolation. For the combined model, the estimated percentage increase in mortality for PM concentrations of 25 and 75 microg/m(3) were 3.3% and 5.4%, respectively. In contrast, the corresponding values from a DLM used in isolation were 1.2% and 3.5%, respectively.

Exercise and sport performance with low doses of caffeine.

PubMed

Spriet, Lawrence L

2014-11-01

Caffeine is a popular work-enhancing supplement that has been actively researched since the 1970s. The majority of research has examined the effects of moderate to high caffeine doses (5-13 mg/kg body mass) on exercise and sport. These caffeine doses have profound effects on the responses to exercise at the whole-body level and are associated with variable results and some undesirable side effects. Low doses of caffeine (<3 mg/kg body mass, ~200 mg) are also ergogenic in some exercise and sport situations, although this has been less well studied. Lower caffeine doses (1) do not alter the peripheral whole-body responses to exercise; (2) improve vigilance, alertness, and mood and cognitive processes during and after exercise; and (3) are associated with few, if any, side effects. Therefore, the ergogenic effect of low caffeine doses appears to result from alterations in the central nervous system. However, several aspects of consuming low doses of caffeine remain unresolved and suffer from a paucity of research, including the potential effects on high-intensity sprint and burst activities. The responses to low doses of caffeine are also variable and athletes need to determine whether the ingestion of ~200 mg of caffeine before and/or during training and competitions is ergogenic on an individual basis.

SU-F-P-19: Fetal Dose Estimate for a High-Dose Fluoroscopy Guided Intervention Using Modern Data Tools

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moirano, J

Purpose: An accurate dose estimate is necessary for effective patient management after a fetal exposure. In the case of a high-dose exposure, it is critical to use all resources available in order to make the most accurate assessment of the fetal dose. This work will demonstrate a methodology for accurate fetal dose estimation using tools that have recently become available in many clinics, and show examples of best practices for collecting data and performing the fetal dose calculation. Methods: A fetal dose estimate calculation was performed using modern data collection tools to determine parameters for the calculation. The reference pointmore » air kerma as displayed by the fluoroscopic system was checked for accuracy. A cumulative dose incidence map and DICOM header mining were used to determine the displayed reference point air kerma. Corrections for attenuation caused by the patient table and pad were measured and applied in order to determine the peak skin dose. The position and depth of the fetus was determined by ultrasound imaging and consultation with a radiologist. The data collected was used to determine a normalized uterus dose from Monte Carlo simulation data. Fetal dose values from this process were compared to other accepted calculation methods. Results: An accurate high-dose fetal dose estimate was made. Comparison to accepted legacy methods were were within 35% of estimated values. Conclusion: Modern data collection and reporting methods ease the process for estimation of fetal dose from interventional fluoroscopy exposures. Many aspects of the calculation can now be quantified rather than estimated, which should allow for a more accurate estimation of fetal dose.« less

SU-F-J-187: The Statistical NTCP and TCP Models in the Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, S; Frometa, T; Pyakuryal, A

2016-06-15

Purpose: The statistical models (SM) are typically used as a subjective description of a population for which there is only limited sample data, and especially in cases where the relationship between variables is known. The normal tissue complications and tumor control are frequently stochastic effects in the Radiotherapy (RT). Based on probabilistic treatments, it recently has been formulated new NTCP and TCP models for the RT. Investigating the particular requirements for their clinical use in the proton therapy (PT) is the goal of this work. Methods: The SM can be used as phenomenological or mechanistic models. The former way allowsmore » fitting real data and getting theirparameters. In the latter one, we should do efforts for determining the parameters through the acceptable estimations, measurements, and/or simulation experiments. Experimental methodologies for determination of the parameters have been developed from the fraction cells surviving the proton irradiation curves in tumor and OAR, and precise RBE models are used for calculating the variable of effective dose. As the executions of these methodologies have a high costs, so we have developed computer tools enable to perform simulation experiments as complement to limitations of the real ones. Results: The requirements for the use of the SM in the PT, such as validation and improvement of the elaborated and existent methodologies for determining the SM parameters and effective dose respectively, were determined. Conclusion: The SM realistically simulates the main processes in the PT, and for this reason these can be implemented in this therapy, which are simples, computable and they have other advantages over some current models. It has been determined some negative aspects for some currently used probabilistic models in the RT, like the LKB NTCP and others derived from logistic functions; which can be improved with the proposed methods in this study.« less

Using a knowledge-based planning solution to select patients for proton therapy.

PubMed

Delaney, Alexander R; Dahele, Max; Tol, Jim P; Kuijper, Ingrid T; Slotman, Ben J; Verbakel, Wilko F A R

2017-08-01

Patient selection for proton therapy by comparing proton/photon treatment plans is time-consuming and prone to bias. RapidPlan™, a knowledge-based-planning solution, uses plan-libraries to model and predict organ-at-risk (OAR) dose-volume-histograms (DVHs). We investigated whether RapidPlan, utilizing an algorithm based only on photon beam characteristics, could generate proton DVH-predictions and whether these could correctly identify patients for proton therapy. Model PROT and Model PHOT comprised 30 head-and-neck cancer proton and photon plans, respectively. Proton and photon knowledge-based-plans (KBPs) were made for ten evaluation-patients. DVH-prediction accuracy was analyzed by comparing predicted-vs-achieved mean OAR doses. KBPs and manual plans were compared using salivary gland and swallowing muscle mean doses. For illustration, patients were selected for protons if predicted Model PHOT mean dose minus predicted Model PROT mean dose (ΔPrediction) for combined OARs was ≥6Gy, and benchmarked using achieved KBP doses. Achieved and predicted Model PROT /Model PHOT mean dose R 2 was 0.95/0.98. Generally, achieved mean dose for Model PHOT /Model PROT KBPs was respectively lower/higher than predicted. Comparing Model PROT /Model PHOT KBPs with manual plans, salivary and swallowing mean doses increased/decreased by <2Gy, on average. ΔPrediction≥6Gy correctly selected 4 of 5 patients for protons. Knowledge-based DVH-predictions can provide efficient, patient-specific selection for protons. A proton-specific RapidPlan-solution could improve results. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative optical coherence tomography imaging of intermediate flow defect phenotypes in ciliary physiology and pathophysiology

NASA Astrophysics Data System (ADS)

Huang, Brendan K.; Gamm, Ute A.; Jonas, Stephan; Khokha, Mustafa K.; Choma, Michael A.

2015-03-01

Cilia-driven fluid flow is a critical yet poorly understood aspect of pulmonary physiology. Here, we demonstrate that optical coherence tomography-based particle tracking velocimetry can be used to quantify subtle variability in cilia-driven flow performance in Xenopus, an important animal model of ciliary biology. Changes in flow performance were quantified in the setting of normal development, as well as in response to three types of perturbations: mechanical (increased fluid viscosity), pharmacological (disrupted serotonin signaling), and genetic (diminished ciliary motor protein expression). Of note, we demonstrate decreased flow secondary to gene knockdown of kif3a, a protein involved in ciliogenesis, as well as a dose-response decrease in flow secondary to knockdown of dnah9, an important ciliary motor protein.

Evaluation of 1.5-T Cell Flash Memory Total Ionizing Dose Response

NASA Astrophysics Data System (ADS)

Clark, Lawrence T.; Holbert, Keith E.; Adams, James W.; Navale, Harshad; Anderson, Blake C.

2015-12-01

Flash memory is an essential part of systems used in harsh environments, experienced by both terrestrial and aerospace TID applications. This paper presents studies of COTS flash memory TID hardness. While there is substantial literature on flash memory TID response, this work focuses for the first time on 1.5 transistor per cell flash memory. The experimental results show hardness varying from about 100 krad(Si) to over 250 krad(Si) depending on the usage model. We explore the circuit and device aspects of the results, based on the extensive reliability literature for this flash memory type. Failure modes indicate both device damage and circuit marginalities. Sector erase failure limits, but read only operation allows TID exceeding 200 krad(Si). The failures are analyzed by type.

Development and implementation of a three-choice serial reaction time task for zebrafish (Danio rerio).

PubMed

Parker, Matthew O; Millington, Mollie E; Combe, Fraser J; Brennan, Caroline H

2012-02-01

Zebrafish are an established and widely utilized developmental genetic model system, but limitations in developed behavioral assays have meant that their potential as a model in behavioral neuroscience has yet to be fully realized. Here, we describe the development of a novel operant behavioral assay to examine a variety of aspects of stimulus control in zebrafish using a 3 choice serial reaction time task (3 CSRTT). Fish were briefly exposed to three spatially distinct, but perceptually identical stimuli, presented in a random order after a fixed-time inter-trial interval (ITI). Entries to the correct response aperture either during the stimulus presentation, or within a brief limited hold period following presentation, were reinforced with illumination of the magazine light and delivery of a small food reward. Following training, premature responding was probed with a long-ITI session three times; once at baseline, once following a saline injection and once following an injection of a low dose of amphetamine (AMPH; 0.025 mg/kg). We predicted that if premature responding was related to impulsivity (as in rodents) it would be reduced following the AMPH injection. Results confirmed that zebrafish could learn to perform a complex operant task similar to tasks developed for rodents which are used to probe sustained attention and impulsivity, but the results from the AMPH trials were inconclusive. This study provides the foundations for development and further validation of this species as a model for some aspects of human attentional and impulse control disorders, such as substance abuse disorder. Copyright © 2011 Elsevier B.V. All rights reserved.

Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy.

PubMed

Dean, Jamie A; Wong, Kee H; Welsh, Liam C; Jones, Ann-Britt; Schick, Ulrike; Newbold, Kate L; Bhide, Shreerang A; Harrington, Kevin J; Nutting, Christopher M; Gulliford, Sarah L

2016-07-01

Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

Design considerations and analysis planning of a phase 2a proof of concept study in rheumatoid arthritis in the presence of possible non-monotonicity.

PubMed

Liu, Feng; Walters, Stephen J; Julious, Steven A

2017-10-02

It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

Radiation dose uncertainty and correction for a mouse orthotopic and xenograft irradiation model.

PubMed

Gan, Gregory N; Altunbas, Cem; Morton, John J; Eagles, Justin; Backus, Jennifer; Dzingle, Wayne; Raben, David; Jimeno, Antonio

2016-01-01

In animal irradiation models, reported dose can vary significantly from the actual doses delivered. We describe an effective method for in vivo dose verification. Mice bearing commercially-available cell line or patient-derived tumor cell orthotopic or flank xenografts were irradiated using a 160 kVp, 25 mA X-ray source. Entrance dose was evaluated using optically-stimulated luminescence dosimeters (OSLD) and exit dose was assessed using radiochromic film dosimetry. Tumor position within the irradiation field was validated using external fiducial markers. The average entrance dose in orthotopic tumors from 10 OSLDs placed on two different animal irradiation days was 514 ± 37 cGy (range: 437-545). Exit dose measurements taken from seven radiochromic films on two separate days were 341 ± 21 cGy (a 34% attenuation). Flank tumor irradiation doses measured by OSLD were 368 ± 9 cGy compared to exit doses of 330 cGy measured by radiochromic film. Variations related to the irradiation model can lead to significant under or overdosing in vivo which can affect tumor control and/or biologic endpoints that are dose-dependent. We recommend that dose measurements be determined empirically based on the mouse model and irradiator used and dose compensation adjustments performed to ensure correct and appropriate doses.

Improved anticoagulant effect of fucosylated chondroitin sulfate orally administered as gastro-resistant tablets.

PubMed

Fonseca, Roberto J C; Sucupira, Isabela D; Oliveira, Stephan Nicollas M C G; Santos, Gustavo R C; Mourão, Paulo A S

2017-04-03

Fucosylated chondroitin sulfate (FucCS) is a potent anticoagulant polysaccharide extracted from sea cucumber. Its anticoagulant activity is attributed to the presence of unique branches of sulfated fucose. Although this glycosaminoglycan exerts an antithrombotic effect following oral administration, high doses are necessary to achieve the maximum effect. The diminished activity of FucCS following oral administration is likely due to its degradation in the gastrointestinal tract and its limited ability to cross the intestinal cell membranes. The latter aspect is particularly difficult to overcome. However, gastro-resistant tablet formulation may help limit the degradation of FucCS in the gastrointestinal tract. In the present work, we found that the oral administration of FucCS as gastro-resistant tablets produces a more potent and prolonged anticoagulant effect compared with its administration as an aqueous solution, with no significant changes in the bleeding tendency or arterial blood pressure. Experiments using animal models of arterial thrombosis initiated by endothelial injury demonstrated that FucCS delivered as gastro-protective tablets produced a potent antithrombotic effect, whereas its aqueous solution was ineffective. However, there was no significant difference between the effects of FucCS delivered as gastro-resistant tablets or as aqueous solution in a venous thrombosis model, likely due to the high dose of thromboplastin used. New oral anticoagulants tested in these experimental models for comparison showed significantly increased bleeding tendencies. Our study provides a framework for developing effective oral anticoagulants based on sulfated polysaccharides from marine organisms. The present results suggest that FucCS is a promising oral anticoagulant.

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

PubMed Central

Ravva, Patanjali; Gastonguay, Marc R.; Lee, Theodore C.; Niaura, Raymond

2015-01-01

Introduction: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response “kinetics.” Response was described as the net effect of the baseline, placebo, and drug responses. Results: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. Conclusions: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline. PMID:25145377

Can the Equivalent Sphere Model Approximate Organ Doses in Space Radiation Environments?

NASA Technical Reports Server (NTRS)

Zi-Wei, Lin

2007-01-01

In space radiation calculations it is often useful to calculate the dose or dose equivalent in blood-forming organs (BFO). the skin or the eye. It has been customary to use a 5cm equivalent sphere to approximate the BFO dose. However previous studies have shown that a 5cm sphere gives conservative dose values for BFO. In this study we use a deterministic radiation transport with the Computerized Anatomical Man model to investigate whether the equivalent sphere model can approximate organ doses in space radiation environments. We find that for galactic cosmic rays environments the equivalent sphere model with an organ-specific constant radius parameter works well for the BFO dose equivalent and marginally well for the BFO dose and the dose equivalent of the eye or the skin. For solar particle events the radius parameters for the organ dose equivalent increase with the shielding thickness, and the model works marginally for BFO but is unacceptable for the eye or the skin The ranges of the radius parameters are also shown and the BFO radius parameters are found to be significantly larger than 5 cm in all eases.

Evaluation of the influence of double and triple Gaussian proton kernel models on accuracy of dose calculations for spot scanning technique.

PubMed

Hirayama, Shusuke; Takayanagi, Taisuke; Fujii, Yusuke; Fujimoto, Rintaro; Fujitaka, Shinichiro; Umezawa, Masumi; Nagamine, Yoshihiko; Hosaka, Masahiro; Yasui, Keisuke; Omachi, Chihiro; Toshito, Toshiyuki

2016-03-01

The main purpose in this study was to present the results of beam modeling and how the authors systematically investigated the influence of double and triple Gaussian proton kernel models on the accuracy of dose calculations for spot scanning technique. The accuracy of calculations was important for treatment planning software (TPS) because the energy, spot position, and absolute dose had to be determined by TPS for the spot scanning technique. The dose distribution was calculated by convolving in-air fluence with the dose kernel. The dose kernel was the in-water 3D dose distribution of an infinitesimal pencil beam and consisted of an integral depth dose (IDD) and a lateral distribution. Accurate modeling of the low-dose region was important for spot scanning technique because the dose distribution was formed by cumulating hundreds or thousands of delivered beams. The authors employed a double Gaussian function as the in-air fluence model of an individual beam. Double and triple Gaussian kernel models were also prepared for comparison. The parameters of the kernel lateral model were derived by fitting a simulated in-water lateral dose profile induced by an infinitesimal proton beam, whose emittance was zero, at various depths using Monte Carlo (MC) simulation. The fitted parameters were interpolated as a function of depth in water and stored as a separate look-up table. These stored parameters for each energy and depth in water were acquired from the look-up table when incorporating them into the TPS. The modeling process for the in-air fluence and IDD was based on the method proposed in the literature. These were derived using MC simulation and measured data. The authors compared the measured and calculated absolute doses at the center of the spread-out Bragg peak (SOBP) under various volumetric irradiation conditions to systematically investigate the influence of the two types of kernel models on the dose calculations. The authors investigated the difference between double and triple Gaussian kernel models. The authors found that the difference between the two studied kernel models appeared at mid-depths and the accuracy of predicting the double Gaussian model deteriorated at the low-dose bump that appeared at mid-depths. When the authors employed the double Gaussian kernel model, the accuracy of calculations for the absolute dose at the center of the SOBP varied with irradiation conditions and the maximum difference was 3.4%. In contrast, the results obtained from calculations with the triple Gaussian kernel model indicated good agreement with the measurements within ±1.1%, regardless of the irradiation conditions. The difference between the results obtained with the two types of studied kernel models was distinct in the high energy region. The accuracy of calculations with the double Gaussian kernel model varied with the field size and SOBP width because the accuracy of prediction with the double Gaussian model was insufficient at the low-dose bump. The evaluation was only qualitative under limited volumetric irradiation conditions. Further accumulation of measured data would be needed to quantitatively comprehend what influence the double and triple Gaussian kernel models had on the accuracy of dose calculations.

Cocaine addiction as a homeostatic reinforcement learning disorder.

PubMed

Keramati, Mehdi; Durand, Audrey; Girardeau, Paul; Gutkin, Boris; Ahmed, Serge H

2017-03-01

Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Microfluidics: a groundbreaking technology for PET tracer production?

PubMed

Rensch, Christian; Jackson, Alexander; Lindner, Simon; Salvamoser, Ruben; Samper, Victor; Riese, Stefan; Bartenstein, Peter; Wängler, Carmen; Wängler, Björn

2013-07-05

Application of microfluidics to Positron Emission Tomography (PET) tracer synthesis has attracted increasing interest within the last decade. The technical advantages of microfluidics, in particular the high surface to volume ratio and resulting fast thermal heating and cooling rates of reagents can lead to reduced reaction times, increased synthesis yields and reduced by-products. In addition automated reaction optimization, reduced consumption of expensive reagents and a path towards a reduced system footprint have been successfully demonstrated. The processing of radioactivity levels required for routine production, use of microfluidic-produced PET tracer doses in preclinical and clinical imaging as well as feasibility studies on autoradiolytic decomposition have all given promising results. However, the number of microfluidic synthesizers utilized for commercial routine production of PET tracers is very limited. This study reviews the state of the art in microfluidic PET tracer synthesis, highlighting critical design aspects, strengths, weaknesses and presenting several characteristics of the diverse PET market space which are thought to have a significant impact on research, development and engineering of microfluidic devices in this field. Furthermore, the topics of batch- and single-dose production, cyclotron to quality control integration as well as centralized versus de-centralized market distribution models are addressed.

Estimating skin sensitization potency from a single dose LLNA.

PubMed

Roberts, David W

2015-04-01

Skin sensitization is an important aspect of safety assessment. The mouse local lymph node assay (LLNA) developed in the 1990 s is an in vivo test used for skin sensitization hazard identification and characterization. More recently a reduced version of the LLNA (rLLNA) has been developed as a means of identifying, but not quantifying, sensitization hazard. The work presented here is aimed at enabling rLLNA data to be used to give quantitative potency information that can be used, inter alia, in modeling and read-across approaches to non-animal based potency estimation. A probit function has been derived enabling estimation of EC3 from a single dose. This has led to development of a modified version of the rLLNA, whereby as a general principle the SI value at 10%, or at a lower concentration if 10% is not testable, is used to calculate the EC3. This version of the rLLNA has been evaluated against a selection of chemicals for which full LLNA data are available, and has been shown to give EC3 values in good agreement with those derived from the full LLNA. Copyright © 2015 Elsevier Inc. All rights reserved.

T Cell Activation Thresholds are Affected by Gravitational

NASA Technical Reports Server (NTRS)

Adams, Charley; Gonzalez, M.; Nelman-Gonzalez, M.

1999-01-01

T cells stimulated in space flight by various mitogenic signals show a dramatic reduction in proliferation and expression of early activation markers. Similar results are also obtained in a ground based model of microgravity, clinorotation, which provides a vector-averaged reduction of the apparent gravity on cells without significant shear force. Here we demonstrate that T cell inhibition is due to an increase in the required threshold for activation. Dose response curves indicate that cells activated during clinorotation require higher stimulation to achieve the same level of activation, as measured by CD69 expression. Interleukin 2 receptor expression, and DNA synthesis. The amount of stimulation necessary for 50% activation is 5 fold in the clinostat relative to static. Correlation of TCR internalization with activation also exhibit a dramatic right shift in clinorotation, demonstrating unequivocally that signal transduction mechanism independent of TCR triggering account for the increased activation threshold. Previous results from space flight experiments are consistent with the dose response curves obtained for clinorotation. Activation thresholds are important aspects of T cell memory, autoimmunity and tolerance Clinorotation is a useful, noninvasive tool for the study of cellular and biochemical event regulating T cell activation threshold and the effects of gravitation forces on these systems.

PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

EPA Science Inventory

Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

Neutrons in active proton therapy: Parameterization of dose and dose equivalent.

PubMed

Schneider, Uwe; Hälg, Roger A; Lomax, Tony

2017-06-01

One of the essential elements of an epidemiological study to decide if proton therapy may be associated with increased or decreased subsequent malignancies compared to photon therapy is an ability to estimate all doses to non-target tissues, including neutron dose. This work therefore aims to predict for patients using proton pencil beam scanning the spatially localized neutron doses and dose equivalents. The proton pencil beam of Gantry 1 at the Paul Scherrer Institute (PSI) was Monte Carlo simulated using GEANT. Based on the simulated neutron dose and neutron spectra an analytical mechanistic dose model was developed. The pencil beam algorithm used for treatment planning at PSI has been extended using the developed model in order to calculate the neutron component of the delivered dose distribution for each treated patient. The neutron dose was estimated for two patient example cases. The analytical neutron dose model represents the three-dimensional Monte Carlo simulated dose distribution up to 85cm from the proton pencil beam with a satisfying precision. The root mean square error between Monte Carlo simulation and model is largest for 138MeV protons and is 19% and 20% for dose and dose equivalent, respectively. The model was successfully integrated into the PSI treatment planning system. In average the neutron dose is increased by 10% or 65% when using 160MeV or 177MeV instead of 138MeV. For the neutron dose equivalent the increase is 8% and 57%. The presented neutron dose calculations allow for estimates of dose that can be used in subsequent epidemiological studies or, should the need arise, to estimate the neutron dose at any point where a subsequent secondary tumour may occur. It was found that the neutron dose to the patient is heavily increased with proton energy. Copyright © 2016. Published by Elsevier GmbH.

The serotonin transporter plays an important role in male sexual behavior: a study in serotonin transporter knockout rats.

PubMed

Chan, Johnny S W; Snoeren, Eelke M S; Cuppen, Edwin; Waldinger, Marcel D; Olivier, Berend; Oosting, Ronald S

2011-01-01

Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels. To investigate the putative role of the SERT in male sexual behavior. After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist ± 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/-) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined. Male rat sexual behaviors of mounts, intromissions, and ejaculations. SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. ± 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of ± 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by ± 8-OH-DPAT of the sexual inhibitory effects of WAY100635. Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of ± 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido. © 2010 International Society for Sexual Medicine.

A meta-analysis of phase III randomized controlled trials with novel oral anticoagulants in atrial fibrillation: comparisons between direct thrombin inhibitors vs. factor Xa inhibitors and different dosing regimens.

PubMed

Providência, Rui; Grove, Erik Lerkevang; Husted, Steen; Barra, Sérgio; Boveda, Serge; Morais, João

2014-12-01

Previous studies evaluating the ability of novel oral anticoagulants (NOAC) to prevent thromboembolism in patients with non-valvular atrial fibrillation (AF) have identified differences between the efficacy and safety of the drugs tested. Whether these differences reflect differences in direct thrombin or Xa inhibition, different dosing regimens or specific aspects of each agent or trial has not yet been explored. A search was performed on MEDLINE, EMBASE and COCHRANE, and ongoing studies were tracked on clinicaltrials.gov. Phase III randomized controlled trials of direct thrombin inhibitors (DTI) and factor Xa inhibitors (FXaI) vs. warfarin in patients with AF were eligible. Data were pooled using random-effects, according to the Mantel-Haenszel model. Sensitivity analyses were performed on DTI, FXaI, once-daily and twice-daily regimens. Seven studies were pooled, including a total of 80,290 patients. Both DTI and FXaI outperformed warfarin regarding stroke or systemic embolism, intracranial bleeding, total and cardiovascular mortality. No significant differences were found between DTI and FXaI or between once-daily and twice-daily regimens. Some drugs performed worse than warfarin regarding some secondary endpoints, including: edoxaban 30 mg bid on ischaemic stroke, dabigatran on acute myocardial infarction, dabigatran 150 mg bid and rivaroxaban 20mgod on gastrointestinal bleeding. Our pooled data do not support the hypothesis of a significant class-effect of DTI or FXaI, nor the benefit of once-daily vs. twice-daily dosing in the setting of AF, reinforcing that the choice of NOAC should be adapted to the specific patient and focused on the agent itself, rather than the pharmacological class or dosing regimen.

Accelerator-based validation of shielding codes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeitlin, Cary; Heilbronn, Lawrence; Miller, Jack

2002-08-12

The space radiation environment poses risks to astronaut health from a diverse set of sources, ranging from low-energy protons and electrons to highly-charged, high-energy atomic nuclei and their associated fragmentation products, including neutrons. The low-energy protons and electrons are the source of most of the radiation dose to Shuttle and ISS crews, while the more energetic particles that comprise the Galactic Cosmic Radiation (protons, He, and heavier nuclei up to Fe) will be the dominant source for crews on long-duration missions outside the earth's magnetic field. Because of this diversity of sources, a broad ground-based experimental effort is required tomore » validate the transport and shielding calculations used to predict doses and dose-equivalents under various mission scenarios. The experimental program of the LBNL group, described here, focuses principally on measurements of charged particle and neutron production in high-energy heavy-ion fragmentation. Other aspects of the program include measurements of the shielding provided by candidate spacesuit materials against low-energy protons (particularly relevant to extra-vehicular activities in low-earth orbit), and the depth-dose relations in tissue for higher-energy protons. The heavy-ion experiments are performed at the Brookhaven National Laboratory's Alternating Gradient Synchrotron and the Heavy-Ion Medical Accelerator in Chiba in Japan. Proton experiments are performed at the Lawrence Berkeley National Laboratory's 88'' Cyclotron with a 55 MeV beam, and at the Loma Linda University Proton Facility with 100 to 250 MeV beam energies. The experimental results are an important component of the overall shielding program, as they allow for simple, well-controlled tests of the models developed to handle the more complex radiation environment in space.« less

Development of an Assessment Model for Sustainable Supply Chain Management in Batik Industry

NASA Astrophysics Data System (ADS)

Mubiena, G. F.; Ma’ruf, A.

2018-03-01

This research proposes a dynamic assessment model for sustainable supply chain management in batik industry. The proposed model identifies the dynamic relationship between economic aspect, environment aspect and social aspect. The economic aspect refers to the supply chain operation reference model. The environment aspect uses carbon emissions and liquid waste as the attribute assessment, while the social aspect focus on employee’s welfare. Lean manufacturing concept was implemented as an alternative approach to sustainability. The simulation result shows that the average of sustainability score for 5 years increased from 65,3% to 70%. Future experiments will be conducted on design improvements to reach the company target on sustainability score.

Pediatric chest and abdominopelvic CT: organ dose estimation based on 42 patient models.

PubMed

Tian, Xiaoyu; Li, Xiang; Segars, W Paul; Paulson, Erik K; Frush, Donald P; Samei, Ehsan

2014-02-01

To estimate organ dose from pediatric chest and abdominopelvic computed tomography (CT) examinations and evaluate the dependency of organ dose coefficients on patient size and CT scanner models. The institutional review board approved this HIPAA-compliant study and did not require informed patient consent. A validated Monte Carlo program was used to perform simulations in 42 pediatric patient models (age range, 0-16 years; weight range, 2-80 kg; 24 boys, 18 girls). Multidetector CT scanners were modeled on those from two commercial manufacturers (LightSpeed VCT, GE Healthcare, Waukesha, Wis; SOMATOM Definition Flash, Siemens Healthcare, Forchheim, Germany). Organ doses were estimated for each patient model for routine chest and abdominopelvic examinations and were normalized by volume CT dose index (CTDI(vol)). The relationships between CTDI(vol)-normalized organ dose coefficients and average patient diameters were evaluated across scanner models. For organs within the image coverage, CTDI(vol)-normalized organ dose coefficients largely showed a strong exponential relationship with the average patient diameter (R(2) > 0.9). The average percentage differences between the two scanner models were generally within 10%. For distributed organs and organs on the periphery of or outside the image coverage, the differences were generally larger (average, 3%-32%) mainly because of the effect of overranging. It is feasible to estimate patient-specific organ dose for a given examination with the knowledge of patient size and the CTDI(vol). These CTDI(vol)-normalized organ dose coefficients enable one to readily estimate patient-specific organ dose for pediatric patients in clinical settings. This dose information, and, as appropriate, attendant risk estimations, can provide more substantive information for the individual patient for both clinical and research applications and can yield more expansive information on dose profiles across patient populations within a practice. © RSNA, 2013.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer

NASA Astrophysics Data System (ADS)

González, S. J.; Pozzi, E. C. C.; Monti Hughes, A.; Provenzano, L.; Koivunoro, H.; Carando, D. G.; Thorp, S. I.; Casal, M. R.; Bortolussi, S.; Trivillin, V. A.; Garabalino, M. A.; Curotto, P.; Heber, E. M.; Santa Cruz, G. A.; Kankaanranta, L.; Joensuu, H.; Schwint, A. E.

2017-10-01

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson’s correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

PubMed

González, S J; Pozzi, E C C; Monti Hughes, A; Provenzano, L; Koivunoro, H; Carando, D G; Thorp, S I; Casal, M R; Bortolussi, S; Trivillin, V A; Garabalino, M A; Curotto, P; Heber, E M; Santa Cruz, G A; Kankaanranta, L; Joensuu, H; Schwint, A E

2017-10-03

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

TH-C-BRD-04: Beam Modeling and Validation with Triple and Double Gaussian Dose Kernel for Spot Scanning Proton Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirayama, S; Takayanagi, T; Fujii, Y

2014-06-15

Purpose: To present the validity of our beam modeling with double and triple Gaussian dose kernels for spot scanning proton beams in Nagoya Proton Therapy Center. This study investigates the conformance between the measurements and calculation results in absolute dose with two types of beam kernel. Methods: A dose kernel is one of the important input data required for the treatment planning software. The dose kernel is the 3D dose distribution of an infinitesimal pencil beam of protons in water and consists of integral depth doses and lateral distributions. We have adopted double and triple Gaussian model as lateral distributionmore » in order to take account of the large angle scattering due to nuclear reaction by fitting simulated inwater lateral dose profile for needle proton beam at various depths. The fitted parameters were interpolated as a function of depth in water and were stored as a separate look-up table for the each beam energy. The process of beam modeling is based on the method of MDACC [X.R.Zhu 2013]. Results: From the comparison results between the absolute doses calculated by double Gaussian model and those measured at the center of SOBP, the difference is increased up to 3.5% in the high-energy region because the large angle scattering due to nuclear reaction is not sufficiently considered at intermediate depths in the double Gaussian model. In case of employing triple Gaussian dose kernels, the measured absolute dose at the center of SOBP agrees with calculation within ±1% regardless of the SOBP width and maximum range. Conclusion: We have demonstrated the beam modeling results of dose distribution employing double and triple Gaussian dose kernel. Treatment planning system with the triple Gaussian dose kernel has been successfully verified and applied to the patient treatment with a spot scanning technique in Nagoya Proton Therapy Center.« less

Influence of different dose calculation algorithms on the estimate of NTCP for lung complications.

PubMed

Hedin, Emma; Bäck, Anna

2013-09-06

Due to limitations and uncertainties in dose calculation algorithms, different algorithms can predict different dose distributions and dose-volume histograms for the same treatment. This can be a problem when estimating the normal tissue complication probability (NTCP) for patient-specific dose distributions. Published NTCP model parameters are often derived for a different dose calculation algorithm than the one used to calculate the actual dose distribution. The use of algorithm-specific NTCP model parameters can prevent errors caused by differences in dose calculation algorithms. The objective of this work was to determine how to change the NTCP model parameters for lung complications derived for a simple correction-based pencil beam dose calculation algorithm, in order to make them valid for three other common dose calculation algorithms. NTCP was calculated with the relative seriality (RS) and Lyman-Kutcher-Burman (LKB) models. The four dose calculation algorithms used were the pencil beam (PB) and collapsed cone (CC) algorithms employed by Oncentra, and the pencil beam convolution (PBC) and anisotropic analytical algorithm (AAA) employed by Eclipse. Original model parameters for lung complications were taken from four published studies on different grades of pneumonitis, and new algorithm-specific NTCP model parameters were determined. The difference between original and new model parameters was presented in relation to the reported model parameter uncertainties. Three different types of treatments were considered in the study: tangential and locoregional breast cancer treatment and lung cancer treatment. Changing the algorithm without the derivation of new model parameters caused changes in the NTCP value of up to 10 percentage points for the cases studied. Furthermore, the error introduced could be of the same magnitude as the confidence intervals of the calculated NTCP values. The new NTCP model parameters were tabulated as the algorithm was varied from PB to PBC, AAA, or CC. Moving from the PB to the PBC algorithm did not require new model parameters; however, moving from PB to AAA or CC did require a change in the NTCP model parameters, with CC requiring the largest change. It was shown that the new model parameters for a given algorithm are different for the different treatment types.

Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

NASA Astrophysics Data System (ADS)

Rutkowska, Eva; Baker, Colin; Nahum, Alan

2010-04-01

A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

SU-E-T-561: Monte Carlo-Based Organ Dose Reconstruction Using Pre-Contoured Human Model for Hodgkins Lymphoma Patients Treated by Cobalt-60 External Beam Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jung, J; Pelletier, C; Lee, C

Purpose: Organ doses for the Hodgkin’s lymphoma patients treated with cobalt-60 radiation were estimated using an anthropomorphic model and Monte Carlo modeling. Methods: A cobalt-60 treatment unit modeled in the BEAMnrc Monte Carlo code was used to produce phase space data. The Monte Carlo simulation was verified with percent depth dose measurement in water at various field sizes. Radiation transport through the lung blocks were modeled by adjusting the weights of phase space data. We imported a precontoured adult female hybrid model and generated a treatment plan. The adjusted phase space data and the human model were imported to themore » XVMC Monte Carlo code for dose calculation. The organ mean doses were estimated and dose volume histograms were plotted. Results: The percent depth dose agreement between measurement and calculation in water phantom was within 2% for all field sizes. The mean organ doses of heart, left breast, right breast, and spleen for the selected case were 44.3, 24.1, 14.6 and 3.4 Gy, respectively with the midline prescription dose of 40.0 Gy. Conclusion: Organ doses were estimated for the patient group whose threedimensional images are not available. This development may open the door to more accurate dose reconstruction and estimates of uncertainties in secondary cancer risk for Hodgkin’s lymphoma patients. This work was partially supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.« less

Radiation Dose Uncertainty and Correction for a Mouse Orthotopic and Xenograft Irradiation Model

PubMed Central

Gan, Gregory N.; Altunbas, Cem; Morton, John J.; Eagles, Justin; Backus, Jennifer; Dzingle, Wayne; Raben, David; Jimeno, Antonio

2016-01-01

Purpose In animal irradiation models, reported dose can vary significantly from the actual doses delivered. We describe an effective method for in vivo dose verification. Materials and Methods Mice bearing commercially-available cell line or patient-derived tumor cell orthotopic or flank xenografts were irradiated using a 160 kVp, 25 mA X-ray source. Entrance dose was evaluated using optically-stimulated luminescence dosimeters (OSLD) and exit dose was assessed using radiochromic film dosimetry. Results Tumor position within the irradiation field was validated using external fiducial markers. The average entrance dose in orthotopic tumors from 10 OSLDs placed on 2 different animal irradiation days was 514±37 cGy (range: 437–545). Exit dose measurements taken from 7 radiochromic films on two separate days were 341±21 cGy (a 34% attenuation). Flank tumor irradiation doses measured by OSLD were 368±9 cGy compared to exit doses of 330 cGy measured by radiochromic film. Conclusion Variations related to the irradiation model can lead to significant under or over- dosing in vivo which can affect tumor control and/or biologic endpoints that are dose dependent. We recommend that dose measurements be determined empirically based on the mouse model and irradiator used and dose compensation adjustments performed to ensure correct and appropriate doses. PMID:26689828

Dose-dependent model of caffeine effects on human vigilance during total sleep deprivation.

PubMed

Ramakrishnan, Sridhar; Laxminarayan, Srinivas; Wesensten, Nancy J; Kamimori, Gary H; Balkin, Thomas J; Reifman, Jaques

2014-10-07

Caffeine is the most widely consumed stimulant to counter sleep-loss effects. While the pharmacokinetics of caffeine in the body is well-understood, its alertness-restoring effects are still not well characterized. In fact, mathematical models capable of predicting the effects of varying doses of caffeine on objective measures of vigilance are not available. In this paper, we describe a phenomenological model of the dose-dependent effects of caffeine on psychomotor vigilance task (PVT) performance of sleep-deprived subjects. We used the two-process model of sleep regulation to quantify performance during sleep loss in the absence of caffeine and a dose-dependent multiplier factor derived from the Hill equation to model the effects of single and repeated caffeine doses. We developed and validated the model fits and predictions on PVT lapse (number of reaction times exceeding 500 ms) data from two separate laboratory studies. At the population-average level, the model captured the effects of a range of caffeine doses (50-300 mg), yielding up to a 90% improvement over the two-process model. Individual-specific caffeine models, on average, predicted the effects up to 23% better than population-average caffeine models. The proposed model serves as a useful tool for predicting the dose-dependent effects of caffeine on the PVT performance of sleep-deprived subjects and, therefore, can be used for determining caffeine doses that optimize the timing and duration of peak performance. Published by Elsevier Ltd.

Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hualin, E-mail: hualin.zhang@northwestern.edu, E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.

2014-02-15

Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was atmore » the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional radiotherapy. A significant portion of the tumor volume received a very large dose in grid therapy, which ensures significant tumor cell killing in these regions. Conversely, some areas received a relatively small dose, thereby sparing interspersed normal cells and increasing radiation tolerance. The radiobiology modeling results indicated that grid therapy could be useful for treating acutely responding melanomas infiltrating radiosensitive normal tissues. The theoretical model predictions were supported by the clinical outcomes. Conclusions: Grid therapy functions by selectively killing infiltrating tumor cells and concomitantly sparing interspersed normal cells. The TR depends on the radiosensitivity of the cell population, dose, tumor size, and location. Because the volumes of very high dose regions are small, the LQ model can be used safely to predict the clinical outcomes of grid therapy. When treating melanomas with a dose of 15 Gy or higher, single fraction grid therapy is clearly advantageous for sparing interspersed normal cells. The existence of a threshold fraction dose, which was found in the authors’ theoretical simulations, was confirmed by clinical observations.« less

A pharmacometric case study regarding the sensitivity of structural model parameter estimation to error in patient reported dosing times.

PubMed

Knights, Jonathan; Rohatagi, Shashank

2015-12-01

Although there is a body of literature focused on minimizing the effect of dosing inaccuracies on pharmacokinetic (PK) parameter estimation, most of the work centers on missing doses. No attempt has been made to specifically characterize the effect of error in reported dosing times. Additionally, existing work has largely dealt with cases in which the compound of interest is dosed at an interval no less than its terminal half-life. This work provides a case study investigating how error in patient reported dosing times might affect the accuracy of structural model parameter estimation under sparse sampling conditions when the dosing interval is less than the terminal half-life of the compound, and the underlying kinetics are monoexponential. Additional effects due to noncompliance with dosing events are not explored and it is assumed that the structural model and reasonable initial estimates of the model parameters are known. Under the conditions of our simulations, with structural model CV % ranging from ~20 to 60 %, parameter estimation inaccuracy derived from error in reported dosing times was largely controlled around 10 % on average. Given that no observed dosing was included in the design and sparse sampling was utilized, we believe these error results represent a practical ceiling given the variability and parameter estimates for the one-compartment model. The findings suggest additional investigations may be of interest and are noteworthy given the inability of current PK software platforms to accommodate error in dosing times.

Esophageal wall dose-surface maps do not improve the predictive performance of a multivariable NTCP model for acute esophageal toxicity in advanced stage NSCLC patients treated with intensity-modulated (chemo-)radiotherapy.

PubMed

Dankers, Frank; Wijsman, Robin; Troost, Esther G C; Monshouwer, René; Bussink, Johan; Hoffmann, Aswin L

2017-05-07

In our previous work, a multivariable normal-tissue complication probability (NTCP) model for acute esophageal toxicity (AET) Grade  ⩾2 after highly conformal (chemo-)radiotherapy for non-small cell lung cancer (NSCLC) was developed using multivariable logistic regression analysis incorporating clinical parameters and mean esophageal dose (MED). Since the esophagus is a tubular organ, spatial information of the esophageal wall dose distribution may be important in predicting AET. We investigated whether the incorporation of esophageal wall dose-surface data with spatial information improves the predictive power of our established NTCP model. For 149 NSCLC patients treated with highly conformal radiation therapy esophageal wall dose-surface histograms (DSHs) and polar dose-surface maps (DSMs) were generated. DSMs were used to generate new DSHs and dose-length-histograms that incorporate spatial information of the dose-surface distribution. From these histograms dose parameters were derived and univariate logistic regression analysis showed that they correlated significantly with AET. Following our previous work, new multivariable NTCP models were developed using the most significant dose histogram parameters based on univariate analysis (19 in total). However, the 19 new models incorporating esophageal wall dose-surface data with spatial information did not show improved predictive performance (area under the curve, AUC range 0.79-0.84) over the established multivariable NTCP model based on conventional dose-volume data (AUC  =  0.84). For prediction of AET, based on the proposed multivariable statistical approach, spatial information of the esophageal wall dose distribution is of no added value and it is sufficient to only consider MED as a predictive dosimetric parameter.

Esophageal wall dose-surface maps do not improve the predictive performance of a multivariable NTCP model for acute esophageal toxicity in advanced stage NSCLC patients treated with intensity-modulated (chemo-)radiotherapy

NASA Astrophysics Data System (ADS)

Dankers, Frank; Wijsman, Robin; Troost, Esther G. C.; Monshouwer, René; Bussink, Johan; Hoffmann, Aswin L.

2017-05-01

In our previous work, a multivariable normal-tissue complication probability (NTCP) model for acute esophageal toxicity (AET) Grade  ⩾2 after highly conformal (chemo-)radiotherapy for non-small cell lung cancer (NSCLC) was developed using multivariable logistic regression analysis incorporating clinical parameters and mean esophageal dose (MED). Since the esophagus is a tubular organ, spatial information of the esophageal wall dose distribution may be important in predicting AET. We investigated whether the incorporation of esophageal wall dose-surface data with spatial information improves the predictive power of our established NTCP model. For 149 NSCLC patients treated with highly conformal radiation therapy esophageal wall dose-surface histograms (DSHs) and polar dose-surface maps (DSMs) were generated. DSMs were used to generate new DSHs and dose-length-histograms that incorporate spatial information of the dose-surface distribution. From these histograms dose parameters were derived and univariate logistic regression analysis showed that they correlated significantly with AET. Following our previous work, new multivariable NTCP models were developed using the most significant dose histogram parameters based on univariate analysis (19 in total). However, the 19 new models incorporating esophageal wall dose-surface data with spatial information did not show improved predictive performance (area under the curve, AUC range 0.79-0.84) over the established multivariable NTCP model based on conventional dose-volume data (AUC  =  0.84). For prediction of AET, based on the proposed multivariable statistical approach, spatial information of the esophageal wall dose distribution is of no added value and it is sufficient to only consider MED as a predictive dosimetric parameter.

SU-E-T-105: An FMEA Survey of Intensity Modulated Radiation Therapy (IMRT) Step and Shoot Dose Delivery Failure Modes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faught, J Tonigan; Johnson, J; Stingo, F

2015-06-15

Purpose: To assess the perception of TG-142 tolerance level dose delivery failures in IMRT and the application of FMEA process to this specific aspect of IMRT. Methods: An online survey was distributed to medical physicists worldwide that briefly described 11 different failure modes (FMs) covered by basic quality assurance in step- and-shoot IMRT at or near TG-142 tolerance criteria levels. For each FM, respondents estimated the worst case H&N patient percent dose error and FMEA scores for Occurrence, Detectability, and Severity. Demographic data was also collected. Results: 181 individual and three group responses were submitted. 84% were from North America.more » Most (76%) individual respondents performed at least 80% clinical work and 92% were nationally certified. Respondent medical physics experience ranged from 2.5–45 years (average 18 years). 52% of individual respondents were at least somewhat familiar with FMEA, while 17% were not familiar. Several IMRT techniques, treatment planning systems and linear accelerator manufacturers were represented. All FMs received widely varying scores ranging from 1–10 for occurrence, at least 1–9 for detectability, and at least 1–7 for severity. Ranking FMs by RPN scores also resulted in large variability, with each FM being ranked both most risky (1st ) and least risky (11th) by different respondents. On average MLC modeling had the highest RPN scores. Individual estimated percent dose errors and severity scores positively correlated (p<0.10) for each FM as expected. No universal correlations were found between the demographic information collected and scoring, percent dose errors, or ranking. Conclusion: FMs investigated overall were evaluated as low to medium risk, with average RPNs less than 110. The ranking of 11 FMs was not agreed upon by the community. Large variability in FMEA scoring may be caused by individual interpretation and/or experience, thus reflecting the subjective nature of the FMEA tool.« less

Dose-Dependent Model of Caffeine Effects on Human Vigilance during Total Sleep Deprivation

DTIC Science & Technology

2014-05-20

does not consider the absorption of caffeine . This is a reasonable approximation for caffeine when ingested via coffee , tea, energy drinks, and most...Dose-dependent model of caffeine effects on human vigilance during total sleep deprivation Sridhar Ramakrishnan a, Srinivas Laxminarayan a, Nancy J...We modeled the dose-dependent effects of caffeine on human vigilance. The model predicted the effects of both single and repeated caffeine doses

ALTERATIONS IN THE ENERGY METABOLISM OF AN ESTUARINE MYSID (MYSIDOPSIS BAHIA) AS INDICATORS OF STRESS FROM CHRONIC PESTICIDE EXPOSURE

EPA Science Inventory

Various aspects of the energy metabolism of an estuarine mysid (Mysidopsis bahia) were examined for different life stages during a life-cycle exposure to the organophosphate pesticide fenthion. Dose-response relationships were developed for several metabolic rate functions (oxyge...

"Cthulhuic Literacy": Teaching Secondary English with a Dose of Lovecraft

ERIC Educational Resources Information Center

Cole, David R.

2014-01-01

This paper suggests how the "weird fiction" of H.P. Lovecraft might be mobilised within secondary English classrooms to examine aspects of visual literacy, literary style, narrative form and intertextuality. The approach that is outlined is characterised, after Lovecraft's famous monster, as a "Cthulhuic literacy" and is…

Glucose-responsive insulin by molecular and physical design

NASA Astrophysics Data System (ADS)

Bakh, Naveed A.; Cortinas, Abel B.; Weiss, Michael A.; Langer, Robert S.; Anderson, Daniel G.; Gu, Zhen; Dutta, Sanjoy; Strano, Michael S.

2017-10-01

The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.

Glucose-responsive insulin by molecular and physical design.

PubMed

Bakh, Naveed A; Cortinas, Abel B; Weiss, Michael A; Langer, Robert S; Anderson, Daniel G; Gu, Zhen; Dutta, Sanjoy; Strano, Michael S

2017-09-22

The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.

Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis.

PubMed

Gong, Qianwen; Janowski, Miroslaw; Luo, Mi; Wei, Hong; Chen, Bingjie; Yang, Guoyuan; Liu, Longqian

2017-06-01

Some uncertainty about the clinical value and dosing of atropine for the treatment of myopia in children remains. To evaluate the efficacy vs the adverse effects of various doses of atropine in the therapy for myopia in children. Data were obtained from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception to April 30, 2016. The reference lists of published reviews and clinicaltrials.gov were searched for additional relevant studies. Key search terms included myopia, refractive errors, and atropine. Only studies published in English were included. Randomized clinical trials and cohort studies that enrolled patients younger than 18 years with myopia who received atropine in at least 1 treatment arm and that reported the annual rate of myopia progression and/or any adverse effects of atropine therapy were included in the analysis. Two reviewers independently abstracted the data. Heterogeneity was statistically quantified by Q, H, and I2 statistics, and a meta-analysis was performed using the random-effects model. The Cochrane Collaboration 6 aspects of bias and the Newcastle-Ottawa Scale were used to assess the risk for bias. The primary outcome was a difference in efficacy and the presence of adverse effects at different doses of atropine vs control conditions. The secondary outcomes included the differences in adverse effects between Asian and white patients. Nineteen unique studies involving 3137 unique children were included in the analysis. The weighted mean differences between the atropine and control groups in myopia progression were 0.50 diopters (D) per year (95% CI, 0.24-0.76 D per year) for low-dose atropine, 0.57 D per year (95% CI, 0.43-0.71 D per year) for moderate-dose atropine, and 0.62 D per year (95% CI, 0.45-0.79 D per year) for high-dose atropine (P < .001), which translated to a high effect size (Cohen d, 0.97, 1.76, and 1.94, respectively). All doses of atropine, therefore, were equally beneficial with respect to myopia progression (P = .15). High-dose atropine were associated with more adverse effects, such as the 43.1% incidence of photophobia compared with 6.3% for low-dose atropine and 17.8% for moderate-dose atropine (χ22 = 7.05; P = .03). In addition, differences in the incidence of adverse effects between Asian and white patients were not identified (χ21 = 0.81; P = .37 for photophobia). This meta-analysis suggests that the efficacy of atropine is dose independent within this range, whereas the adverse effects are dose dependent.

In Vivo Cardiotoxicity Induced by Sodium Aescinate in Zebrafish Larvae.

PubMed

Liang, Jinfeng; Jin, Wangdong; Li, Hongwen; Liu, Hongcui; Huang, Yanfeng; Shan, Xiaowen; Li, Chunqi; Shan, Letian; Efferth, Thomas

2016-02-23

Sodium aescinate (SA) is a widely-applied triterpene saponin product derived from horse chestnut seeds, possessing vasoactive and organ-protective activities with oral or injection administration in the clinic. To date, no toxicity or adverse events in SA have been reported, by using routine models (in vivo or in vitro), which are insufficient to predict all aspects of its pharmacological and toxicological actions. In this study, taking advantage of transparent zebrafish larvae (Danio rerio), we evaluated cardiovascular toxicity of SA at doses of 1/10 MNLC, 1/3 MNLC, MNLC and LC10 by yolk sac microinjection. The qualitative and quantitative cardiotoxicity in zebrafish was assessed at 48 h post-SA treatment, using specific phenotypic endpoints: heart rate, heart rhythm, heart malformation, pericardial edema, circulation abnormalities, thrombosis and hemorrhage. The results showed that SA at 1/10 MNLC and above doses could induce obvious cardiac and pericardial malformations, whilst 1/3 MNLC and above doses could induce significant cardiac malfunctions (heart rate and circulation decrease/absence), as compared to untreated or vehicle-treated control groups. Such cardiotoxic manifestations occurred in more than 50% to 100% of all zebrafish treated with SA at MNLC and LC10. Our findings have uncovered the potential cardiotoxicity of SA for the first time, suggesting more attention to the risk of its clinical application. Such a time- and cost-saving zebrafish cardiotoxicity assay is very valid and reliable for rapid prediction of compound toxicity during drug research and development.

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study.

PubMed

Ansari, Marc; Curtis, Patricia Huezo-Diaz; Uppugunduri, Chakradhara Rao S; Rezgui, Mohammed Aziz; Nava, Tiago; Mlakar, Vid; Lesne, Laurence; Théoret, Yves; Chalandon, Yves; Dupuis, Lee L; Schechter, Tao; Bartelink, Imke H; Boelens, Jaap J; Bredius, Robbert; Dalle, Jean-Hugues; Azarnoush, Saba; Sedlacek, Petr; Lewis, Victor; Champagne, Martin; Peters, Christina; Bittencourt, Henrique; Krajinovic, Maja

2017-10-31

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 ( GSTA1 ) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (N o Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

PubMed Central

Ansari, Marc; Curtis, Patricia Huezo-Diaz; Uppugunduri, Chakradhara Rao S.; Rezgui, Mohammed Aziz; Nava, Tiago; Mlakar, Vid; Lesne, Laurence; Théoret, Yves; Chalandon, Yves; Dupuis, Lee L.; Schechter, Tao; Bartelink, Imke H.; Boelens, Jaap J.; Bredius, Robbert; Dalle, Jean-Hugues; Azarnoush, Saba; Sedlacek, Petr; Lewis, Victor; Champagne, Martin; Peters, Christina; Bittencourt, Henrique; Krajinovic, Maja

2017-01-01

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (No Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered). PMID:29207608

High dose-per-pulse electron beam dosimetry - A model to correct for the ion recombination in the Advanced Markus ionization chamber.

PubMed

Petersson, Kristoffer; Jaccard, Maud; Germond, Jean-François; Buchillier, Thierry; Bochud, François; Bourhis, Jean; Vozenin, Marie-Catherine; Bailat, Claude

2017-03-01

The purpose of this work was to establish an empirical model of the ion recombination in the Advanced Markus ionization chamber for measurements in high dose rate/dose-per-pulse electron beams. In addition, we compared the observed ion recombination to calculations using the standard Boag two-voltage-analysis method, the more general theoretical Boag models, and the semiempirical general equation presented by Burns and McEwen. Two independent methods were used to investigate the ion recombination: (a) Varying the grid tension of the linear accelerator (linac) gun (controls the linac output) and measuring the relative effect the grid tension has on the chamber response at different source-to-surface distances (SSD). (b) Performing simultaneous dose measurements and comparing the dose-response, in beams with varying dose rate/dose-per-pulse, with the chamber together with dose rate/dose-per-pulse independent Gafchromic™ EBT3 film. Three individual Advanced Markus chambers were used for the measurements with both methods. All measurements were performed in electron beams with varying mean dose rate, dose rate within pulse, and dose-per-pulse (10 -2  ≤ mean dose rate ≤ 10 3 Gy/s, 10 2  ≤ mean dose rate within pulse ≤ 10 7  Gy/s, 10 -4  ≤ dose-per-pulse ≤ 10 1  Gy), which was achieved by independently varying the linac gun grid tension, and the SSD. The results demonstrate how the ion collection efficiency of the chamber decreased as the dose-per-pulse increased, and that the ion recombination was dependent on the dose-per-pulse rather than the dose rate, a behavior predicted by Boag theory. The general theoretical Boag models agreed well with the data over the entire investigated dose-per-pulse range, but only for a low polarizing chamber voltage (50 V). However, the two-voltage-analysis method and the Burns & McEwen equation only agreed with the data at low dose-per-pulse values (≤ 10 -2 and ≤ 10 -1  Gy, respectively). An empirical model of the ion recombination in the chamber was found by fitting a logistic function to the data. The ion collection efficiency of the Advanced Markus ionization chamber decreases for measurements in electron beams with increasingly higher dose-per-pulse. However, this chamber is still functional for dose measurements in beams with dose-per-pulse values up toward and above 10 Gy, if the ion recombination is taken into account. Our results show that existing models give a less-than-accurate description of the observed ion recombination. This motivates the use of the presented empirical model for measurements with the Advanced Markus chamber in high dose-per-pulse electron beams, as it enables accurate absorbed dose measurements (uncertainty estimation: 2.8-4.0%, k = 1). The model depends on the dose-per-pulse in the beam, and it is also influenced by the polarizing chamber voltage, with increasing ion recombination with a lowering of the voltage. © 2017 American Association of Physicists in Medicine.

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

PubMed

Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

2015-10-01

An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Estimating peak skin and eye lens dose from neuroperfusion examinations: use of Monte Carlo based simulations and comparisons to CTDIvol, AAPM Report No. 111, and ImPACT dosimetry tool values.

PubMed

Zhang, Di; Cagnon, Chris H; Villablanca, J Pablo; McCollough, Cynthia H; Cody, Dianna D; Zankl, Maria; Demarco, John J; McNitt-Gray, Michael F

2013-09-01

CT neuroperfusion examinations are capable of delivering high radiation dose to the skin or lens of the eyes of a patient and can possibly cause deterministic radiation injury. The purpose of this study is to: (a) estimate peak skin dose and eye lens dose from CT neuroperfusion examinations based on several voxelized adult patient models of different head size and (b) investigate how well those doses can be approximated by some commonly used CT dose metrics or tools, such as CTDIvol, American Association of Physicists in Medicine (AAPM) Report No. 111 style peak dose measurements, and the ImPACT organ dose calculator spreadsheet. Monte Carlo simulation methods were used to estimate peak skin and eye lens dose on voxelized patient models, including GSF's Irene, Frank, Donna, and Golem, on four scanners from the major manufacturers at the widest collimation under all available tube potentials. Doses were reported on a per 100 mAs basis. CTDIvol measurements for a 16 cm CTDI phantom, AAPM Report No. 111 style peak dose measurements, and ImPACT calculations were performed for available scanners at all tube potentials. These were then compared with results from Monte Carlo simulations. The dose variations across the different voxelized patient models were small. Dependent on the tube potential and scanner and patient model, CTDIvol values overestimated peak skin dose by 26%-65%, and overestimated eye lens dose by 33%-106%, when compared to Monte Carlo simulations. AAPM Report No. 111 style measurements were much closer to peak skin estimates ranging from a 14% underestimate to a 33% overestimate, and with eye lens dose estimates ranging from a 9% underestimate to a 66% overestimate. The ImPACT spreadsheet overestimated eye lens dose by 2%-82% relative to voxelized model simulations. CTDIvol consistently overestimates dose to eye lens and skin. The ImPACT tool also overestimated dose to eye lenses. As such they are still useful as a conservative predictor of dose for CT neuroperfusion studies. AAPM Report No. 111 style measurements are a better predictor of both peak skin and eye lens dose than CTDIvol and ImPACT for the patient models used in this study. It should be remembered that both the AAPM Report No. 111 peak dose metric and CTDIvol dose metric are dose indices and were not intended to represent actual organ doses.

Estimating peak skin and eye lens dose from neuroperfusion examinations: Use of Monte Carlo based simulations and comparisons to CTDIvol, AAPM Report No. 111, and ImPACT dosimetry tool values

PubMed Central

Zhang, Di; Cagnon, Chris H.; Villablanca, J. Pablo; McCollough, Cynthia H.; Cody, Dianna D.; Zankl, Maria; Demarco, John J.; McNitt-Gray, Michael F.

2013-01-01

Purpose: CT neuroperfusion examinations are capable of delivering high radiation dose to the skin or lens of the eyes of a patient and can possibly cause deterministic radiation injury. The purpose of this study is to: (a) estimate peak skin dose and eye lens dose from CT neuroperfusion examinations based on several voxelized adult patient models of different head size and (b) investigate how well those doses can be approximated by some commonly used CT dose metrics or tools, such as CTDIvol, American Association of Physicists in Medicine (AAPM) Report No. 111 style peak dose measurements, and the ImPACT organ dose calculator spreadsheet. Methods: Monte Carlo simulation methods were used to estimate peak skin and eye lens dose on voxelized patient models, including GSF's Irene, Frank, Donna, and Golem, on four scanners from the major manufacturers at the widest collimation under all available tube potentials. Doses were reported on a per 100 mAs basis. CTDIvol measurements for a 16 cm CTDI phantom, AAPM Report No. 111 style peak dose measurements, and ImPACT calculations were performed for available scanners at all tube potentials. These were then compared with results from Monte Carlo simulations. Results: The dose variations across the different voxelized patient models were small. Dependent on the tube potential and scanner and patient model, CTDIvol values overestimated peak skin dose by 26%–65%, and overestimated eye lens dose by 33%–106%, when compared to Monte Carlo simulations. AAPM Report No. 111 style measurements were much closer to peak skin estimates ranging from a 14% underestimate to a 33% overestimate, and with eye lens dose estimates ranging from a 9% underestimate to a 66% overestimate. The ImPACT spreadsheet overestimated eye lens dose by 2%–82% relative to voxelized model simulations. Conclusions: CTDIvol consistently overestimates dose to eye lens and skin. The ImPACT tool also overestimated dose to eye lenses. As such they are still useful as a conservative predictor of dose for CT neuroperfusion studies. AAPM Report No. 111 style measurements are a better predictor of both peak skin and eye lens dose than CTDIvol and ImPACT for the patient models used in this study. It should be remembered that both the AAPM Report No. 111 peak dose metric and CTDIvol dose metric are dose indices and were not intended to represent actual organ doses. PMID:24007152

JADA: a graphical user interface for comprehensive internal dose assessment in nuclear medicine.

PubMed

Grimes, Joshua; Uribe, Carlos; Celler, Anna

2013-07-01

The main objective of this work was to design a comprehensive dosimetry package that would keep all aspects of internal dose calculation within the framework of a single software environment and that would be applicable for a variety of dose calculation approaches. Our MATLAB-based graphical user interface (GUI) can be used for processing data obtained using pure planar, pure SPECT, or hybrid planar/SPECT imaging. Time-activity data for source regions are obtained using a set of tools that allow the user to reconstruct SPECT images, load images, coregister a series of planar images, and to perform two-dimensional and three-dimensional image segmentation. Curve fits are applied to the acquired time-activity data to construct time-activity curves, which are then integrated to obtain time-integrated activity coefficients. Subsequently, dose estimates are made using one of three methods. The organ level dose calculation subGUI calculates mean organ doses that are equivalent to dose assessment performed by OLINDA/EXM. Voxelized dose calculation options, which include the voxel S value approach and Monte Carlo simulation using the EGSnrc user code DOSXYZnrc, are available within the process 3D image data subGUI. The developed internal dosimetry software package provides an assortment of tools for every step in the dose calculation process, eliminating the need for manual data transfer between programs. This saves times and minimizes user errors, while offering a versatility that can be used to efficiently perform patient-specific internal dose calculations in a variety of clinical situations.

Toward a unified approach to dose-response modeling in ecotoxicology.

PubMed

Ritz, Christian

2010-01-01

This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

Estimating the Effects of Astronaut Career Ionizing Radiation Dose Limits on Manned Interplanetary Flight Programs

NASA Technical Reports Server (NTRS)

Koontz, Steven L.; Rojdev, Kristina; Valle, Gerard D.; Zipay, John J.; Atwell, William S.

2013-01-01

The Hybrid Inflatable DSH combined with electric propulsion and high power solar-electric power systems offer a near TRL-now solution to the space radiation crew dose problem that is an inevitable aspect of long term manned interplanetary flight. Spreading program development and launch costs over several years can lead to a spending plan that fits with NASA's current and future budgetary limitations, enabling early manned interplanetary operations with space radiation dose control, in the near future while biomedical research, nuclear electric propulsion and active shielding research and development proceed in parallel. Furthermore, future work should encompass laboratory validation of HZETRN calculations, as previous laboratory investigations have not considered large shielding thicknesses and the calculations presented at these thicknesses are currently performed via extrapolation.

OVERVIEW, PRACTICAL TIPS AND POTENTIAL PITFALLS OF USING AUTOMATIC EXPOSURE CONTROL IN CT: SIEMENS CARE DOSE 4D.

PubMed

Söderberg, Marcus

2016-06-01

Today, computed tomography (CT) systems routinely use automatic exposure control (AEC), which modulates the tube current. However, for optimal use, there are several aspects of an AEC system that need to be considered. The purpose of this study was to provide an overview of the Siemens CARE Dose 4D AEC system, discuss practical tips and demonstrate potential pitfalls. Two adult anthropomorphic phantoms were examined using two different Siemens CT systems. When optimising the CT radiation dose and image quality, the projection angle of the localiser, patient centring, protocol selection, scanning direction and the use of protective devices requires special attention. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Probabilistic Radiological Performance Assessment Modeling and Uncertainty

NASA Astrophysics Data System (ADS)

Tauxe, J.

2004-12-01

A generic probabilistic radiological Performance Assessment (PA) model is presented. The model, built using the GoldSim systems simulation software platform, concerns contaminant transport and dose estimation in support of decision making with uncertainty. Both the U.S. Nuclear Regulatory Commission (NRC) and the U.S. Department of Energy (DOE) require assessments of potential future risk to human receptors of disposal of LLW. Commercially operated LLW disposal facilities are licensed by the NRC (or agreement states), and the DOE operates such facilities for disposal of DOE-generated LLW. The type of PA model presented is probabilistic in nature, and hence reflects the current state of knowledge about the site by using probability distributions to capture what is expected (central tendency or average) and the uncertainty (e.g., standard deviation) associated with input parameters, and propagating through the model to arrive at output distributions that reflect expected performance and the overall uncertainty in the system. Estimates of contaminant release rates, concentrations in environmental media, and resulting doses to human receptors well into the future are made by running the model in Monte Carlo fashion, with each realization representing a possible combination of input parameter values. Statistical summaries of the results can be compared to regulatory performance objectives, and decision makers are better informed of the inherently uncertain aspects of the model which supports their decision-making. While this information may make some regulators uncomfortable, they must realize that uncertainties which were hidden in a deterministic analysis are revealed in a probabilistic analysis, and the chance of making a correct decision is now known rather than hoped for. The model includes many typical features and processes that would be part of a PA, but is entirely fictitious. This does not represent any particular site and is meant to be a generic example. A practitioner could, however, start with this model as a GoldSim template and, by adding site specific features and parameter values (distributions), use this model as a starting point for a real model to be used in real decision making.

USE OF EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) TO CONSTRUCT A PBPK /MODEL FOR CARBOFURAN WITH THE REPORTED EXPERIMENTAL DATA IN THE RAT

EPA Science Inventory

To better understand the relationships among carbofuran exposure, dose, and effects, a physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed for the rat using the Exposure Related Dose Estimating Model (ERDEM) framework.

Endoscopic management of acute peptic ulcer bleeding.

PubMed

Lu, Yidan; Chen, Yen-I; Barkun, Alan

2014-12-01

This review discusses the indications, technical aspects, and comparative effectiveness of the endoscopic treatment of upper gastrointestinal bleeding caused by peptic ulcer. Pre-endoscopic considerations, such as the use of prokinetics and timing of endoscopy, are reviewed. In addition, this article examines aspects of postendoscopic care such as the effectiveness, dosing, and duration of postendoscopic proton-pump inhibitors, Helicobacter pylori testing, and benefits of treatment in terms of preventing rebleeding; and the use of nonsteroidal anti-inflammatory drugs, antiplatelet agents, and oral anticoagulants, including direct thrombin and Xa inhibitors, following acute peptic ulcer bleeding. Copyright © 2014 Elsevier Inc. All rights reserved.

Parotid gland mean dose as a xerostomia predictor in low-dose domains.

PubMed

Gabryś, Hubert Szymon; Buettner, Florian; Sterzing, Florian; Hauswald, Henrik; Bangert, Mark

2017-09-01

Xerostomia is a common side effect of radiotherapy resulting from excessive irradiation of salivary glands. Typically, xerostomia is modeled by the mean dose-response characteristic of parotid glands and prevented by mean dose constraints to either contralateral or both parotid glands. The aim of this study was to investigate whether normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands are suitable for the prediction of xerostomia in a highly conformal low-dose regime of modern intensity-modulated radiotherapy (IMRT) techniques. We present a retrospective analysis of 153 head and neck cancer patients treated with radiotherapy. The Lyman Kutcher Burman (LKB) model was used to evaluate predictive power of the parotid gland mean dose with respect to xerostomia at 6 and 12 months after the treatment. The predictive performance of the model was evaluated by receiver operating characteristic (ROC) curves and precision-recall (PR) curves. Average mean doses to ipsilateral and contralateral parotid glands were 25.4 Gy and 18.7 Gy, respectively. QUANTEC constraints were met in 74% of patients. Mild to severe (G1+) xerostomia prevalence at both 6 and 12 months was 67%. Moderate to severe (G2+) xerostomia prevalence at 6 and 12 months was 20% and 15%, respectively. G1 + xerostomia was predicted reasonably well with area under the ROC curve ranging from 0.69 to 0.76. The LKB model failed to provide reliable G2 + xerostomia predictions at both time points. Reduction of the mean dose to parotid glands below QUANTEC guidelines resulted in low G2 + xerostomia rates. In this dose domain, the mean dose models predicted G1 + xerostomia fairly well, however, failed to recognize patients at risk of G2 + xerostomia. There is a need for the development of more flexible models able to capture complexity of dose response in this dose regime.

Stochastic Human Exposure and Dose Simulation Model for Pesticides

EPA Science Inventory

SHEDS-Pesticides (Stochastic Human Exposure and Dose Simulation Model for Pesticides) is a physically-based stochastic model developed to quantify exposure and dose of humans to multimedia, multipathway pollutants. Probabilistic inputs are combined in physical/mechanistic algorit...

A Phase 2 Trial on the Effect of Low-Dose versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)

DTIC Science & Technology

2014-10-01

number/communicate to site coordinator N/A Task V.5 (mo 6-47): implement methods to educate/monitor participants on aspects of vit D3 and calcium...potential side effects of vit D3 supplementation CRFs for adverse event reporting have been developed and included in the protocols submitted for IRB...Task VI.3 (mo 6-47): document acceptance of storage sample in the CGRP database and vit D3 study database The process for storage of sample in the

Biomedical and environmental aspects of the thorium fuel cycle: a selected, annotated bibliography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faust, R.A.; Fore, C.S.; Cone, M.V.

1979-07-01

This bibliography was compiled to assist in the evaluation of the health and environmental consequences of high specific activity thorium and related nuclides which could be released to the environment by activities related to the Thorium Fuel Cycle. The general scope covers studies regarding potential releases, environmental transport, metabolism, dosimetry, dose assessment, and overall risk assessment for radionuclides specific to the NASAP project. This publication of 740 abstracted references highlights the biological and medical aspects of thorium 228 and thorium 232 in man and animals. Similar studies on related nuclides such as radium 224, radium 226, radium 228, and thoriummore » 230 are also emphasized. Additional categories relevant to these radionuclides are included as follows: chemical analysis; ecological aspects; energy; geological aspects; instrumentation; legal and political aspects; monitoring, measurement and analysis; physical aspects; production; radiation safety and control; and waste disposal and management. Environmental assessment and sources categories were used for entries which contain a multiple use of categories. Leading authors appear alphabetically within each category. Indexes are provided for : author(s), geographic location, keywords, title, and publication description. The bibliography contains literature dating from December 1925 to February 1978.« less

Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

NASA Technical Reports Server (NTRS)

Chappelli, Lori J.; Cucinotta, Francis A.

2010-01-01

BACKGROUND: There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies. DOSE RESPONSE MODELS: The Harderian Gland data of Alpen et al.[1-3] was re-analyzed [4] using non-linear least square regression. The data set measured the induction of Harderian gland tumors in mice by high-energy protons, helium, neon, iron, niobium and lanthanum with LET s ranging from 0.4 to 950 keV/micron. We were able to strengthen the individual ion models by combining data for all ions into a model that relates both radiation dose and LET for the ion to tumor prevalence. We compared models based on Targeted Effects (TE) to one motivated by Non-targeted Effects (NTE) that included a bystander term that increased tumor induction at low doses non-linearly. When comparing fitted models to the experimental data, we considered the adjusted R2, the Akaike Information Criteria (AIC), and the Bayesian Information Criteria (BIC) to test for Goodness of fit.In the adjusted R2test, the model with the highest R2values provides a better fit to the available data. In the AIC and BIC tests, the model with the smaller values of the summary value provides the better fit. The non-linear NTE models fit the combined data better than the TE models that are linear at low doses. We evaluated the differences in the relative biological effectiveness (RBE) and found the NTE model provides a higher RBE at low dose compared to the TE model. POWER ANALYSIS: The final NTE model estimates were used to simulate example data to consider the design of new experiments to detect NTE at low dose for validation. Power and sample sizes were calculated for a variety of radiation qualities including some not considered in the Harderian Gland data set and with different background tumor incidences. We considered different experimental designs with varying number of doses and varying low doses dependant on the LET of the radiation. The optimal design to detect a NTE for an individual ion had 4 doses equally spaced below a maximal dose where bending due to cell sterilization was < 2%. For example at 100 keV/micron we would irradiate at 0.03 Gy, 0.065 Gy, 0.13 Gy, and 0.26 Gy and require 850 mice including a control dose for a sensitivity to detect NTE with 80% power. Sample sizes could be improved by combining ions similar to the methods used with the Harderian Gland data.

Prevention of Transfusion-Associated Graft-versus-Host Disease by Irradiation: Technical Aspect of a New Ferrous Sulphate Dosimetric System

PubMed Central

Del Lama, Lucas Sacchini; de Góes, Evamberto Garcia; Petchevist, Paulo César Dias; Moretto, Edson Lara; Borges, José Carlos; Covas, Dimas Tadeu; de Almeida, Adelaide

2013-01-01

Irradiation of whole blood and blood components before transfusion is currently the only accepted method to prevent Transfusion-Associated Graft-Versus-Host-Disease (TA-GVHD). However, choosing the appropriate technique to determine the dosimetric parameters associated with blood irradiation remains an issue. We propose a dosimetric system based on the standard Fricke Xylenol Gel (FXG) dosimeter and an appropriate phantom. The modified dosimeter was previously calibrated using a 60Co teletherapy unit and its validation was accomplished with a 137Cs blood irradiator. An ionization chamber, standard FXG, radiochromic film and thermoluminescent dosimeters (TLDs) were used as reference dosimeters to determine the dose response and dose rate of the 60Co unit. The dose distributions in a blood irradiator were determined with the modified FXG, the radiochromic film, and measurements by TLD dosimeters. A linear response for absorbed doses up to 54 Gy was obtained with our system. Additionally, the dose rate uncertainties carried out with gel dosimetry were lower than 5% and differences lower than 4% were noted when the absorbed dose responses were compared with ionization chamber, film and TLDs. PMID:23762345

Dosimetric aspects of breast radiotherapy with three-dimensional and intensity-modulated radiotherapy helical tomotherapy planning modules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yadav, Poonam; Service of Radiation Therapy, University of Wisconsin Aspirus Cancer Center, Wisconsin Rapids, WI; Yan, Yue, E-mail: yyan5@mdanderson.org

In this work, we investigated the dosimetric differences between the intensity-modulated radiotherapy (IMRT) plans and the three-dimensional (3D) helical plans based on the TomoTherapy system. A total of 15 patients with supine setup were randomly selected from the data base. For patients with lumpectomy planning target volume (PTV), regional lymph nodes were also included as part of the target. For dose sparing, the significant differences between the helical IMRT and helical 3D were only found in the heart and contralateral breast. For the dose to the heart, helical IMRT reduced the maximum point dose by 6.98 Gy compared to themore » helical 3D plan (p = 0.01). For contralateral breast, the helical IMRT plans significantly reduced the maximum point dose by 5.6 Gy compared to the helical 3D plan. However, compared to the helical 3D plan, the helical IMRT plan increased the volume for lower dose (13.08% increase in V{sub 5} {sub Gy}, p = 0.01). In general, there are no significant differences in dose sparing between helical IMRT and helical 3D plans.« less

Analytical model for out-of-field dose in photon craniospinal irradiation

NASA Astrophysics Data System (ADS)

Taddei, Phillip J.; Jalbout, Wassim; Howell, Rebecca M.; Khater, Nabil; Geara, Fady; Homann, Kenneth; Newhauser, Wayne D.

2013-11-01

The prediction of late effects after radiotherapy in organs outside a treatment field requires accurate estimations of out-of-field dose. However, out-of-field dose is not calculated accurately by commercial treatment planning systems (TPSs). The purpose of this study was to develop and test an analytical model for out-of-field dose during craniospinal irradiation (CSI) from photon beams produced by a linear accelerator. In two separate evaluations of the model, we measured absorbed dose for a 6 MV CSI using thermoluminescent dosimeters placed throughout an anthropomorphic phantom and fit the measured data to an analytical model of absorbed dose versus distance outside of the composite field edge. These measurements were performed in two separate clinics—the University of Texas MD Anderson Cancer Center (MD Anderson) and the American University of Beirut Medical Center (AUBMC)—using the same phantom but different linear accelerators and TPSs commissioned for patient treatments. The measurement at AUBMC also included in-field locations. Measured dose values were compared to those predicted by TPSs and parameters were fit to the model in each setting. In each clinic, 95% of the measured data were contained within a factor of 0.2 and one root mean square deviation of the model-based values. The root mean square deviations of the mathematical model were 0.91 cGy Gy-1 and 1.67 cGy Gy-1 in the MD Anderson and AUBMC clinics, respectively. The TPS predictions agreed poorly with measurements in regions of sharp dose gradient, e.g., near the field edge. At distances greater than 1 cm from the field edge, the TPS underestimated the dose by an average of 14% ± 24% and 44% ± 19% in the MD Anderson and AUBMC clinics, respectively. The in-field measured dose values of the measurement at AUBMC matched the dose values calculated by the TPS to within 2%. Dose algorithms in TPSs systematically underestimated the actual out-of-field dose. Therefore, it is important to use an improved model based on measurements when estimating out-of-field dose. The model proposed in this study performed well for this purpose in two clinics and may be applicable in other clinics with similar treatment field configurations.

Simulation and experimental study of aspect ratio limitation in Fresnel zone plates for hard-x-ray optics.

PubMed

Liu, Jianpeng; Shao, Jinhai; Zhang, Sichao; Ma, Yaqi; Taksatorn, Nit; Mao, Chengwen; Chen, Yifang; Deng, Biao; Xiao, Tiqiao

2015-11-10

For acquiring high-contrast and high-brightness images in hard-x-ray optics, Fresnel zone plates with high aspect ratios (zone height/zone width) have been constantly pursued. However, knowledge of aspect ratio limits remains limited. This work explores the achievable aspect ratio limit in polymethyl methacrylate (PMMA) by electron-beam lithography (EBL) under 100 keV, and investigates the lithographic factors for this limitation. Both Monte Carlo simulation and EBL on thick PMMA are applied to investigate the profile evolution with exposure doses over 100 nm wide dense zones. A high-resolution scanning electron microscope at low acceleration mode for charging free is applied to characterize the resultant zone profiles. It was discovered for what we believe is the first time that the primary electron-beam spreading in PMMA and the proximity effect due to extra exposure from neighboring areas could be the major causes of limiting the aspect ratio. Using the optimized lithography condition, a 100 nm zone plate with aspect ratio of 15/1 was fabricated and its focusing property was characterized at the Shanghai Synchrotron Radiation Facility. The aspect ratio limit found in this work should be extremely useful for guiding further technical development in nanofabrication of high-quality Fresnel zone plates.

Room model based Monte Carlo simulation study of the relationship between the airborne dose rate and the surface-deposited radon progeny.

PubMed

Sun, Kainan; Field, R William; Steck, Daniel J

2010-01-01

The quantitative relationships between radon gas concentration, the surface-deposited activities of various radon progeny, the airborne radon progeny dose rate, and various residential environmental factors were investigated through a Monte Carlo simulation study based on the extended Jacobi room model. Airborne dose rates were calculated from the unattached and attached potential alpha-energy concentrations (PAECs) using two dosimetric models. Surface-deposited (218)Po and (214)Po were significantly correlated with radon concentration, PAECs, and airborne dose rate (p-values <0.0001) in both non-smoking and smoking environments. However, in non-smoking environments, the deposited radon progeny were not highly correlated to the attached PAEC. In multiple linear regression analysis, natural logarithm transformation was performed for airborne dose rate as a dependent variable, as well as for radon and deposited (218)Po and (214)Po as predictors. In non-smoking environments, after adjusting for the effect of radon, deposited (214)Po was a significant positive predictor for one dose model (RR 1.46, 95% CI 1.27-1.67), while deposited (218)Po was a negative predictor for the other dose model (RR 0.90, 95% CI 0.83-0.98). In smoking environments, after adjusting for radon and room size, deposited (218)Po was a significant positive predictor for one dose model (RR 1.10, 95% CI 1.02-1.19), while a significant negative predictor for the other model (RR 0.90, 95% CI 0.85-0.95). After adjusting for radon and deposited (218)Po, significant increases of 1.14 (95% CI 1.03-1.27) and 1.13 (95% CI 1.05-1.22) in the mean dose rates were found for large room sizes relative to small room sizes in the different dose models.

Multicentre dose audit for clinical trials of radiation therapy in Asia.

PubMed

Mizuno, Hideyuki; Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C R Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-05-01

A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Monitoring late-onset toxicities in phase I trials using predicted risks

PubMed Central

Bekele, B. Nebiyou; Ji, Yuan; Shen, Yu; Thall, Peter F.

2008-01-01

Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average. PMID:18084008

A Generalized QMRA Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2016-10-01

Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0

Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.

PubMed

Long-Boyle, Janel R; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J; Dvorak, Christopher C

2015-04-01

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

EPA and EFSA approaches for Benchmark Dose modeling

EPA Science Inventory

Benchmark dose (BMD) modeling has become the preferred approach in the analysis of toxicological dose-response data for the purpose of deriving human health toxicity values. The software packages most often used are Benchmark Dose Software (BMDS, developed by EPA) and PROAST (de...

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

PubMed

Guckenberger, Matthias; Klement, Rainer Johannes; Allgäuer, Michael; Appold, Steffen; Dieckmann, Karin; Ernst, Iris; Ganswindt, Ute; Holy, Richard; Nestle, Ursula; Nevinny-Stickel, Meinhard; Semrau, Sabine; Sterzing, Florian; Wittig, Andrea; Andratschke, Nicolaus; Flentje, Michael

2013-10-01

To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

Animal and human dose-response models for Brucella species.

PubMed

Teske, Sondra S; Huang, Yin; Tamrakar, Sushil B; Bartrand, Timothy A; Weir, Mark H; Haas, Charles N

2011-10-01

Human Brucellosis is one of the most common zoonotic diseases worldwide. Disease transmission often occurs through the handling of domestic livestock, as well as ingestion of unpasteurized milk and cheese, but can have enhanced infectivity if aerosolized. Because there is no human vaccine available, rising concerns about the threat of Brucellosis to human health and its inclusion in the Center for Disease Control's Category B Bioterrorism/Select Agent List make a better understanding of the dose-response relationship of this microbe necessary. Through an extensive peer-reviewed literature search, candidate dose-response data were appraised so as to surpass certain standards for quality. The statistical programming language, "R," was used to compute the maximum likelihood estimation to fit two models, the exponential and the approximate beta-Poisson (widely used for quantitative risk assessment) to dose-response data. Dose-response models were generated for prevalent species of Brucella: Br. suis, Br. melitensis, and Br. abortus. Dose-response models were created for aerosolized Br. suis exposure to guinea pigs from pooled studies. A parallel model for guinea pigs inoculated through both aerosol and subcutaneous routes with Br. melitensis showed that the median infectious dose corresponded to a 30 colony-forming units (CFU) dose of Br. suis, much less than the N(50) dose of about 94 CFU for Br. melitensis organisms. When Br. melitensis was tested subcutaneously on mice, the N(50) dose was higher, 1,840 CFU. A dose-response model was constructed from pooled data for mice, rhesus macaques, and humans inoculated through three routes (subcutaneously/aerosol/intradermally) with Br. melitensis. © 2011 Society for Risk Analysis.

SU-D-BRC-05: Effects of Motion and Variable RBE in a Lung Patient Treated with Passively Scattered Protons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirkovic, D; Titt, U; Mohan, R

2016-06-15

Purpose: To evaluate effects of motion and variable relative biological effectiveness (RBE) in a lung cancer patient treated with passively scattered proton therapy using dose volume histograms associated with patient dose computed using three different methods. Methods: A proton treatment plan of a lung cancer patient optimized using clinical treatment planning system (TPS) was used to construct a detailed Monte Carlo (MC) model of the beam delivery system and the patient specific aperture and compensator. A phase space file containing all particles transported through the beam line was collected at the distal surface of the range compensator and subsequently transportedmore » through two different patient models. The first model was based on the average CT used by the TPS and the second model included all 10 phases of the corresponding 4DCT. The physical dose and proton linear energy transfer (LET) were computed in each voxel of two models and used to compute constant and variable RBE MC dose on average CT and 4D CT. The MC computed doses were compared to the TPS dose using dose volume histograms for relevant structures. Results: The results show significant differences in doses to the target and critical structures suggesting the need for more accurate proton dose computation methods. In particular, the 4D dose shows reduced coverage of the target and higher dose to the spinal cord, while variable RBE dose shows higher lung dose. Conclusion: The methodology developed in this pilot study is currently used for the analysis of a cohort of ∼90 lung patients from a clinical trial comparing proton and photon therapy for lung cancer. The results from this study will help us in determining the clinical significance of more accurate dose computation models in proton therapy.« less

Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inskip, Peter D., E-mail: inskippeter@gmail.com; Sigurdson, Alice J.; Veiga, Lene

Objectives: The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose–response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods: This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands,more » and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site–specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results: Linear dose–response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions: The results suggest that the effect of high-dose irradiation is consistent with a linear dose–response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment.« less

Efficacy and safety of a multifactor intervention to improve therapeutic adherence in patients with chronic obstructive pulmonary disease (COPD): protocol for the ICEPOC study.

PubMed

Barnestein-Fonseca, Pilar; Leiva-Fernández, José; Vidal-España, Francisca; García-Ruiz, Antonio; Prados-Torres, Daniel; Leiva-Fernández, Francisca

2011-02-14

Low therapeutic adherence to medication is very common. Clinical effectiveness is related to dose rate and route of administration and so poor therapeutic adherence can reduce the clinical benefit of treatment. The therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is extremely poor according to most studies. The research about COPD adherence has mainly focussed on quantifying its effect, and few studies have researched factors that affect non-adherence. Our study will evaluate the effectiveness of a multifactor intervention to improve the therapeutic adherence of COPD patients. A randomized controlled clinical trial with 140 COPD diagnosed patients selected by a non-probabilistic method of sampling. Subjects will be randomly allocated into two groups, using the block randomization technique. Every patient in each group will be visited four times during the year of the study. Motivational aspects related to adherence (beliefs and behaviour): group and individual interviews; cognitive aspects: information about illness; skills: inhaled technique training. Reinforcement of the cognitive-emotional aspects and inhaled technique training will be carried out in all visits of the intervention group. Adherence to a prescribed treatment involves a behavioural change. Cognitive, emotional and motivational aspects influence this change and so we consider the best intervention procedure to improve adherence would be a cognitive and emotional strategy which could be applied in daily clinical practice. Our hypothesis is that the application of a multifactor intervention (COPD information, dose reminders and reinforcing audiovisual material, motivational aspects and inhalation technique training) to COPD patients taking inhaled treatment will give a 25% increase in the number of patients showing therapeutic adherence in this group compared to the control group.We will evaluate the effectiveness of this multifactor intervention on patient adherence to inhaled drugs considering that it will be right and feasible to the clinical practice context. Current Controlled Trials ISRCTN18841601.

Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease.

PubMed

Capurro, Valeria; Busquet, Perrine; Lopes, Joao Pedro; Bertorelli, Rosalia; Tarozzo, Glauco; Bolognesi, Maria Laura; Piomelli, Daniele; Reggiani, Angelo; Cavalli, Andrea

2013-01-01

Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aβ-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

Pharmacological Characterization of Memoquin, a Multi-Target Compound for the Treatment of Alzheimer's Disease

PubMed Central

Capurro, Valeria; Busquet, Perrine; Lopes, Joao Pedro; Bertorelli, Rosalia; Tarozzo, Glauco; Bolognesi, Maria Laura; Piomelli, Daniele; Reggiani, Angelo; Cavalli, Andrea

2013-01-01

Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7–15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aβ-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD. PMID:23441223

Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.

PubMed

Royce, Simon G; Dang, William; Ververis, Katherine; De Sampayo, Nishika; El-Osta, Assam; Tang, Mimi L K; Karagiannis, Tom C

2011-12-01

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially abrogate aspects of remodeling. One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid). Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p < 0.01), reduced subepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

Dose-response relationship in the treatment of gastrointestinal disorders.

PubMed

Weihrauch, T R; Demol, P

1989-08-01

Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

Assessing doses to terrestrial wildlife at a radioactive waste disposal site: inter-comparison of modelling approaches.

PubMed

Johansen, M P; Barnett, C L; Beresford, N A; Brown, J E; Černe, M; Howard, B J; Kamboj, S; Keum, D-K; Smodiš, B; Twining, J R; Vandenhove, H; Vives i Batlle, J; Wood, M D; Yu, C

2012-06-15

Radiological doses to terrestrial wildlife were examined in this model inter-comparison study that emphasised factors causing variability in dose estimation. The study participants used varying modelling approaches and information sources to estimate dose rates and tissue concentrations for a range of biota types exposed to soil contamination at a shallow radionuclide waste burial site in Australia. Results indicated that the dominant factor causing variation in dose rate estimates (up to three orders of magnitude on mean total dose rates) was the soil-to-organism transfer of radionuclides that included variation in transfer parameter values as well as transfer calculation methods. Additional variation was associated with other modelling factors including: how participants conceptualised and modelled the exposure configurations (two orders of magnitude); which progeny to include with the parent radionuclide (typically less than one order of magnitude); and dose calculation parameters, including radiation weighting factors and dose conversion coefficients (typically less than one order of magnitude). Probabilistic approaches to model parameterisation were used to encompass and describe variable model parameters and outcomes. The study confirms the need for continued evaluation of the underlying mechanisms governing soil-to-organism transfer of radionuclides to improve estimation of dose rates to terrestrial wildlife. The exposure pathways and configurations available in most current codes are limited when considering instances where organisms access subsurface contamination through rooting, burrowing, or using different localised waste areas as part of their habitual routines. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Comparison of Genotoxic Damage in Monolayer Cell Cultures and Three-Dimensional Tissue-Like Cell Assemblies

NASA Technical Reports Server (NTRS)

Behravesh, E.; Emami, K.; Wu, H.; Gonda, S.

2004-01-01

Assessing the biological risks associated with exposure to the high-energy charged particles encountered in space is essential for the success of long-term space exploration. Although prokaryotic and eukaryotic cell models developed in our laboratory and others have advanced our understanding of many aspects of genotoxicity, in vitro models are needed to assess the risk to humans from space radiation insults. Such models must be representative of the cellular interactions present in tissues and capable of quantifying I genotoxic damage. Toward this overall goal, the objectives of this study were to examine the effect of the localized microenvironment of cells, cultured as either 2-dimensional (2D) monolayers or 3-dimensional (3D) aggregates, on the rate and type of genotoxic damage resulting from exposure to iron charged particles, a significant portion of space radiation. We used rodent transgenic cell lines containing 50-70 copies of a LacI transgene to provide the enhanced sensitivity required to quantify mutational frequency and type in the 1,100-bp LacI target as well as assessment of DNA,damage to the entire 45-kbp construct. Cultured cells were exposed to high-enerir on charged particles at Brookhaven National Laboratory s Alternating Gradient Synchrotron facility for a total dose of 0, 0.1, 0.25,0.5, 1.0, or 2.0 Gy and allowed to recover for 0, 1, or 7 days, after which mutational type and frequency were evaluated. The mutational frequency was found to be higher in 3D samples than in 2D samples at all radiation doses. Mutational frequency also was higher at 7 days after irradiation than immediately after exposure. DNA sequencing of the mutant targets revealed that deletional mutations contributed an increasingly high percentage (up to 27%) of all mutations in cells as the dose was increased from 0.5 to 2 Gy. Several mutants also showed large and complex deletions in multiple locations within the Lac1 target. However, no differences in mutational type were found between the 2D and the 3D samples. These 3D tissue-like model systems can reduce the uncertainty involved in extrapolating risk between in vitro cellular and in vivo models.

The importance of applicator design for intraluminal brachytherapy of rectal cancer.

PubMed

Hansen, Johnny Witterseh; Jakobsen, Anders

2006-09-01

An important aspect of designing an applicator for radiation treatment of rectal cancer is the ability to minimize dose to the mucosa and noninvolved parts of the rectum wall. For this reason we investigated a construction of a flexible multichannel applicator with several channels placed along the periphery of a cylinder and a construction of a rigid cylinder with a central channel and interchangeable shields. Calculations of the dose gradient, dose homogeneity in the tumor, and shielding ability were performed for the two applicators in question. Furthermore, the influence on dose distribution around a flexible multichannel applicator from an unintended off-axis positioning of the source inside a bent channel was investigated by film measurements on a single bent catheter. Calculations showed that a single-channel applicator with interchangeable shields yields a higher degree of shielding and has a better dose homogeneity in the tumor volume than that of a multi-channel applicator. A single-channel applicator with interchangeable shields was manufactured, and the influence of different size of shield angle on dose rate in front of and behind the shields was measured. While dose rate in front of the shield and shielding ability are closely independent of the size of the shield angle when measured 1 cm from the applicator surface, dose rate in more distant volumes will to some extent be influenced by shield angle due to volume scatter conditions.

The importance of applicator design for intraluminal brachytherapy of rectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hansen, Johnny Witterseh; Jakobsen, Anders; Department of Oncology, Hospital of Vejle, DK-7100 Vejle

2006-09-15

An important aspect of designing an applicator for radiation treatment of rectal cancer is the ability to minimize dose to the mucosa and noninvolved parts of the rectum wall. For this reason we investigated a construction of a flexible multichannel applicator with several channels placed along the periphery of a cylinder and a construction of a rigid cylinder with a central channel and interchangeable shields. Calculations of the dose gradient, dose homogeneity in the tumor, and shielding ability were performed for the two applicators in question. Furthermore, the influence on dose distribution around a flexible multichannel applicator from an unintendedmore » off-axis positioning of the source inside a bent channel was investigated by film measurements on a single bent catheter. Calculations showed that a single-channel applicator with interchangeable shields yields a higher degree of shielding and has a better dose homogeneity in the tumor volume than that of a multichannel applicator. A single-channel applicator with interchangeable shields was manufactured, and the influence of different size of shield angle on dose rate in front of and behind the shields was measured. While dose rate in front of the shield and shielding ability are closely independent of the size of the shield angle when measured 1 cm from the applicator surface, dose rate in more distant volumes will to some extent be influenced by shield angle due to volume scatter conditions.« less

PARMA: PHITS-based Analytical Radiation Model in the Atmosphere--Verification of Its Accuracy in Estimating Cosmic Radiation Doses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sato, Tatsuhiko; Satoh, Daiki; Endo, Akira

Estimation of cosmic-ray spectra in the atmosphere has been an essential issue in the evaluation of the aircrew doses. We therefore developed an analytical model that can predict the terrestrial neutron, proton, He nucleus, muon, electron, positron and photon spectra at altitudes below 20 km, based on the Monte Carlo simulation results of cosmic-ray propagation in the atmosphere performed by the PHITS code. The model was designated PARMA. In order to examine the accuracy of PARMA in terms of the neutron dose estimation, we measured the neutron dose rates at the altitudes between 20 to 10400 m, using our developedmore » dose monitor DARWIN mounted on an aircraft. Excellent agreement was observed between the measured dose rates and the corresponding data calculated by PARMA coupled with the fluence-to-dose conversion coefficients, indicating the applicability of the model to be utilized in the route-dose calculation.« less

Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases

PubMed Central

Cabeza-Arvelaiz, Yofre; Schiestl, Robert H.

2012-01-01

The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs. PMID:22970289

Simplification of an MCNP model designed for dose rate estimation

NASA Astrophysics Data System (ADS)

Laptev, Alexander; Perry, Robert

2017-09-01

A study was made to investigate the methods of building a simplified MCNP model for radiological dose estimation. The research was done using an example of a complicated glovebox with extra shielding. The paper presents several different calculations for neutron and photon dose evaluations where glovebox elements were consecutively excluded from the MCNP model. The analysis indicated that to obtain a fast and reasonable estimation of dose, the model should be realistic in details that are close to the tally. Other details may be omitted.

JOURNAL CLUB: Quantification of Fetal Dose Reduction if Abdominal CT Is Limited to the Top of the Iliac Crests in Pregnant Patients With Trauma.

PubMed

Corwin, Michael T; Seibert, J Anthony; Fananapazir, Ghaneh; Lamba, Ramit; Boone, John M

2016-04-01

The purposes of this study were to correlate fetal z-axis location within the maternal abdomen on CT with gestational age and estimate fetal dose reduction of a study limited to the abdomen only, with its lower aspect at the top of the iliac crests, compared with full abdominopelvic CT in pregnant trauma patients. We performed a study of pregnant patients who underwent CT of the abdomen and pelvis for trauma at a single institution over a 10-year period. The inferior aspect of maternal liver, spleen, gallbladder, pancreas, adrenals, and kidneys was recorded as above or below the iliac crests. The distance from the iliac crest to the top of the fetus or gestational sac was determined. The CT images of the limited and full scanning studies were independently reviewed by two blinded radiologists to identify traumatic injuries. Fetal dose profiles, including both scatter and primary radiation, were computed analytically along the central axis of the patient to estimate fetal dose reduction. Linear regression analysis was performed between gestational age and distance of the fetus to the iliac crests. Thirty-five patients were included (mean age, 26.2 years). Gestational age ranged from 5 to 38 weeks, with 5, 19, and 11 gestations in the first, second, and third trimesters, respectively. All solid organs were above the iliac crests in all patients. In three of six patients, traumatic findings in the pelvis would have been missed with the limited study. There was high correlation between gestational age and distance of the fetus to the iliac crests (R(2) = 0.84). The mean gestational age at which the top of the fetus was at the iliac crest was 17.3 weeks. Using the limited scanning study, fetuses at 5, 20, and 40 weeks of gestation would receive an estimated 4.3%, 26.2%, and 59.9% of the dose, respectively, compared with the dose for the full scanning study. In pregnant patients in our series with a history of trauma, CT of the abdomen only was an effective technique to reduce fetal radiation exposure compared with full abdomen and pelvis CT.

Can the Equivalent Sphere Model Approximate Organ Doses in Space?

NASA Technical Reports Server (NTRS)

Lin, Zi-Wei

2007-01-01

For space radiation protection it is often useful to calculate dose or dose,equivalent in blood forming organs (BFO). It has been customary to use a 5cm equivalent sphere to. simulate the BFO dose. However, many previous studies have concluded that a 5cm sphere gives very different dose values from the exact BFO values. One study [1] . concludes that a 9 cm sphere is a reasonable approximation for BFO'doses in solar particle event environments. In this study we use a deterministic radiation transport [2] to investigate the reason behind these observations and to extend earlier studies. We take different space radiation environments, including seven galactic cosmic ray environments and six large solar particle events, and calculate the dose and dose equivalent in the skin, eyes and BFO using their thickness distribution functions from the CAM (Computerized Anatomical Man) model [3] The organ doses have been evaluated with a water or aluminum shielding of an areal density from 0 to 20 g/sq cm. We then compare with results from the equivalent sphere model and determine in which cases and at what radius parameters the equivalent sphere model is a reasonable approximation. Furthermore, we address why the equivalent sphere model is not a good approximation in some cases. For solar particle events, we find that the radius parameters for the organ dose equivalent increase significantly with the shielding thickness, and the model works marginally for BFO but is unacceptable for the eye or the skin. For galactic cosmic rays environments, the equivalent sphere model with an organ-specific constant radius parameter works well for the BFO dose equivalent, marginally well for the BFO dose and the dose equivalent of the eye or the skin, but is unacceptable for the dose of the eye or the skin. The ranges of the radius parameters are also being investigated, and the BFO radius parameters are found to be significantly, larger than 5 cm in all cases, consistent with the conclusion of an earlier study [I]. The radius parameters for the dose equivalent in GCR environments are approximately between 10 and I I cm for the BFO, 3.7 to 4.8 cm for the eye, and 3.5 to 5.6 cm for the skin; while the radius parameters are between 10 and 13 cm for the BFO dose.

Disposition of smoked cannabis with high {Delta}{sup 9}-tetrahydrocannabinol content: A kinetic model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hunault, Claudine C., E-mail: claudine.hunault@rivm.n; Eijkeren, Jan C.H. van; Mensinga, Tjeert T.

Introduction: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3 mg, 49.1 mg, and 69.4 mg THC. Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters.more » The median pharmacokinetic parameters generated by the model were C{sub max} = 175 ng/mL, T{sub max} = 14 min, and AUC{sub 0-8h} = 8150 ng x min/mL for the 69.4 mg THC dose. Median model results show an almost linear dose response relation for C{sub max}/Dose = 2.8 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 136 x 10{sup -6} min/mL. However, for increasing dose level, there was a clear decreasing trend: C{sub max}/Dose = 3.4, 2.6 and 2.5 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 157, 133 and 117 x 10{sup -6} min/mL for the 29.3, 49.1 and 69.4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).« less

Disposition of smoked cannabis with high Δ(9)-tetrahydrocannabinol content: a kinetic model.

PubMed

Hunault, Claudine C; van Eijkeren, Jan C H; Mensinga, Tjeert T; de Vries, Irma; Leenders, Marianne E C; Meulenbelt, Jan

2010-08-01

No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%). Copyright © 2010 Elsevier Inc. All rights reserved.

Pediatric Chest and Abdominopelvic CT: Organ Dose Estimation Based on 42 Patient Models

PubMed Central

Tian, Xiaoyu; Li, Xiang; Segars, W. Paul; Paulson, Erik K.; Frush, Donald P.

2014-01-01

Purpose To estimate organ dose from pediatric chest and abdominopelvic computed tomography (CT) examinations and evaluate the dependency of organ dose coefficients on patient size and CT scanner models. Materials and Methods The institutional review board approved this HIPAA–compliant study and did not require informed patient consent. A validated Monte Carlo program was used to perform simulations in 42 pediatric patient models (age range, 0–16 years; weight range, 2–80 kg; 24 boys, 18 girls). Multidetector CT scanners were modeled on those from two commercial manufacturers (LightSpeed VCT, GE Healthcare, Waukesha, Wis; SOMATOM Definition Flash, Siemens Healthcare, Forchheim, Germany). Organ doses were estimated for each patient model for routine chest and abdominopelvic examinations and were normalized by volume CT dose index (CTDIvol). The relationships between CTDIvol-normalized organ dose coefficients and average patient diameters were evaluated across scanner models. Results For organs within the image coverage, CTDIvol-normalized organ dose coefficients largely showed a strong exponential relationship with the average patient diameter (R2 > 0.9). The average percentage differences between the two scanner models were generally within 10%. For distributed organs and organs on the periphery of or outside the image coverage, the differences were generally larger (average, 3%–32%) mainly because of the effect of overranging. Conclusion It is feasible to estimate patient-specific organ dose for a given examination with the knowledge of patient size and the CTDIvol. These CTDIvol-normalized organ dose coefficients enable one to readily estimate patient-specific organ dose for pediatric patients in clinical settings. This dose information, and, as appropriate, attendant risk estimations, can provide more substantive information for the individual patient for both clinical and research applications and can yield more expansive information on dose profiles across patient populations within a practice. © RSNA, 2013 PMID:24126364

TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, V; Epelman, M; Feng, M

2014-06-15

Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUDmore » (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01-CA132834.« less

Proof of concept and dose estimation with binary responses under model uncertainty.

PubMed

Klingenberg, B

2009-01-30

This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.

User Guide for GoldSim Model to Calculate PA/CA Doses and Limits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, F.

2016-10-31

A model to calculate doses for solid waste disposal at the Savannah River Site (SRS) and corresponding disposal limits has been developed using the GoldSim commercial software. The model implements the dose calculations documented in SRNL-STI-2015-00056, Rev. 0 “Dose Calculation Methodology and Data for Solid Waste Performance Assessment (PA) and Composite Analysis (CA) at the Savannah River Site”.

Quality assurance of HDR prostate plans: program implementation at a community hospital.

PubMed

Rush, Jennifer B; Thomas, Michael D

2005-01-01

Adenocarcinoma of the prostate is currently the most commonly diagnosed cancer in men in the United States, and the second leading cause of cancer mortality. The utilization of radiation therapy is regarded as the definitive local therapy of choice for intermediate- and high-risk disease, in which there is increased risk for extracapsular extension, seminal vesicle invasion, or regional node involvement. High-dose-rate (HDR) brachytherapy is a logical treatment modality to deliver the boost dose to an external beam radiation therapy (EBRT) treatment to increase local control rates. From a treatment perspective, the utilization of a complicated treatment delivery system, the compressed time frame in which the procedure is performed, and the small number of large dose fractions make the implementation of a comprehensive quality assurance (QA) program imperative. One aspect of this program is the QA of the HDR treatment plan. Review of regulatory and medical physics professional publications shows that substantial general guidance is available. We provide some insight to the implementation of an HDR prostate plan program at a community hospital. One aspect addressed is the utilization of the low-dose-rate (LDR) planning system and the use of existing ultrasound image sets to familiarize the radiation therapy team with respect to acceptable HDR implant geometries. Additionally, the use of the LDR treatment planning system provided a means to prospectively determine the relationship between the treated isodose volume and the product of activity and time for the department's planning protocol prior to the first HDR implant. For the first 12 HDR prostate implants, the root-mean-square (RMS) deviation was 3.05% between the predicted product of activity and time vs. the actual plan values. Retrospective re-evaluation of the actual implant data reduced the RMS deviation to 2.36%.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde- known as Lyral: quantitative aspects and risk assessment of an important fragrance allergen.

PubMed

Johansen, J D; Frosch, P J; Svedman, C; Andersen, K E; Bruze, M; Pirker, C; Menné, T

2003-06-01

Hydroxyisohexyl 3-cyclohexene carboxaldehyde, also known as Lyral, is a fragrance ingredient identified as the cause of contact allergic reactions in 2-3% of eczema patients undergoing patch testing. Lyral has been included in the standard patch test series in many clinics due to its importance as an allergen. It has been used without restrictions in cosmetic products, until now. In the present study, the dose-response relationship of Lyral contact allergy was studied with doses relevant for normal exposure in cosmetic products. 18 eczema patients, who previously had given a positive patch test to Lyral 5% petrolatum, were included along with 7 control subjects. All cases were tested with a serial dilution of Lyral in ethanol 6% to 6 p.p.m and subjected to a 2-week, repeated open application test with a low dose of Lyral in ethanol. In the case of no reaction, this was followed by another 2 weeks of testing with a higher dose. The test was performed at the volar aspect of the forearm. In 16 of 18 cases (89%), a positive use test developed, 11 reacting to the low and 5 to the high concentration. None reacted to the vehicle control of ethanol applied to the contralateral arm. All controls were negative to both the test solutions of Lyral and the ethanol control. The difference between the test and the control group was statistically significant (Fisher's test, P < 0.001). It is concluded that Lyral at the current usage levels is inducing sensitization in the community. The same levels were shown to elicit allergic contact dermatitis in almost all sensitized individuals. A significant reduction in usage concentrations is recommended to prevent contact allergic reactions.

QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single-Hit Dose-Response Models.

PubMed

Nilsen, Vegard; Wyller, John

2016-01-01

Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson-distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional "single-hit" dose-response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose-response models in terms of probability generating functions. It is shown formally that the theoretical single-hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single-hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single-hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose-response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose-response assessment as well as practical risk characterization are discussed. © 2016 Society for Risk Analysis.

Treatment of Hailey-Hailey Disease With Low-Dose Naltrexone.

PubMed

Albers, Lauren N; Arbiser, Jack L; Feldman, Ron J

2017-10-01

Hailey-Hailey disease is a severe genetic blistering disease of intertriginous skin locations that can lead to poor quality of life and increased morbidities. Multiple therapies are available with inconsistent outcomes and potentially severe adverse effects. To determine whether low-dose naltrexone is an effective treatment for Hailey-Hailey disease. This study was a case series performed at a dermatology outpatient clinic of 3 patients with severe Hailey-Hailey disease recalcitrant to at least 4 therapies. Low-dose naltrexone, 3 mg nightly, titrated to 4.5 mg nightly in 2 patients. Reduction in size of lesions as well as subjective improvement of symptoms. All 3 patients noted significant healing of erosions and plaques starting from the peripheral aspect within 1 to 2 weeks of treatment, and clinical resolution of lesions within 2 months. Discontinuation of low-dose naltrexone resulted in flaring of symptoms, which cleared within 2 to 3 days on rechallenge with low-dose naltrexone. We present herein 3 cases of patients with severe Hailey-Hailey disease treated with low-dose naltrexone who achieved clinical resolution of symptoms. The success of these cases suggests low-dose naltrexone as a novel therapy for Hailey-Hailey disease. The possible mechanism may involve low-dose naltrexone influencing opioid or toll-like receptor signaling to improve calcium mobilization and improve keratinocyte differentiation and wound healing. Future studies are needed to clarify the mechanism and to define the role of low-dose naltrexone for treatment of Hailey-Hailey disease.

Comparison of three light doses in the photodynamic treatment of actinic keratosis using mathematical modeling

NASA Astrophysics Data System (ADS)

Vignion-Dewalle, Anne-Sophie; Betrouni, Nacim; Tylcz, Jean-Baptiste; Vermandel, Maximilien; Mortier, Laurent; Mordon, Serge

2015-05-01

Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for cancer therapy. Although high efficacy is demonstrated for PDT using standardized protocols in nonhyperkeratotic actinic keratoses, alternative light doses expected to increase efficiency, to reduce adverse effects or to expand the use of PDT, are still being evaluated and refined. We propose a comparison of the three most common light doses in the treatment of actinic keratosis with 5-aminolevulinic acid PDT through mathematical modeling. The proposed model is based on an iterative procedure that involves determination of the local fluence rate, updating of the local optical properties, and estimation of the local damage induced by the therapy. This model was applied on a simplified skin sample model including an actinic keratosis lesion, with three different light doses (red light dose, 37 J/cm2, 75 mW/cm2, 500 s blue light dose, 10 J/cm2, 10 mW/cm2, 1000 s and daylight dose, 9000 s). Results analysis shows that the three studied light doses, although all efficient, lead to variable local damage. Defining reference damage enables the nonoptimal parameters for the current light doses to be refined and the treatment to be more suitable.

NAIRAS aircraft radiation model development, dose climatology, and initial validation.

PubMed

Mertens, Christopher J; Meier, Matthias M; Brown, Steven; Norman, Ryan B; Xu, Xiaojing

2013-10-01

[1] The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a real-time, global, physics-based model used to assess radiation exposure to commercial aircrews and passengers. The model is a free-running physics-based model in the sense that there are no adjustment factors applied to nudge the model into agreement with measurements. The model predicts dosimetric quantities in the atmosphere from both galactic cosmic rays (GCR) and solar energetic particles, including the response of the geomagnetic field to interplanetary dynamical processes and its subsequent influence on atmospheric dose. The focus of this paper is on atmospheric GCR exposure during geomagnetically quiet conditions, with three main objectives. First, provide detailed descriptions of the NAIRAS GCR transport and dosimetry methodologies. Second, present a climatology of effective dose and ambient dose equivalent rates at typical commercial airline altitudes representative of solar cycle maximum and solar cycle minimum conditions and spanning the full range of geomagnetic cutoff rigidities. Third, conduct an initial validation of the NAIRAS model by comparing predictions of ambient dose equivalent rates with tabulated reference measurement data and recent aircraft radiation measurements taken in 2008 during the minimum between solar cycle 23 and solar cycle 24. By applying the criterion of the International Commission on Radiation Units and Measurements (ICRU) on acceptable levels of aircraft radiation dose uncertainty for ambient dose equivalent greater than or equal to an annual dose of 1 mSv, the NAIRAS model is within 25% of the measured data, which fall within the ICRU acceptable uncertainty limit of 30%. The NAIRAS model predictions of ambient dose equivalent rate are generally within 50% of the measured data for any single-point comparison. The largest differences occur at low latitudes and high cutoffs, where the radiation dose level is low. Nevertheless, analysis suggests that these single-point differences will be within 30% when a new deterministic pion-initiated electromagnetic cascade code is integrated into NAIRAS, an effort which is currently underway.

NAIRAS aircraft radiation model development, dose climatology, and initial validation

NASA Astrophysics Data System (ADS)

Mertens, Christopher J.; Meier, Matthias M.; Brown, Steven; Norman, Ryan B.; Xu, Xiaojing

2013-10-01

The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a real-time, global, physics-based model used to assess radiation exposure to commercial aircrews and passengers. The model is a free-running physics-based model in the sense that there are no adjustment factors applied to nudge the model into agreement with measurements. The model predicts dosimetric quantities in the atmosphere from both galactic cosmic rays (GCR) and solar energetic particles, including the response of the geomagnetic field to interplanetary dynamical processes and its subsequent influence on atmospheric dose. The focus of this paper is on atmospheric GCR exposure during geomagnetically quiet conditions, with three main objectives. First, provide detailed descriptions of the NAIRAS GCR transport and dosimetry methodologies. Second, present a climatology of effective dose and ambient dose equivalent rates at typical commercial airline altitudes representative of solar cycle maximum and solar cycle minimum conditions and spanning the full range of geomagnetic cutoff rigidities. Third, conduct an initial validation of the NAIRAS model by comparing predictions of ambient dose equivalent rates with tabulated reference measurement data and recent aircraft radiation measurements taken in 2008 during the minimum between solar cycle 23 and solar cycle 24. By applying the criterion of the International Commission on Radiation Units and Measurements (ICRU) on acceptable levels of aircraft radiation dose uncertainty for ambient dose equivalent greater than or equal to an annual dose of 1 mSv, the NAIRAS model is within 25% of the measured data, which fall within the ICRU acceptable uncertainty limit of 30%. The NAIRAS model predictions of ambient dose equivalent rate are generally within 50% of the measured data for any single-point comparison. The largest differences occur at low latitudes and high cutoffs, where the radiation dose level is low. Nevertheless, analysis suggests that these single-point differences will be within 30% when a new deterministic pion-initiated electromagnetic cascade code is integrated into NAIRAS, an effort which is currently underway.

NAIRAS aircraft radiation model development, dose climatology, and initial validation

PubMed Central

Mertens, Christopher J; Meier, Matthias M; Brown, Steven; Norman, Ryan B; Xu, Xiaojing

2013-01-01

[1] The Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) is a real-time, global, physics-based model used to assess radiation exposure to commercial aircrews and passengers. The model is a free-running physics-based model in the sense that there are no adjustment factors applied to nudge the model into agreement with measurements. The model predicts dosimetric quantities in the atmosphere from both galactic cosmic rays (GCR) and solar energetic particles, including the response of the geomagnetic field to interplanetary dynamical processes and its subsequent influence on atmospheric dose. The focus of this paper is on atmospheric GCR exposure during geomagnetically quiet conditions, with three main objectives. First, provide detailed descriptions of the NAIRAS GCR transport and dosimetry methodologies. Second, present a climatology of effective dose and ambient dose equivalent rates at typical commercial airline altitudes representative of solar cycle maximum and solar cycle minimum conditions and spanning the full range of geomagnetic cutoff rigidities. Third, conduct an initial validation of the NAIRAS model by comparing predictions of ambient dose equivalent rates with tabulated reference measurement data and recent aircraft radiation measurements taken in 2008 during the minimum between solar cycle 23 and solar cycle 24. By applying the criterion of the International Commission on Radiation Units and Measurements (ICRU) on acceptable levels of aircraft radiation dose uncertainty for ambient dose equivalent greater than or equal to an annual dose of 1 mSv, the NAIRAS model is within 25% of the measured data, which fall within the ICRU acceptable uncertainty limit of 30%. The NAIRAS model predictions of ambient dose equivalent rate are generally within 50% of the measured data for any single-point comparison. The largest differences occur at low latitudes and high cutoffs, where the radiation dose level is low. Nevertheless, analysis suggests that these single-point differences will be within 30% when a new deterministic pion-initiated electromagnetic cascade code is integrated into NAIRAS, an effort which is currently underway. PMID:26213513

Modeling late rectal toxicities based on a parameterized representation of the 3D dose distribution

NASA Astrophysics Data System (ADS)

Buettner, Florian; Gulliford, Sarah L.; Webb, Steve; Partridge, Mike

2011-04-01

Many models exist for predicting toxicities based on dose-volume histograms (DVHs) or dose-surface histograms (DSHs). This approach has several drawbacks as firstly the reduction of the dose distribution to a histogram results in the loss of spatial information and secondly the bins of the histograms are highly correlated with each other. Furthermore, some of the complex nonlinear models proposed in the past lack a direct physical interpretation and the ability to predict probabilities rather than binary outcomes. We propose a parameterized representation of the 3D distribution of the dose to the rectal wall which explicitly includes geometrical information in the form of the eccentricity of the dose distribution as well as its lateral and longitudinal extent. We use a nonlinear kernel-based probabilistic model to predict late rectal toxicity based on the parameterized dose distribution and assessed its predictive power using data from the MRC RT01 trial (ISCTRN 47772397). The endpoints under consideration were rectal bleeding, loose stools, and a global toxicity score. We extract simple rules identifying 3D dose patterns related to a specifically low risk of complication. Normal tissue complication probability (NTCP) models based on parameterized representations of geometrical and volumetric measures resulted in areas under the curve (AUCs) of 0.66, 0.63 and 0.67 for predicting rectal bleeding, loose stools and global toxicity, respectively. In comparison, NTCP models based on standard DVHs performed worse and resulted in AUCs of 0.59 for all three endpoints. In conclusion, we have presented low-dimensional, interpretable and nonlinear NTCP models based on the parameterized representation of the dose to the rectal wall. These models had a higher predictive power than models based on standard DVHs and their low dimensionality allowed for the identification of 3D dose patterns related to a low risk of complication.

Temporal changes in biological responses and uncertainty in assessing risks of endocrine-disrupting chemicals: Insights from intensive time-course studies with fish

EPA Science Inventory

Most toxicological testing focuses on defining concentration/dose-response relationships, with little consideration given to temporal aspects of the expression of chemical effects. Yet, both variablesdose and timeare critical to robust evaluations of potential risks. Over the p...

Challenges and requirements of mask data processing for multi-beam mask writer

NASA Astrophysics Data System (ADS)

Choi, Jin; Lee, Dong Hyun; Park, Sinjeung; Lee, SookHyun; Tamamushi, Shuichi; Shin, In Kyun; Jeon, Chan Uk

2015-07-01

To overcome the resolution and throughput of current mask writer for advanced lithography technologies, the platform of e-beam writer have been evolved by the developments of hardware and software in writer. Especially, aggressive optical proximity correction (OPC) for unprecedented extension of optical lithography and the needs of low sensitivity resist for high resolution result in the limit of variable shaped beam writer which is widely used for mass production. The multi-beam mask writer is attractive candidate for photomask writing of sub-10nm device because of its high speed and the large degree of freedom which enable high dose and dose modulation for each pixel. However, the higher dose and almost unlimited appetite for dose modulation challenge the mask data processing (MDP) in aspects of extreme data volume and correction method. Here, we discuss the requirements of mask data processing for multi-beam mask writer and presents new challenges of the data format, data flow, and correction method for user and supplier MDP tool.

Experimental eczema. 12 effects of x-rays in experimental eczema (combined injury) (in French)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adatto, R.

1961-01-01

Contact dermatitis was induced in guinea pig nipples by local application of 2,4-dinitrochlorobenzene after previous sensitization. No effect of x irradiation on the histologic aspects of the developing dermatitis could be detected when doses of 800 or 1600 r were given 2 to 16 days after sensitization or repeated 100-r doses were given. Although a 800-r dose had no detectable effect on epithelium, it was found to alter the eczematous reaction when given 72 hr before the eliciting application of dinitrocitlorobenzene in sensitized animals. Eczematous epithelium in irradiated skin showed swelling of cells, indistinct cell boundaries, diminished numbers of nuclei,more » and fewer mitoses blocked by colchicine; none of these changes was produced by eczema alone. The changes in epidermis induced by irradiation with 800 r before eliciting eczema resembled those produced by much higher x-ray doses (2400 r), indicating that eczema augments the cellular changes induced by irradiation.« less

SOME ASPECTS OF THE ACETYL CHOLINE METABOLISM SHORTLY AFTER EXPOSURE TO A SUBLETHAL DOSE OF $gamma$-RAYS (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Demin, N.N.; Korneeva, N.V.

1962-01-01

Following up previous findings (Radiobiologiya 1: 761 (1961)) that exposure of rats to gamma rays at a dose of 800 r affects the animals' acetyl choline metabolism, similar exposure tests were carried out at sublethal doses. After exposing the white rats weighing 180 to 200 g to a dose of 100 r from a Co/ sup 60/ source, groups of them were killed at the end periods ranging from 10 minutes to 24 hours. Comparison of the acetyl choline content in the brain, liver, and the small intestine of the test and the control animals, it was found that themore » short, 13-sec exposure to the 460 r/min source caused noticeable changes even after 10 minutes in the free and bound acetyl chollne concentration, the activity of the acetyl choline esterase and of the nonspecific choline esterase in the tested tissues. These changes are probably due to compensating reactions of the organism. (TTT)« less

A carcinogenic potency database of the standardized results of animal bioassays

PubMed Central

Gold, Lois Swirsky; Sawyer, Charles B.; Magaw, Renae; Backman, Georganne M.; De Veciana, Margarita; Levinson, Robert; Hooper, N. Kim; Havender, William R.; Bernstein, Leslie; Peto, Richard; Pike, Malcolm C.; Ames, Bruce N.

1984-01-01

The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold. PMID:6525996

Development of the Updated Environmental Protection Agency Manual of Protective Action Guides (PAGS) and Protective Actions for Nuclear Incidents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carter, L.M.

2008-07-01

As a student intern with the United States Environmental Protection Agency (EPA) Headquarters, the author was trained in the National Response Plan (NRP) and assisted in the editing of the new (unpublished) EPA Protective Action Guides (PAGs) [1] which has been revised in light of the perceived post 9/11 potential for 'Dirty Bomb' and 'Improvised Nuclear Device' attacks on civilian areas. Technical aspects and the public policy aspects of developing the new guides are discussed. Early Phase initial responses discussed include: Notification of state and/or local authorities, immediate evacuation/sheltering prior to release information or measurements, monitoring of releases and exposuremore » rate measurements, estimation of dose consequences, implementation of protective actions in other areas. The new PAG clarifies the use of 1992 PAGs [2] for incidents other than nuclear power plant accidents, lowers projected thyroid dose for potassium iodine (KI), provides drinking water guidance, includes guidance for long-term site restoration, and updates dosimetry from ICRP 26 to ICRP 60. (authors)« less

Recent Advancement and Technological Aspects of Pulsatile Drug Delivery System - A Laconic Review.

PubMed

Pandit, Vinay; Kumar, Ajay; Ashawat, Mahendra S; Verma, Chander P; Kumar, Pravin

2017-01-01

Pulsatile drug delivery system (PDDS) shows potential significance in the field of drug delivery to release the maximum amount of drug at a definite site and at specific time. PDDS are mainly time controlled delivery devices having a definite pause period for drug release, which is not affected by acidity, alkalinity, motility and enzymes present in the gastrointestinal tract. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. The review article, discuss the general concepts, marketed formulations and patents or any other recent advancement in pulsatile release technology. It also highlights on diseases requiring therapy by pulsatile release, various researches on herbal pulsatile formulations and quality control aspects of PDDS. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparison of organ dose and dose equivalent using ray tracing of male and female Voxel phantoms to space flight phantom torso data

NASA Astrophysics Data System (ADS)

Kim, Myung-Hee; Qualls, Garry; Slaba, Tony; Cucinotta, Francis A.

Phantom torso experiments have been flown on the space shuttle and International Space Station (ISS) providing validation data for radiation transport models of organ dose and dose equivalents. We describe results for space radiation organ doses using a new human geometry model based on detailed Voxel phantoms models denoted for males and females as MAX (Male Adult voXel) and Fax (Female Adult voXel), respectively. These models represent the human body with much higher fidelity than the CAMERA model currently used at NASA. The MAX and FAX models were implemented for the evaluation of directional body shielding mass for over 1500 target points of major organs. Radiation exposure to solar particle events (SPE), trapped protons, and galactic cosmic rays (GCR) were assessed at each specific site in the human body by coupling space radiation transport models with the detailed body shielding mass of MAX/FAX phantom. The development of multiple-point body-shielding distributions at each organ site made it possible to estimate the mean and variance of space dose equivalents at the specific organ. For the estimate of doses to the blood forming organs (BFOs), active marrow distributions in adult were accounted at bone marrow sites over the human body. We compared the current model results to space shuttle and ISS phantom torso experiments and to calculations using the CAMERA model.

Comparison of Organ Dose and Dose Equivalent Using Ray Tracing of Male and Female Voxel Phantoms to Space Flight Phantom Torso Data

NASA Technical Reports Server (NTRS)

Kim, Myung-Hee Y.; Qualls, Garry D.; Cucinotta, Francis A.

2008-01-01

Phantom torso experiments have been flown on the space shuttle and International Space Station (ISS) providing validation data for radiation transport models of organ dose and dose equivalents. We describe results for space radiation organ doses using a new human geometry model based on detailed Voxel phantoms models denoted for males and females as MAX (Male Adult voXel) and Fax (Female Adult voXel), respectively. These models represent the human body with much higher fidelity than the CAMERA model currently used at NASA. The MAX and FAX models were implemented for the evaluation of directional body shielding mass for over 1500 target points of major organs. Radiation exposure to solar particle events (SPE), trapped protons, and galactic cosmic rays (GCR) were assessed at each specific site in the human body by coupling space radiation transport models with the detailed body shielding mass of MAX/FAX phantom. The development of multiple-point body-shielding distributions at each organ site made it possible to estimate the mean and variance of space dose equivalents at the specific organ. For the estimate of doses to the blood forming organs (BFOs), active marrow distributions in adult were accounted at bone marrow sites over the human body. We compared the current model results to space shuttle and ISS phantom torso experiments and to calculations using the CAMERA model.

Optimal mapping of terrestrial gamma dose rates using geological parent material and aerogeophysical survey data.

PubMed

Rawlins, B G; Scheib, C; Tyler, A N; Beamish, D

2012-12-01

Regulatory authorities need ways to estimate natural terrestrial gamma radiation dose rates (nGy h⁻¹) across the landscape accurately, to assess its potential deleterious health effects. The primary method for estimating outdoor dose rate is to use an in situ detector supported 1 m above the ground, but such measurements are costly and cannot capture the landscape-scale variation in dose rates which are associated with changes in soil and parent material mineralogy. We investigate the potential for improving estimates of terrestrial gamma dose rates across Northern Ireland (13,542 km²) using measurements from 168 sites and two sources of ancillary data: (i) a map based on a simplified classification of soil parent material, and (ii) dose estimates from a national-scale, airborne radiometric survey. We used the linear mixed modelling framework in which the two ancillary variables were included in separate models as fixed effects, plus a correlation structure which captures the spatially correlated variance component. We used a cross-validation procedure to determine the magnitude of the prediction errors for the different models. We removed a random subset of 10 terrestrial measurements and formed the model from the remainder (n = 158), and then used the model to predict values at the other 10 sites. We repeated this procedure 50 times. The measurements of terrestrial dose vary between 1 and 103 (nGy h⁻¹). The median absolute model prediction errors (nGy h⁻¹) for the three models declined in the following order: no ancillary data (10.8) > simple geological classification (8.3) > airborne radiometric dose (5.4) as a single fixed effect. Estimates of airborne radiometric gamma dose rate can significantly improve the spatial prediction of terrestrial dose rate.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function.

PubMed

Katsube, Takayuki; Wajima, Toshihiro; Ishibashi, Toru; Arjona Ferreira, Juan Camilo; Echols, Roger

2017-01-01

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (T f >MIC ) for an MIC range of 0.25 to 16 μg/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided >90% PTA for 75% T f >MIC for an MIC of ≤4 μg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect. Copyright © 2016 American Society for Microbiology.

Changes in Liver Metabolic Gene Expression after Radiation Exposure

NASA Technical Reports Server (NTRS)

Peters, C. P.; Wotring, Virginia E.

2012-01-01

The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments.

Harnessing the theoretical foundations of the exponential and beta-Poisson dose-response models to quantify parameter uncertainty using Markov Chain Monte Carlo.

PubMed

Schmidt, Philip J; Pintar, Katarina D M; Fazil, Aamir M; Topp, Edward

2013-09-01

Dose-response models are the essential link between exposure assessment and computed risk values in quantitative microbial risk assessment, yet the uncertainty that is inherent to computed risks because the dose-response model parameters are estimated using limited epidemiological data is rarely quantified. Second-order risk characterization approaches incorporating uncertainty in dose-response model parameters can provide more complete information to decisionmakers by separating variability and uncertainty to quantify the uncertainty in computed risks. Therefore, the objective of this work is to develop procedures to sample from posterior distributions describing uncertainty in the parameters of exponential and beta-Poisson dose-response models using Bayes's theorem and Markov Chain Monte Carlo (in OpenBUGS). The theoretical origins of the beta-Poisson dose-response model are used to identify a decomposed version of the model that enables Bayesian analysis without the need to evaluate Kummer confluent hypergeometric functions. Herein, it is also established that the beta distribution in the beta-Poisson dose-response model cannot address variation among individual pathogens, criteria to validate use of the conventional approximation to the beta-Poisson model are proposed, and simple algorithms to evaluate actual beta-Poisson probabilities of infection are investigated. The developed MCMC procedures are applied to analysis of a case study data set, and it is demonstrated that an important region of the posterior distribution of the beta-Poisson dose-response model parameters is attributable to the absence of low-dose data. This region includes beta-Poisson models for which the conventional approximation is especially invalid and in which many beta distributions have an extreme shape with questionable plausibility. © Her Majesty the Queen in Right of Canada 2013. Reproduced with the permission of the Minister of the Public Health Agency of Canada.

Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses.

PubMed

Harborne, Lyndal R; Sattar, Naveed; Norman, Jane E; Fleming, Richard

2005-08-01

Metformin treatment of women with polycystic ovary syndrome (PCOS) is widespread, as determined by studies with diverse patient populations. No comparative examination of weight changes or metabolite responses to different doses has been reported. The aim of this study was to determine whether different doses of metformin (1500 or 2550 mg/d) would have different effects on body weight, circulating hormones, markers of inflammation, and lipid profiles. The study included prospective cohorts randomized to two doses of metformin. The study was performed at a university teaching hospital with patients from gynecology/endocrinology clinics. The patients studied were obese (body mass index, 30 to <37 kg/m2; n = 42) and morbidly obese (body mass index, > or =37 kg/m2; n = 41) women with PCOS. Patients were randomized to two doses of metformin, and parameters were assessed after 4 and 8 months. The main outcome measures were changes in body mass, circulating hormones, markers of inflammation, and lipid profiles. Intention to treat analyses showed significant weight loss in both dose groups. Only the obese subgroup showed a dose relationship (1.5 and 3.6 kg in 1500- and 2550-mg groups, respectively; P = 0.04). The morbidly obese group showed similar reductions (3.9 and 3.8 kg) in both groups. Suppression of androstenedione was significant with both metformin doses, but there was no clear dose relationship. Generally, beneficial changes in lipid profiles were not related to dose. Weight loss is a feature of protracted metformin therapy in obese women with PCOS, with greater weight reduction potentially achievable with higher doses. Additional studies are required to determine whether other aspects of the disorder may benefit from the higher dose of metformin.

Normal tissue complication probability modeling of radiation-induced hypothyroidism after head-and-neck radiation therapy.

PubMed

Bakhshandeh, Mohsen; Hashemi, Bijan; Mahdavi, Seied Rabi Mehdi; Nikoofar, Alireza; Vasheghani, Maryam; Kazemnejad, Anoshirvan

2013-02-01

To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with α/β = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D(50) estimated from the models was approximately 44 Gy. The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication. Copyright © 2013 Elsevier Inc. All rights reserved.

Model Uncertainty and Bayesian Model Averaged Benchmark Dose Estimation for Continuous Data

EPA Science Inventory

The benchmark dose (BMD) approach has gained acceptance as a valuable risk assessment tool, but risk assessors still face significant challenges associated with selecting an appropriate BMD/BMDL estimate from the results of a set of acceptable dose-response models. Current approa...

POPULATION EXPOSURE AND DOSE MODEL FOR AIR TOXICS: A BENZENE CASE STUDY

EPA Science Inventory

The EPA's National Exposure Research Laboratory (NERL) is developing a human exposure and dose model called the Stochastic Human Exposure and Dose Simulation model for Air Toxics (SHEDS-AirToxics) to characterize population exposure to air toxics in support of the National Air ...

TU-C-18A-01: Models of Risk From Low-Dose Radiation Exposures: What Does the Evidence Say?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bushberg, J; Boreham, D; Ulsh, B

2014-06-15

At dose levels of (approximately) 500 mSv or more, increased cancer incidence and mortality have been clearly demonstrated. However, at the low doses of radiation used in medical imaging, the relationship between dose and cancer risk is not well established. As such, assumptions about the shape of the dose-response curve are made. These assumptions, or risk models, are used to estimate potential long term effects. Common models include 1) the linear non-threshold (LNT) model, 2) threshold models with either a linear or curvilinear dose response above the threshold, and 3) a hormetic model, where the risk is initially decreased belowmore » background levels before increasing. The choice of model used when making radiation risk or protection calculations and decisions can have significant implications on public policy and health care decisions. However, the ongoing debate about which risk model best describes the dose-response relationship at low doses of radiation makes informed decision making difficult. This symposium will review the two fundamental approaches to determining the risk associated with low doses of ionizing radiation, namely radiation epidemiology and radiation biology. The strengths and limitations of each approach will be reviewed, the results of recent studies presented, and the appropriateness of different risk models for various real world scenarios discussed. Examples of well-designed and poorly-designed studies will be provided to assist medical physicists in 1) critically evaluating publications in the field and 2) communicating accurate information to medical professionals, patients, and members of the general public. Equipped with the best information that radiation epidemiology and radiation biology can currently provide, and an understanding of the limitations of such information, individuals and organizations will be able to make more informed decisions regarding questions such as 1) how much shielding to install at medical facilities, 2) at what dose level are risk vs. benefit discussions with patients appropriate, 3) at what dose level should we tell a pregnant woman that the baby’s health risk from a prenatal radiation exposure is “significant”, 4) is informed consent needed for patients undergoing medical imaging, and 5) at what dose level is evacuation appropriate after a radiological accident. Examples of the tremendous impact that choosing different risks models can have on the answers to these types of questions will be given.A moderated panel discussion will allow audience members to pose questions to the faculty members, each of whom is an established expert in his respective discipline. Learning Objectives: Understand the fundamental principles, strengths and limitations of radiation epidemiology and radiation biology for determining the risk from exposures to low doses of ionizing radiation Become familiar with common models of risk used to describe the dose-response relationship at low dose levels Learn to identify strengths and weaknesses in studies designed to measure the effect of low doses of ionizing radiation Understand the implications of different risk models on public policy and health care decisions.« less

Sci—Fri PM: Dosimetry—04: Radiation out-of-field dose in the treatment of pediatric central nervous system malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taddei, P J; Tannous, J; Nabha, R

Children diagnosed with central nervous system (CNS) malignancies often receive radiotherapy, which can cause radiogenic late effects. In order to identify and reduce the risk of these late effects, we must understand the radiation doses that these children receive. Modern treatment planning systems accurately estimate the absorbed dose within the treatment fields but poorly estimate the dose outside them. The purpose of our study was to measure the out-of-field dose for children receiving localized radiotherapy for CNS cancer and apply an analytical model for estimating dose as a function of distance from the field edge. Radiation fields designed for amore » 12-year-old boy treated in our clinic were applied to an anthropomorphic phantom containing more than 200 thermoluminescent dosimeters. A double-Gaussian function of absorbed dose versus distance from the field edge (i.e., 50% isodose line) was applied, and parameters were allowed to vary and were fit to the model by minimizing the root mean square deviation, RMSD. The fitted model accurately predicted the dose from distances of 4 cm to 50 cm (RMSD = 0.54 cGy/Gy), but the model was not useful in estimating dose for distances less than 4 cm because of wide variation in measured dose, and the double-Gaussian model failed by systematically underestimating the dose beyond 50 cm. In conclusion, the double-Gaussian model may be applicable for points at distances from the field edge between 4 cm and 50 cm, where most children's radiosensitive tissues are located, but for points beyond 50 cm, an improvement should be investigated.« less

Straightening Beta: Overdispersion of Lethal Chromosome Aberrations following Radiotherapeutic Doses Leads to Terminal Linearity in the Alpha–Beta Model

PubMed Central

Shuryak, Igor; Loucas, Bradford D.; Cornforth, Michael N.

2017-01-01

Recent technological advances allow precise radiation delivery to tumor targets. As opposed to more conventional radiotherapy—where multiple small fractions are given—in some cases, the preferred course of treatment may involve only a few (or even one) large dose(s) per fraction. Under these conditions, the choice of appropriate radiobiological model complicates the tasks of predicting radiotherapy outcomes and designing new treatment regimens. The most commonly used model for this purpose is the venerable linear-quadratic (LQ) formalism as it applies to cell survival. However, predictions based on the LQ model are frequently at odds with data following very high acute doses. In particular, although the LQ predicts a continuously bending dose–response relationship for the logarithm of cell survival, empirical evidence over the high-dose region suggests that the survival response is instead log-linear with dose. Here, we show that the distribution of lethal chromosomal lesions among individual human cells (lymphocytes and fibroblasts) exposed to gamma rays and X rays is somewhat overdispersed, compared with the Poisson distribution. Further, we show that such overdispersion affects the predicted dose response for cell survival (the fraction of cells with zero lethal lesions). This causes the dose response to approximate log-linear behavior at high doses, even when the mean number of lethal lesions per cell is well fitted by the continuously curving LQ model. Accounting for overdispersion of lethal lesions provides a novel, mechanistically based explanation for the observed shapes of cell survival dose responses that, in principle, may offer a tractable and clinically useful approach for modeling the effects of high doses per fraction. PMID:29312888

Estimating radiation dose to organs of patients undergoing conventional and novel multidetector CT exams using Monte Carlo simulations

NASA Astrophysics Data System (ADS)

Angel, Erin

Advances in Computed Tomography (CT) technology have led to an increase in the modality's diagnostic capabilities and therefore its utilization, which has in turn led to an increase in radiation exposure to the patient population. As a result, CT imaging currently constitutes approximately half of the collective exposure to ionizing radiation from medical procedures. In order to understand the radiation risk, it is necessary to estimate the radiation doses absorbed by patients undergoing CT imaging. The most widely accepted risk models are based on radiosensitive organ dose as opposed to whole body dose. In this research, radiosensitive organ dose was estimated using Monte Carlo based simulations incorporating detailed multidetector CT (MDCT) scanner models, specific scan protocols, and using patient models based on accurate patient anatomy and representing a range of patient sizes. Organ dose estimates were estimated for clinical MDCT exam protocols which pose a specific concern for radiosensitive organs or regions. These dose estimates include estimation of fetal dose for pregnant patients undergoing abdomen pelvis CT exams or undergoing exams to diagnose pulmonary embolism and venous thromboembolism. Breast and lung dose were estimated for patients undergoing coronary CTA imaging, conventional fixed tube current chest CT, and conventional tube current modulated (TCM) chest CT exams. The correlation of organ dose with patient size was quantified for pregnant patients undergoing abdomen/pelvis exams and for all breast and lung dose estimates presented. Novel dose reduction techniques were developed that incorporate organ location and are specifically designed to reduce close to radiosensitive organs during CT acquisition. A generalizable model was created for simulating conventional and novel attenuation-based TCM algorithms which can be used in simulations estimating organ dose for any patient model. The generalizable model is a significant contribution of this work as it lays the foundation for the future of simulating TCM using Monte Carlo methods. As a result of this research organ dose can be estimated for individual patients undergoing specific conventional MDCT exams. This research also brings understanding to conventional and novel close reduction techniques in CT and their effect on organ dose.

WE-AB-207B-06: Dose and Biological Uncertainties in Sarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marteinsdottir, M; University of Iceland, Reykjavik; Schuemann, J

2016-06-15

Purpose: To understand the clinical impact of key uncertainties in proton therapy potentially affecting the analysis of clinical trials, namely the assumption of using a constant relative biological effectiveness (RBE) of 1.1 compared to variable RBE for proton therapy and the use of analytical dose calculation (ADC) methods. Methods: Proton dose distributions were compared for analytical and Monte Carlo (TOPAS) dose calculations. In addition, differences between using a constant RBE of 1.1 (RBE-constant) were compared with four different RBE models (to assess model variations). 10 patients were selected from an ongoing clinical trial on IMRT versus scanned protons for sarcoma.more » Comparisons were performed using dosimetric indices based on dose-volume histogram analyses and γ-index analyses. Results: For three of the RBE-models the mean dose, D95, D50 and D02 (dose values covering 95%, 50% and 2% of the target volume, respectively) were up to 5% lower than for RBE-constant. The dosimetric indices for one of the RBE-models were around 9% lower than for the RBE-constant model. The differences for V90 (the percentage of the target volume covered by 90% of the prescription dose) were up to 40% for three RBE-models, whereas for one the difference was around 95%. All ADC dosimetric indices were up to 5% larger than for RBE-constant. The γ-index passing rate for the target volume with a 3%/3mm criterion was above 97% for all models except for one, which was below 24%. Conclusion: Interpretation of clinical trials on sarcoma may depend on dose calculation uncertainties (as assessed by Monte Carlo). In addition, the biological dose distribution depends notably on which RBE model is utilized. The current practice of using a constant RBE of 1.1 may overestimate the target dose by as much as 5% for biological dose calculations. Performing an RBE uncertainty analysis is recommended for trial analysis. U19 projects - U19 CA 021239. PI: Delaney.« less

LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models.

PubMed

King, Christopher R

2002-01-01

Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated (192)Ir HDR brachytherapy, and (125)I and (103)Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses (<70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the alpha/beta ratio is low). Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low alpha/beta ratio) as the current evidence suggests.

Modeling the Car Crash Crisis Management System Using HiLA

NASA Astrophysics Data System (ADS)

Hölzl, Matthias; Knapp, Alexander; Zhang, Gefei

An aspect-oriented modeling approach to the Car Crash Crisis Management System (CCCMS) using the High-Level Aspect (HiLA) language is described. HiLA is a language for expressing aspects for UML static structures and UML state machines. In particular, HiLA supports both a static graph transformational and a dynamic approach of applying aspects. Furthermore, it facilitates methodologically turning use case descriptions into state machines: for each main success scenario, a base state machine is developed; all extensions to this main success scenario are covered by aspects. Overall, the static structure of the CCCMS is modeled in 43 classes, the main success scenarios in 13 base machines, the use case extensions in 47 static and 31 dynamic aspects, most of which are instantiations of simple aspect templates.

A comparison of newborn stylized and tomographic models for dose assessment in paediatric radiology

NASA Astrophysics Data System (ADS)

Staton, R. J.; Pazik, F. D.; Nipper, J. C.; Williams, J. L.; Bolch, W. E.

2003-04-01

Establishment of organ doses from diagnostic and interventional examinations is a key component to quantifying the radiation risks from medical exposures and for formulating corresponding dose-reduction strategies. Radiation transport models of human anatomy provide a convenient method for simulating radiological examinations. At present, two classes of models exist: stylized mathematical models and tomographic voxel models. In the present study, organ dose comparisons are made for projection radiographs of both a stylized and a tomographic model of the newborn patient. Sixteen separate radiographs were simulated for each model at x-ray technique factors typical of newborn examinations: chest, abdomen, thorax and head views in the AP, PA, left LAT and right LAT projection orientation. For AP and PA radiographs of the torso (chest, abdomen and thorax views), the effective dose assessed for the tomographic model exceeds that for the stylized model with per cent differences ranging from 19% (AP abdominal view) to 43% AP chest view. In contrast, the effective dose for the stylized model exceeds that for the tomographic model for all eight lateral views including those of the head, with per cent differences ranging from 9% (LLAT chest view) to 51% (RLAT thorax view). While organ positioning differences do exist between the models, a major factor contributing to differences in effective dose is the models' exterior trunk shape. In the tomographic model, a more elliptical shape is seen thus providing for less tissue shielding for internal organs in the AP and PA directions, with corresponding increased tissue shielding in the lateral directions. This observation is opposite of that seen in comparisons of stylized and tomographic models of the adult.

Trace element supplementation in the biogas production from wheat stillage--optimization of metal dosing.

PubMed

Schmidt, Thomas; Nelles, Michael; Scholwin, Frank; Pröter, Jürgen

2014-09-01

A trace element dosing strategy for the anaerobic digestion of wheat stillage was developed in this study. Mesophilic CSTR reactors were operated with the sulfuric substrate wheat stillage in some cases under trace element deficiency. After supplementing trace elements during the start-up, one of the elements of Fe, Ni, Co, Mo, and W were depleted in one digester while still augmenting the other elements to determine minimum requirements for each element. The depletion of Fe and Ni resulted in a rapid accumulation of volatile fatty acids while Co and W seem to have a long-term effect. Based on the results it was possible to reduce the dosing of trace elements, which is positive with reference to economic and environmental aspects. Copyright © 2014 Elsevier Ltd. All rights reserved.

Deep Bleeder Acoustic Coagulation (DBAC)-part II: in vivo testing of a research prototype system.

PubMed

Sekins, K Michael; Barnes, Stephen R; Fan, Liexiang; Hopple, Jerry D; Hsu, Stephen J; Kook, John; Lee, Chi-Yin; Maleke, Caroline; Zeng, Xiaozheng Jenny; Moreau-Gobard, Romain; Ahiekpor-Dravi, Alexis; Funka-Lea, Gareth; Eaton, John; Wong, Keith; Keneman, Scott; Mitchell, Stuart B; Dunmire, Barbrina; Kucewicz, John C; Clubb, Fred J; Miller, Matthew W; Crum, Lawrence A

2015-01-01

Deep Bleeder Acoustic Coagulation (DBAC) is an ultrasound image-guided high-intensity focused ultrasound (HIFU) method proposed to automatically detect and localize (D&L) and treat deep, bleeding, combat wounds in the limbs of soldiers. A prototype DBAC system consisting of an applicator and control unit was developed for testing on animals. To enhance control, and thus safety, of the ultimate human DBAC autonomous product system, a thermal coagulation strategy that minimized cavitation, boiling, and non-linear behaviors was used. The in vivo DBAC applicator design had four therapy tiles (Tx) and two 3D (volume) imaging probes (Ix) and was configured to be compatible with a porcine limb bleeder model developed in this research. The DBAC applicator was evaluated under quantitative test conditions (e.g., bleeder depths, flow rates, treatment time limits, and dose exposure time limits) in an in vivo study (final exam) comprising 12 bleeder treatments in three swine. To quantify blood flow rates, the "bleeder" targets were intact arterial branches, i.e., the superficial femoral artery (SFA) and a deep femoral artery (DFA). D&L identified, characterized, and targeted bleeders. The therapy sequence selected Tx arrays and determined the acoustic power and Tx beam steering, focus, and scan patterns. The user interface commands consisted of two buttons: "Start D&L" and "Start Therapy." Targeting accuracy was assessed by necropsy and histologic exams and efficacy (vessel coagulative occlusion) by angiography and histology. The D&L process (Part I article, J Ther Ultrasound, 2015 (this issue)) executed fully in all cases in under 5 min and targeting evaluation showed 11 of 12 thermal lesions centered on the correct vessel subsection, with minimal damage to adjacent structures. The automated therapy sequence also executed properly, with select manual steps. Because the dose exposure time limit (t dose ≤ 30 s) was associated with nonefficacious treatment, 60-s dosing and dual-dosing was also pursued. Thrombogenic evidence (blood clotting) and collagen denaturation (vessel shrinkage) were found in necropsy and histologically in all targeted SFAs. Acute SFA reductions in blood flow (20-30 %) were achieved in one subject, and one partial and one complete vessel occlusion were confirmed angiographically. The complete occlusion case was achieved with a dual dose (90 s total exposure) with focal intensity ≈500 W/cm(2) (spatial average, temporal average). While not meeting all in vivo objectives, the overall performance of the DBAC applicator was positive. In particular, D&L automation workflow was verified during each of the tests, with processing times well under specified (10 min) limits, and all bleeder branches were detected and localized. Further, gross necropsy and tissue examination confirmed that the HIFU thermal lesions were coincident with the target vessel locations in over 90 % of the multi-array dosing treatments. The SFA/DFA bleeder models selected, and the protocols used, were the most suitable practical model options for the given DBAC anatomical and bleeder requirements. The animal models were imperfect in some challenging aspects, including requiring tissue-mimicking material (TMM) standoffs to achieve deep target depths, thereby introducing device-tissue motion, with resultant imaging artifacts. The model "bleeders" involved intact vessels, which are subject to less efficient heating and coagulation cascade behaviors than true puncture injuries.

Convolution-based estimation of organ dose in tube current modulated CT

NASA Astrophysics Data System (ADS)

Tian, Xiaoyu; Segars, W. Paul; Dixon, Robert L.; Samei, Ehsan

2016-05-01

Estimating organ dose for clinical patients requires accurate modeling of the patient anatomy and the dose field of the CT exam. The modeling of patient anatomy can be achieved using a library of representative computational phantoms (Samei et al 2014 Pediatr. Radiol. 44 460-7). The modeling of the dose field can be challenging for CT exams performed with a tube current modulation (TCM) technique. The purpose of this work was to effectively model the dose field for TCM exams using a convolution-based method. A framework was further proposed for prospective and retrospective organ dose estimation in clinical practice. The study included 60 adult patients (age range: 18-70 years, weight range: 60-180 kg). Patient-specific computational phantoms were generated based on patient CT image datasets. A previously validated Monte Carlo simulation program was used to model a clinical CT scanner (SOMATOM Definition Flash, Siemens Healthcare, Forchheim, Germany). A practical strategy was developed to achieve real-time organ dose estimation for a given clinical patient. CTDIvol-normalized organ dose coefficients ({{h}\\text{Organ}} ) under constant tube current were estimated and modeled as a function of patient size. Each clinical patient in the library was optimally matched to another computational phantom to obtain a representation of organ location/distribution. The patient organ distribution was convolved with a dose distribution profile to generate {{≤ft(\\text{CTD}{{\\text{I}}\\text{vol}}\\right)}\\text{organ, \\text{convolution}}} values that quantified the regional dose field for each organ. The organ dose was estimated by multiplying {{≤ft(\\text{CTD}{{\\text{I}}\\text{vol}}\\right)}\\text{organ, \\text{convolution}}} with the organ dose coefficients ({{h}\\text{Organ}} ). To validate the accuracy of this dose estimation technique, the organ dose of the original clinical patient was estimated using Monte Carlo program with TCM profiles explicitly modeled. The discrepancy between the estimated organ dose and dose simulated using TCM Monte Carlo program was quantified. We further compared the convolution-based organ dose estimation method with two other strategies with different approaches of quantifying the irradiation field. The proposed convolution-based estimation method showed good accuracy with the organ dose simulated using the TCM Monte Carlo simulation. The average percentage error (normalized by CTDIvol) was generally within 10% across all organs and modulation profiles, except for organs located in the pelvic and shoulder regions. This study developed an improved method that accurately quantifies the irradiation field under TCM scans. The results suggested that organ dose could be estimated in real-time both prospectively (with the localizer information only) and retrospectively (with acquired CT data).

Comparison of Data on Mutation Frequencies of Mice Caused by Radiation with Low Dose Model

NASA Astrophysics Data System (ADS)

Manabe, Yuichiro; Bando, Masako

2013-09-01

We propose low dose (LD) model, the extension of LDM model which was proposed in the previous paper [Y. Manabe et al.: J. Phys. Soc. Jpn. 81 (2012) 104004] to estimate biological damage caused by irradiation. LD model takes account of cell death effect in addition to the proliferation, apoptosis, repair which were included in LDM model. As a typical example of estimation, we apply LD model to the experiment of mutation frequency on the responses induced by the exposure to low levels of ionizing radiation. The most famous and extensive experiments are those summarized by Russell and Kelly [Proc. Natl. Acad. Sci. U.S.A. 79 (1982) 539], which are known as ``mega-mouse project''. This provides us with important information of the frequencies of transmitted specific-locus mutations induced in mouse spermatogonia stem-cells. It is found that the numerical results of the mutation frequency of mice are in reasonable agreement with the experimental data: the LD model reproduces the total dose and dose rate dependence of data reasonably. In order to see such dose-rate dependence more explicitly, we introduce the dose-rate effectiveness factor (DREF). This represents a sort of dose rate dependent effect, which are to be competitive with proliferation effect of broken cells induced by irradiation.

Validation of Monte Carlo simulation of mammography with TLD measurement and depth dose calculation with a detailed breast model

NASA Astrophysics Data System (ADS)

Wang, Wenjing; Qiu, Rui; Ren, Li; Liu, Huan; Wu, Zhen; Li, Chunyan; Li, Junli

2017-09-01

Mean glandular dose (MGD) is not only determined by the compressed breast thickness (CBT) and the glandular content, but also by the distribution of glandular tissues in breast. Depth dose inside the breast in mammography has been widely concerned as glandular dose decreases rapidly with increasing depth. In this study, an experiment using thermo luminescent dosimeters (TLDs) was carried out to validate Monte Carlo simulations of mammography. Percent depth doses (PDDs) at different depth values were measured inside simple breast phantoms of different thicknesses. The experimental values were well consistent with the values calculated by Geant4. Then a detailed breast model with a CBT of 4 cm and a glandular content of 50%, which has been constructed in previous work, was used to study the effects of the distribution of glandular tissues in breast with Geant4. The breast model was reversed in direction of compression to get a reverse model with a different distribution of glandular tissues. Depth dose distributions and glandular tissue dose conversion coefficients were calculated. It revealed that the conversion coefficients were about 10% larger when the breast model was reversed, for glandular tissues in the reverse model are concentrated in the upper part of the model.

Using the Monte Carlo method for assessing the tissue and organ doses of patients in dental radiography

NASA Astrophysics Data System (ADS)

Makarevich, K. O.; Minenko, V. F.; Verenich, K. A.; Kuten, S. A.

2016-05-01

This work is dedicated to modeling dental radiographic examinations to assess the absorbed doses of patients and effective doses. For simulating X-ray spectra, the TASMIP empirical model is used. Doses are assessed on the basis of the Monte Carlo method by using MCNP code for voxel phantoms of ICRP. The results of the assessment of doses to individual organs and effective doses for different types of dental examinations and features of X-ray tube are presented.

Configuration and validation of an analytical model predicting secondary neutron radiation in proton therapy using Monte Carlo simulations and experimental measurements.

PubMed

Farah, J; Bonfrate, A; De Marzi, L; De Oliveira, A; Delacroix, S; Martinetti, F; Trompier, F; Clairand, I

2015-05-01

This study focuses on the configuration and validation of an analytical model predicting leakage neutron doses in proton therapy. Using Monte Carlo (MC) calculations, a facility-specific analytical model was built to reproduce out-of-field neutron doses while separately accounting for the contribution of intra-nuclear cascade, evaporation, epithermal and thermal neutrons. This model was first trained to reproduce in-water neutron absorbed doses and in-air neutron ambient dose equivalents, H*(10), calculated using MCNPX. Its capacity in predicting out-of-field doses at any position not involved in the training phase was also checked. The model was next expanded to enable a full 3D mapping of H*(10) inside the treatment room, tested in a clinically relevant configuration and finally consolidated with experimental measurements. Following the literature approach, the work first proved that it is possible to build a facility-specific analytical model that efficiently reproduces in-water neutron doses and in-air H*(10) values with a maximum difference less than 25%. In addition, the analytical model succeeded in predicting out-of-field neutron doses in the lateral and vertical direction. Testing the analytical model in clinical configurations proved the need to separate the contribution of internal and external neutrons. The impact of modulation width on stray neutrons was found to be easily adjustable while beam collimation remains a challenging issue. Finally, the model performance agreed with experimental measurements with satisfactory results considering measurement and simulation uncertainties. Analytical models represent a promising solution that substitutes for time-consuming MC calculations when assessing doses to healthy organs. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Three-Dimensional Radiobiologic Dosimetry: Application of Radiobiologic Modeling to Patient-Specific 3-Dimensional Imaging–Based Internal Dosimetry

PubMed Central

Prideaux, Andrew R.; Song, Hong; Hobbs, Robert F.; He, Bin; Frey, Eric C.; Ladenson, Paul W.; Wahl, Richard L.; Sgouros, George

2010-01-01

Phantom-based and patient-specific imaging-based dosimetry methodologies have traditionally yielded mean organ-absorbed doses or spatial dose distributions over tumors and normal organs. In this work, radiobiologic modeling is introduced to convert the spatial distribution of absorbed dose into biologically effective dose and equivalent uniform dose parameters. The methodology is illustrated using data from a thyroid cancer patient treated with radioiodine. Methods Three registered SPECT/CT scans were used to generate 3-dimensional images of radionuclide kinetics (clearance rate) and cumulated activity. The cumulated activity image and corresponding CT scan were provided as input into an EGSnrc-based Monte Carlo calculation: The cumulated activity image was used to define the distribution of decays, and an attenuation image derived from CT was used to define the corresponding spatial tissue density and composition distribution. The rate images were used to convert the spatial absorbed dose distribution to a biologically effective dose distribution, which was then used to estimate a single equivalent uniform dose for segmented volumes of interest. Equivalent uniform dose was also calculated from the absorbed dose distribution directly. Results We validate the method using simple models; compare the dose-volume histogram with a previously analyzed clinical case; and give the mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for an illustrative case of a pediatric thyroid cancer patient with diffuse lung metastases. The mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for the tumor were 57.7, 58.5, and 25.0 Gy, respectively. Corresponding values for normal lung tissue were 9.5, 9.8, and 8.3 Gy, respectively. Conclusion The analysis demonstrates the impact of radiobiologic modeling on response prediction. The 57% reduction in the equivalent dose value for the tumor reflects a high level of dose nonuniformity in the tumor and a corresponding reduced likelihood of achieving a tumor response. Such analyses are expected to be useful in treatment planning for radionuclide therapy. PMID:17504874

Estimation of the Dose and Dose Rate Effectiveness Factor

NASA Technical Reports Server (NTRS)

Chappell, L.; Cucinotta, F. A.

2013-01-01

Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

Pharmacokinetic-pharmacodynamic modeling of the effect of varenicline on nicotine craving in adult smokers.

PubMed

Ravva, Patanjali; Gastonguay, Marc R; Faessel, Hélène M; Lee, Theodore C; Niaura, Raymond

2015-01-01

Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response "kinetics." Response was described as the net effect of the baseline, placebo, and drug responses. Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4 hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Adeno-Associated Virus-Mediated Correction of a Canine Model of Glycogen Storage Disease Type Ia

PubMed Central

Weinstein, David A.; Correia, Catherine E.; Conlon, Thomas; Specht, Andrew; Verstegen, John; Onclin-Verstegen, Karine; Campbell-Thompson, Martha; Dhaliwal, Gurmeet; Mirian, Layla; Cossette, Holly; Falk, Darin J.; Germain, Sean; Clement, Nathalie; Porvasnik, Stacy; Fiske, Laurie; Struck, Maggie; Ramirez, Harvey E.; Jordan, Juan; Andrutis, Karl; Chou, Janice Y.; Byrne, Barry J.

2010-01-01

Abstract Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is caused by a deficiency in glucose-6-phosphatase-α. Patients with GSDIa are unable to maintain glucose homeostasis and suffer from severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and lactic acidosis. The canine model of GSDIa is naturally occurring and recapitulates almost all aspects of the human form of disease. We investigated the potential of recombinant adeno-associated virus (rAAV) vector-based therapy to treat the canine model of GSDIa. After delivery of a therapeutic rAAV2/8 vector to a 1-day-old GSDIa dog, improvement was noted as early as 2 weeks posttreatment. Correction was transient, however, and by 2 months posttreatment the rAAV2/8-treated dog could no longer sustain normal blood glucose levels after 1 hr of fasting. The same animal was then dosed with a therapeutic rAAV2/1 vector delivered via the portal vein. Two months after rAAV2/1 dosing, both blood glucose and lactate levels were normal at 4 hr postfasting. With more prolonged fasting, the dog still maintained near-normal glucose concentrations, but lactate levels were elevated by 9 hr, indicating that partial correction was achieved. Dietary glucose supplementation was discontinued starting 1 month after rAAV2/1 delivery and the dog continues to thrive with minimal laboratory abnormalities at 23 months of age (18 months after rAAV2/1 treatment). These results demonstrate that delivery of rAAV vectors can mediate significant correction of the GSDIa phenotype and that gene transfer may be a promising alternative therapy for this disease and other genetic diseases of the liver. PMID:20163245

Effect of Qingnao tablet on blood viscosity of rat model of blood stasis induced by epinephrine

NASA Astrophysics Data System (ADS)

Xie, Guoqi; Hao, Shaojun; Ma, Zhenzhen; Liu, Xiaobin; Li, Jun; Li, Wenjun; Zhang, Zhengchen

2018-04-01

To establish a rat model of blood stasis with adrenaline (Adr) subcutaneous injection and ice bath stimulation. The effects of different doses on the blood viscosity of blood stasis model rats were observed. The rats were randomly divided into 6 groups: blank control group (no model), model group, positive control group, high, middle and low dose group. The whole blood viscosity and plasma viscosity were detected by blood viscosity instrument. Compared with the blank group, model group, high shear, low shear whole blood viscosity and plasma viscosity were significantly increased, TT PT significantly shortened, APTT was significantly prolonged, FIB increased significantly, indicating that the model was successful. Compared with the model group, can significantly reduce the Naoluotong group (cut, low cut). Qingnaopian high dose group (low cut), middle dose group (cut, low shear blood viscosity) (P<0.01), Can significantly reduce Naoluotong qingnaopian group, high dose group (P<0.01), plasma viscosity decreased qingnaopian plasma viscosity in low dose group (P<0.05). Conclusion: qingnaopian could improve the blood rheology of blood stasis mice abnormal index, decrease the blood viscosity, blood stasis has certain hemostatic effect.

Requirements Modeling with the Aspect-oriented User Requirements Notation (AoURN): A Case Study

NASA Astrophysics Data System (ADS)

Mussbacher, Gunter; Amyot, Daniel; Araújo, João; Moreira, Ana

The User Requirements Notation (URN) is a recent ITU-T standard that supports requirements engineering activities. The Aspect-oriented URN (AoURN) adds aspect-oriented concepts to URN, creating a unified framework that allows for scenario-based, goal-oriented, and aspect-oriented modeling. AoURN is applied to the car crash crisis management system (CCCMS), modeling its functional and non-functional requirements (NFRs). AoURN generally models all use cases, NFRs, and stakeholders as individual concerns and provides general guidelines for concern identification. AoURN handles interactions between concerns, capturing their dependencies and conflicts as well as the resolutions. We present a qualitative comparison of aspect-oriented techniques for scenario-based and goal-oriented requirements engineering. An evaluation carried out based on the metrics adapted from literature and a task-based evaluation suggest that AoURN models are more scalable than URN models and exhibit better modularity, reusability, and maintainability.

Influence of different dose calculation algorithms on the estimate of NTCP for lung complications

PubMed Central

Bäck, Anna

2013-01-01

Due to limitations and uncertainties in dose calculation algorithms, different algorithms can predict different dose distributions and dose‐volume histograms for the same treatment. This can be a problem when estimating the normal tissue complication probability (NTCP) for patient‐specific dose distributions. Published NTCP model parameters are often derived for a different dose calculation algorithm than the one used to calculate the actual dose distribution. The use of algorithm‐specific NTCP model parameters can prevent errors caused by differences in dose calculation algorithms. The objective of this work was to determine how to change the NTCP model parameters for lung complications derived for a simple correction‐based pencil beam dose calculation algorithm, in order to make them valid for three other common dose calculation algorithms. NTCP was calculated with the relative seriality (RS) and Lyman‐Kutcher‐Burman (LKB) models. The four dose calculation algorithms used were the pencil beam (PB) and collapsed cone (CC) algorithms employed by Oncentra, and the pencil beam convolution (PBC) and anisotropic analytical algorithm (AAA) employed by Eclipse. Original model parameters for lung complications were taken from four published studies on different grades of pneumonitis, and new algorithm‐specific NTCP model parameters were determined. The difference between original and new model parameters was presented in relation to the reported model parameter uncertainties. Three different types of treatments were considered in the study: tangential and locoregional breast cancer treatment and lung cancer treatment. Changing the algorithm without the derivation of new model parameters caused changes in the NTCP value of up to 10 percentage points for the cases studied. Furthermore, the error introduced could be of the same magnitude as the confidence intervals of the calculated NTCP values. The new NTCP model parameters were tabulated as the algorithm was varied from PB to PBC, AAA, or CC. Moving from the PB to the PBC algorithm did not require new model parameters; however, moving from PB to AAA or CC did require a change in the NTCP model parameters, with CC requiring the largest change. It was shown that the new model parameters for a given algorithm are different for the different treatment types. PACS numbers: 87.53.‐j, 87.53.Kn, 87.55.‐x, 87.55.dh, 87.55.kd PMID:24036865

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

PubMed

Dropkin, Greg

2016-11-24

Analyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour. GAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 - 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy. For all solid cancer incidence, RR estimated from 0 - 100 mGy and 0 - 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 - 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort. Non-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.

SU-E-T-226: Correction of a Standard Model-Based Dose Calculator Using Measurement Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, M; Jiang, S; Lu, W

Purpose: To propose a hybrid method that combines advantages of the model-based and measurement-based method for independent dose calculation. Modeled-based dose calculation, such as collapsed-cone-convolution/superposition (CCCS) or the Monte-Carlo method, models dose deposition in the patient body accurately; however, due to lack of detail knowledge about the linear accelerator (LINAC) head, commissioning for an arbitrary machine is tedious and challenging in case of hardware changes. On the contrary, the measurement-based method characterizes the beam property accurately but lacks the capability of dose disposition modeling in heterogeneous media. Methods: We used a standard CCCS calculator, which is commissioned by published data,more » as the standard model calculator. For a given machine, water phantom measurements were acquired. A set of dose distributions were also calculated using the CCCS for the same setup. The difference between the measurements and the CCCS results were tabulated and used as the commissioning data for a measurement based calculator. Here we used a direct-ray-tracing calculator (ΔDRT). The proposed independent dose calculation consists of the following steps: 1. calculate D-model using CCCS. 2. calculate D-ΔDRT using ΔDRT. 3. combine Results: D=D-model+D-ΔDRT. Results: The hybrid dose calculation was tested on digital phantoms and patient CT data for standard fields and IMRT plan. The results were compared to dose calculated by the treatment planning system (TPS). The agreement of the hybrid and the TPS was within 3%, 3 mm for over 98% of the volume for phantom studies and lung patients. Conclusion: The proposed hybrid method uses the same commissioning data as those for the measurement-based method and can be easily extended to any non-standard LINAC. The results met the accuracy, independence, and simple commissioning criteria for an independent dose calculator.« less

Development of a Monte Carlo multiple source model for inclusion in a dose calculation auditing tool.

PubMed

Faught, Austin M; Davidson, Scott E; Fontenot, Jonas; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

2017-09-01

The Imaging and Radiation Oncology Core Houston (IROC-H) (formerly the Radiological Physics Center) has reported varying levels of agreement in their anthropomorphic phantom audits. There is reason to believe one source of error in this observed disagreement is the accuracy of the dose calculation algorithms and heterogeneity corrections used. To audit this component of the radiotherapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Elekta 6 MV and 10 MV therapeutic x-ray beams were commissioned based on measurement of central axis depth dose data for a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open field measurements consisting of depth dose data and dose profiles for field sizes ranging from 3 × 3 cm 2 to 30 × 30 cm 2 . The models were then benchmarked against measurements in IROC-H's anthropomorphic head and neck and lung phantoms. Validation results showed 97.9% and 96.8% of depth dose data passed a ±2% Van Dyk criterion for 6 MV and 10 MV models respectively. Dose profile comparisons showed an average agreement using a ±2%/2 mm criterion of 98.0% and 99.0% for 6 MV and 10 MV models respectively. Phantom plan comparisons were evaluated using ±3%/2 mm gamma criterion, and averaged passing rates between Monte Carlo and measurements were 87.4% and 89.9% for 6 MV and 10 MV models respectively. Accurate multiple source models for Elekta 6 MV and 10 MV x-ray beams have been developed for inclusion in an independent dose calculation tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.

Predictors of High-grade Esophagitis After Definitive Three-dimensional Conformal Therapy, Intensity-modulated Radiation Therapy, or Proton Beam Therapy for Non-small cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gomez, Daniel R., E-mail: dgomez@mdanderson.org; Tucker, Susan L.; Martel, Mary K.

2012-11-15

Introduction: We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). Methods and Materials: Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade {>=}3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. Results:more » Overall, 652 patients were included: 405 patients were treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade {>=}3 RE were 8%, 28%, and 6%, respectively, with a median time to onset of 42 days (range, 11-93 days). A fit of the fractional DVH LKB model demonstrated that the fractional effective dose was significantly different (P=.046) than 1 (fractional mean dose) indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (P=.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (P=.105). Conclusions: Fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE, estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT.« less

Predictors of high-grade esophagitis after definitive three-dimensional conformal therapy, intensity-modulated radiation therapy, or proton beam therapy for non-small cell lung cancer.

PubMed

Gomez, Daniel R; Tucker, Susan L; Martel, Mary K; Mohan, Radhe; Balter, Peter A; Lopez Guerra, Jose Luis; Liu, Hongmei; Komaki, Ritsuko; Cox, James D; Liao, Zhongxing

2012-11-15

We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade≥3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. Overall, 652 patients were included: 405 patients were treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade≥3 RE were 8%, 28%, and 6%, respectively, with a median time to onset of 42 days (range, 11-93 days). A fit of the fractional DVH LKB model demonstrated that the fractional effective dose was significantly different (P=.046) than 1 (fractional mean dose) indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (P=.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (P=.105). Fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE, estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT. Copyright © 2012 Elsevier Inc. All rights reserved.

Organ Dose-Rate Calculations for Small Mammals at Maralinga, the Nevada Test Site, Hanford and Fukushima: A Comparison of Ellipsoidal and Voxelized Dosimetric Methodologies.

PubMed

Caffrey, Emily A; Johansen, Mathew P; Higley, Kathryn A

2015-10-01

Radiological dosimetry for nonhuman biota typically relies on calculations that utilize the Monte Carlo simulations of simple, ellipsoidal geometries with internal radioactivity distributed homogeneously throughout. In this manner it is quick and easy to estimate whole-body dose rates to biota. Voxel models are detailed anatomical phantoms that were first used for calculating radiation dose to humans, which are now being extended to nonhuman biota dose calculations. However, if simple ellipsoidal models provide conservative dose-rate estimates, then the additional labor involved in creating voxel models may be unnecessary for most scenarios. Here we show that the ellipsoidal method provides conservative estimates of organ dose rates to small mammals. Organ dose rates were calculated for environmental source terms from Maralinga, the Nevada Test Site, Hanford and Fukushima using both the ellipsoidal and voxel techniques, and in all cases the ellipsoidal method yielded more conservative dose rates by factors of 1.2-1.4 for photons and 5.3 for beta particles. Dose rates for alpha-emitting radionuclides are identical for each method as full energy absorption in source tissue is assumed. The voxel procedure includes contributions to dose from organ-to-organ irradiation (shown here to comprise 2-50% of total dose from photons and 0-93% of total dose from beta particles) that is not specifically quantified in the ellipsoidal approach. Overall, the voxel models provide robust dosimetry for the nonhuman mammals considered in this study, and though the level of detail is likely extraneous to demonstrating regulatory compliance today, voxel models may nevertheless be advantageous in resolving ongoing questions regarding the effects of ionizing radiation on wildlife.

Skin dose mapping for fluoroscopically guided interventions.

PubMed

Johnson, Perry B; Borrego, David; Balter, Stephen; Johnson, Kevin; Siragusa, Daniel; Bolch, Wesley E

2011-10-01

To introduce a new skin dose mapping software system for interventional fluoroscopy dose assessment and to analyze the benefits and limitations of patient-phantom matching. In this study, a new software system was developed for visualizing patient skin dose during interventional fluoroscopy procedures. The system works by translating the reference point air kerma to the location of the patient's skin, which is represented by a computational model. In order to orient the model with the x-ray source, geometric parameters found within the radiation dose structured report (RDSR) are used along with a limited number of in-clinic measurements. The output of the system is a visual indication of skin dose mapped onto an anthropomorphic model at a resolution of 5 mm. In order to determine if patient-dependent and patient-sculpted models increase accuracy, peak skin dose was calculated for each of 26 patient-specific models and compared with doses calculated using an elliptical stylized model, a reference hybrid model, a matched patient-dependent model and one patient-sculpted model. Results were analyzed in terms of a percent difference using the doses calculated using the patient-specific model as the true standard. Anthropometric matching, including the use of both patient-dependent and patient-sculpted phantoms, was shown most beneficial for left lateral and anterior-posterior projections. In these cases, the percent difference using a reference model was between 8 and 20%, using a patient-dependent model between 7 and 15%, and using a patient-sculpted model between 3 and 7%. Under the table tube configurations produced errors less than 5% in most situations due to the flattening affects of the table and pad, and the fact that table height is the main determination of source-to-skin distance for these configurations. In addition to these results, several skin dose maps were produced and a prototype display system was placed on the in-clinic monitor of an interventional fluoroscopy system. The skin dose mapping program developed in this work represents a new tool that, as the RDSR becomes available through automated export or real-time streaming, can provide the interventional physician information needed to modify behavior when clinically appropriate. The program is nonproprietary and transferable, and also functions independent to the software systems already installed on the control room workstation. The next step will be clinical implementation where the workflow will be optimized along with further analysis of real-time capabilities.

Population Pharmacokinetics of Busulfan in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplant: A Model-Based Dosing Algorithm for Personalized Therapy and Implementation into Routine Clinical Use

PubMed Central

Long-Boyle, Janel; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J.; Dvorak, Christopher C.

2014-01-01

Background Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared to conventional dosing. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration-at-steady-state, Css) and implement a simple, model-based tool for the initial dosing of busulfan in children undergoing HCT. Patients and Methods Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone HCT with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the non-linear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly, Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Results Modeling of busulfan time-concentration data indicates busulfan CL displays non-linearity in children, decreasing up to approximately 20% between the concentrations of 250–2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan CL were actual body weight and age. The percentage of individuals achieving a therapeutic Css was significantly higher in subjects receiving initial doses based on the population PK model (81%) versus historical controls dosed on conventional guidelines (52%) (p = 0.02). Conclusion When compared to the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults. PMID:25162216

Numerical Analysis of Organ Doses Delivered During Computed Tomography Examinations Using Japanese Adult Phantoms with the WAZA-ARI Dosimetry System.

PubMed

Takahashi, Fumiaki; Sato, Kaoru; Endo, Akira; Ono, Koji; Ban, Nobuhiko; Hasegawa, Takayuki; Katsunuma, Yasushi; Yoshitake, Takayasu; Kai, Michiaki

2015-08-01

A dosimetry system for computed tomography (CT) examinations, named WAZA-ARI, is being developed to accurately assess radiation doses to patients in Japan. For dose calculations in WAZA-ARI, organ doses were numerically analyzed using average adult Japanese male (JM) and female (JF) phantoms with the Particle and Heavy Ion Transport code System (PHITS). Experimental studies clarified the photon energy distribution of emitted photons and dose profiles on the table for some multi-detector row CT (MDCT) devices. Numerical analyses using a source model in PHITS could specifically take into account emissions of x rays from the tube to the table with attenuation of photons through a beam-shaping filter for each MDCT device based on the experiment results. The source model was validated by measuring the CT dose index (CTDI). Numerical analyses with PHITS revealed a concordance of organ doses with body sizes of the JM and JF phantoms. The organ doses in the JM phantoms were compared with data obtained using previously developed systems. In addition, the dose calculations in WAZA-ARI were verified with previously reported results by realistic NUBAS phantoms and radiation dose measurement using a physical Japanese model (THRA1 phantom). The results imply that numerical analyses using the Japanese phantoms and specified source models can give reasonable estimates of dose for MDCT devices for typical Japanese adults.

Modeling and design of a cone-beam CT head scanner using task-based imaging performance optimization

NASA Astrophysics Data System (ADS)

Xu, J.; Sisniega, A.; Zbijewski, W.; Dang, H.; Stayman, J. W.; Wang, X.; Foos, D. H.; Aygun, N.; Koliatsos, V. E.; Siewerdsen, J. H.

2016-04-01

Detection of acute intracranial hemorrhage (ICH) is important for diagnosis and treatment of traumatic brain injury, stroke, postoperative bleeding, and other head and neck injuries. This paper details the design and development of a cone-beam CT (CBCT) system developed specifically for the detection of low-contrast ICH in a form suitable for application at the point of care. Recognizing such a low-contrast imaging task to be a major challenge in CBCT, the system design began with a rigorous analysis of task-based detectability including critical aspects of system geometry, hardware configuration, and artifact correction. The imaging performance model described the three-dimensional (3D) noise-equivalent quanta using a cascaded systems model that included the effects of scatter, scatter correction, hardware considerations of complementary metal-oxide semiconductor (CMOS) and flat-panel detectors (FPDs), and digitization bit depth. The performance was analyzed with respect to a low-contrast (40-80 HU), medium-frequency task representing acute ICH detection. The task-based detectability index was computed using a non-prewhitening observer model. The optimization was performed with respect to four major design considerations: (1) system geometry (including source-to-detector distance (SDD) and source-to-axis distance (SAD)); (2) factors related to the x-ray source (including focal spot size, kVp, dose, and tube power); (3) scatter correction and selection of an antiscatter grid; and (4) x-ray detector configuration (including pixel size, additive electronics noise, field of view (FOV), and frame rate, including both CMOS and a-Si:H FPDs). Optimal design choices were also considered with respect to practical constraints and available hardware components. The model was verified in comparison to measurements on a CBCT imaging bench as a function of the numerous design parameters mentioned above. An extended geometry (SAD  =  750 mm, SDD  =  1100 mm) was found to be advantageous in terms of patient dose (20 mGy) and scatter reduction, while a more isocentric configuration (SAD  =  550 mm, SDD  =  1000 mm) was found to give a more compact and mechanically favorable configuration with minor tradeoff in detectability. An x-ray source with a 0.6 mm focal spot size provided the best compromise between spatial resolution requirements and x-ray tube power. Use of a modest anti-scatter grid (8:1 GR) at a 20 mGy dose provided slight improvement (~5-10%) in the detectability index, but the benefit was lost at reduced dose. The potential advantages of CMOS detectors over FPDs were quantified, showing that both detectors provided sufficient spatial resolution for ICH detection, while the former provided a potentially superior low-dose performance, and the latter provided the requisite FOV for volumetric imaging in a centered-detector geometry. Task-based imaging performance modeling provides an important starting point for CBCT system design, especially for the challenging task of ICH detection, which is somewhat beyond the capabilities of existing CBCT platforms. The model identifies important tradeoffs in system geometry and hardware configuration, and it supports the development of a dedicated CBCT system for point-of-care application. A prototype suitable for clinical studies is in development based on this analysis.

The energy-dependent electron loss model: backscattering and application to heterogeneous slab media.

PubMed

Lee, Tae Kyu; Sandison, George A

2003-01-21

Electron backscattering has been incorporated into the energy-dependent electron loss (EL) model and the resulting algorithm is applied to predict dose deposition in slab heterogeneous media. This algorithm utilizes a reflection coefficient from the interface that is computed on the basis of Goudsmit-Saunderson theory and an average energy for the backscattered electrons based on Everhart's theory. Predictions of dose deposition in slab heterogeneous media are compared to the Monte Carlo based dose planning method (DPM) and a numerical discrete ordinates method (DOM). The slab media studied comprised water/Pb, water/Al, water/bone, water/bone/water, and water/lung/water, and incident electron beam energies of 10 MeV and 18 MeV. The predicted dose enhancement due to backscattering is accurate to within 3% of dose maximum even for lead as the backscattering medium. Dose discrepancies at large depths beyond the interface were as high as 5% of dose maximum and we speculate that this error may be attributed to the EL model assuming a Gaussian energy distribution for the electrons at depth. The computational cost is low compared to Monte Carlo simulations making the EL model attractive as a fast dose engine for dose optimization algorithms. The predictive power of the algorithm demonstrates that the small angle scattering restriction on the EL model can be overcome while retaining dose calculation accuracy and requiring only one free variable, chi, in the algorithm to be determined in advance of calculation.

The energy-dependent electron loss model: backscattering and application to heterogeneous slab media

NASA Astrophysics Data System (ADS)

Lee, Tae Kyu; Sandison, George A.

2003-01-01

Electron backscattering has been incorporated into the energy-dependent electron loss (EL) model and the resulting algorithm is applied to predict dose deposition in slab heterogeneous media. This algorithm utilizes a reflection coefficient from the interface that is computed on the basis of Goudsmit-Saunderson theory and an average energy for the backscattered electrons based on Everhart's theory. Predictions of dose deposition in slab heterogeneous media are compared to the Monte Carlo based dose planning method (DPM) and a numerical discrete ordinates method (DOM). The slab media studied comprised water/Pb, water/Al, water/bone, water/bone/water, and water/lung/water, and incident electron beam energies of 10 MeV and 18 MeV. The predicted dose enhancement due to backscattering is accurate to within 3% of dose maximum even for lead as the backscattering medium. Dose discrepancies at large depths beyond the interface were as high as 5% of dose maximum and we speculate that this error may be attributed to the EL model assuming a Gaussian energy distribution for the electrons at depth. The computational cost is low compared to Monte Carlo simulations making the EL model attractive as a fast dose engine for dose optimization algorithms. The predictive power of the algorithm demonstrates that the small angle scattering restriction on the EL model can be overcome while retaining dose calculation accuracy and requiring only one free variable, χ, in the algorithm to be determined in advance of calculation.

SU-E-T-373: Evaluation and Reduction of Contralateral Skin /subcutaneous Dose for Tangential Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Butson, M; Carroll, S; Whitaker, M

2015-06-15

Purpose: Tangential breast irradiation is a standard treatment technique for breast cancer therapy. One aspect of dose delivery includes dose delivered to the skin caused by electron contamination. This effect is especially important for highly oblique beams used on the medical tangent where the electron contamination deposits dose on the contralateral breast side. This work aims to investigate and predict as well as define a method to reduce this dose during tangential breast radiotherapy. Methods: Analysis and calculation of breast skin and subcutaneous dose is performed using a Varian Eclipse planning system, AAA algorithm for 6MV x-ray treatments. Measurements weremore » made using EBT3 Gafchromic film to verify the accuracy of planning data. Various materials were tested to assess their ability to remove electron contamination on the contralateral breast. Results: Results showed that the Varian Eclipse AAA algorithm could accurately estimate contralateral breast dose in the build-up region at depths of 2mm or deeper. Surface dose was underestimated by the AAA algorithm. Doses up to 12% of applied dose were seen on the contralateral breast surface and up to 9 % at 2mm depth. Due to the nature of this radiation, being mainly low energy electron contamination, a bolus material could be used to reduce this dose to less than 3%. This is accomplished by 10 mm of superflab bolus or by 1 mm of lead. Conclusion: Contralateral breast skin and subcutaneous dose is present for tangential breast treatment and has been measured to be up to 12% of applied dose from the medial tangent beam. This dose is deposited at shallow depths and is accurately calculated by the Eclipse AAA algorithm at depths of 2mm or greater. Bolus material placed over the contralateral can be used to effectively reduce this skin dose.« less

[Study of the effect of colloidal solution of silver nanoparticles on parameters of cardio- and hemo-dynamics in rabbits].

PubMed

Pryskoka, A O

2014-01-01

Metal nanoparticles and silver nanoparticles in particular are extensively studied recently considering their prominent antimicrobial properties. Nevertheless, their toxicity aspects and probable side effects remain not well studied. In this article the results of study of the influence of silver nanoparticles onto a cardiovascular system in an in vivo experiment were provided, changes in parameters of cardio- and hemodynamics were defined, and the principles of such influence were identified. Dose-dependent effect of these nanoparticles was established when administered in dose of 4.3 mg/kg three times and 20 mg/kg once.

Optimization of the intravenous glucose tolerance test in T2DM patients using optimal experimental design.

PubMed

Silber, Hanna E; Nyberg, Joakim; Hooker, Andrew C; Karlsson, Mats O

2009-06-01

Intravenous glucose tolerance test (IVGTT) provocations are informative, but complex and laborious, for studying the glucose-insulin system. The objective of this study was to evaluate, through optimal design methodology, the possibilities of more informative and/or less laborious study design of the insulin modified IVGTT in type 2 diabetic patients. A previously developed model for glucose and insulin regulation was implemented in the optimal design software PopED 2.0. The following aspects of the study design of the insulin modified IVGTT were evaluated; (1) glucose dose, (2) insulin infusion, (3) combination of (1) and (2), (4) sampling times, (5) exclusion of labeled glucose. Constraints were incorporated to avoid prolonged hyper- and/or hypoglycemia and a reduced design was used to decrease run times. Design efficiency was calculated as a measure of the improvement with an optimal design compared to the basic design. The results showed that the design of the insulin modified IVGTT could be substantially improved by the use of an optimized design compared to the standard design and that it was possible to use a reduced number of samples. Optimization of sample times gave the largest improvement followed by insulin dose. The results further showed that it was possible to reduce the total sample time with only a minor loss in efficiency. Simulations confirmed the predictions from PopED. The predicted uncertainty of parameter estimates (CV) was low in all tested cases, despite the reduction in the number of samples/subject. The best design had a predicted average CV of parameter estimates of 19.5%. We conclude that improvement can be made to the design of the insulin modified IVGTT and that the most important design factor was the placement of sample times followed by the use of an optimal insulin dose. This paper illustrates how complex provocation experiments can be improved by sequential modeling and optimal design.

The Potential Neurotoxic Effects of Low-Dose Sarin Exposure in a Guinea Pig Model

DTIC Science & Technology

2002-01-01

1 THE POTENTIAL NEUROTOXIC EFFECTS OF LOW-DOSE SARIN EXPOSURE IN A GUINEA PIG MODEL Melinda R. Roberson, PhD, Michelle B. Schmidt...Proving Ground, MD 21010 USA ABSTRACT This study is assessing the effects in guinea pigs of repeated low-dose exposure to the nerve...COVERED - 4. TITLE AND SUBTITLE The Potential Neurotoxic Effects Of Low-Dose Sarin Exposure In A Guinea Pig Model 5a. CONTRACT NUMBER 5b

Knowledge-based IMRT planning for individual liver cancer patients using a novel specific model.

PubMed

Yu, Gang; Li, Yang; Feng, Ziwei; Tao, Cheng; Yu, Zuyi; Li, Baosheng; Li, Dengwang

2018-03-27

The purpose of this work is to benchmark RapidPlan against clinical plans for liver Intensity-modulated radiotherapy (IMRT) treatment of patients with special anatomical characteristics, and to investigate the prediction capability of the general model (Model-G) versus our specific model (Model-S). A library consisting of 60 liver cancer patients with IMRT planning was used to set up two models (Model-S, Model-G), using the RapidPlan knowledge-based planning system. Model-S consisted of 30 patients with special anatomical characteristics where the distance from planning target volume (PTV) to the right kidney was less than three centimeters and Model-G was configurated using all 60 patients in this library. Knowledge-based IMRT plans were created for the evaluation group formed of 13 patients similar to those included in Model-S by Model-G, Model-S and manually (M), named RPG-plans, RPS-plans and M-plans, respectively. The differences in the dose-volume histograms (DVHs) were compared, not only between RP-plans and their respective M-plans, but also between RPG-plans and RPS-plans. For all 13 patients, RapidPlan could automatically produce clinically acceptable plans. Comparing RP-plans to M-plans, RP-plans improved V 95% of PTV and had greater dose sparing in the right kidney. For the normal liver, RPG-plans delivered similar doses, while RPS-plans delivered a higher dose than M-plans. With respect to RapidPlan models, RPS-plans had better conformity index (CI) values and delivered lower doses to the right kidney V 20Gy and maximizing point doses to spinal cord, while delivering higher doses to the normal liver. The study shows that RapidPlan can create high-quality plans, and our specific model can improve the CI of PTV, resulting in more sparing of OAR in IMRT for individual liver cancer patients.

Influence of dose calculation algorithms on the predicted dose distribution and NTCP values for NSCLC patients.

PubMed

Nielsen, Tine B; Wieslander, Elinore; Fogliata, Antonella; Nielsen, Morten; Hansen, Olfred; Brink, Carsten

2011-05-01

To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms. Six dose algorithms from four different treatment planning systems were investigated: Eclipse AAA, Oncentra MasterPlan Collapsed Cone and Pencil Beam, Pinnacle Collapsed Cone and XiO Multigrid Superposition, and Fast Fourier Transform Convolution. Twenty NSCLC patients treated in the period 2001-2006 at the same accelerator were included and the accelerator used for treatments were modeled in the different systems. The treatment plans were recalculated with the same number of monitor units and beam arrangements across the dose algorithms. Dose volume histograms of the GTV, PTV, combined lungs (excluding the GTV), and heart were exported and evaluated. NTCP values for heart and lungs were calculated using the relative seriality model and the LKB model, respectively. Furthermore, NTCP for the lungs were calculated from two different model parameter sets. Calculations and evaluations were performed both including and excluding density corrections. There are found statistical significant differences between the calculated dose to heart, lung, and targets across the algorithms. Mean lung dose and V20 are not very sensitive to change between the investigated dose calculation algorithms. However, the different dose levels for the PTV averaged over the patient population are varying up to 11%. The predicted NTCP values for pneumonitis vary between 0.20 and 0.24 or 0.35 and 0.48 across the investigated dose algorithms depending on the chosen model parameter set. The influence of the use of density correction in the dose calculation on the predicted NTCP values depends on the specific dose calculation algorithm and the model parameter set. For fixed values of these, the changes in NTCP can be up to 45%. Calculated NTCP values for pneumonitis are more sensitive to the choice of algorithm than mean lung dose and V20 which are also commonly used for plan evaluation. The NTCP values for heart complication are, in this study, not very sensitive to the choice of algorithm. Dose calculations based on density corrections result in quite different NTCP values than calculations without density corrections. It is therefore important when working with NTCP planning to use NTCP parameter values based on calculations and treatments similar to those for which the NTCP is of interest.

Space radiation absorbed dose distribution in a human phantom

NASA Technical Reports Server (NTRS)

Badhwar, G. D.; Atwell, W.; Badavi, F. F.; Yang, T. C.; Cleghorn, T. F.

2002-01-01

The radiation risk to astronauts has always been based on measurements using passive thermoluminescent dosimeters (TLDs). The skin dose is converted to dose equivalent using an average radiation quality factor based on model calculations. The radiological risk estimates, however, are based on organ and tissue doses. This paper describes results from the first space flight (STS-91, 51.65 degrees inclination and approximately 380 km altitude) of a fully instrumented Alderson Rando phantom torso (with head) to relate the skin dose to organ doses. Spatial distributions of absorbed dose in 34 1-inch-thick sections measured using TLDs are described. There is about a 30% change in dose as one moves from the front to the back of the phantom body. Small active dosimeters were developed specifically to provide time-resolved measurements of absorbed dose rates and quality factors at five organ locations (brain, thyroid, heart/lung, stomach and colon) inside the phantom. Using these dosimeters, it was possible to separate the trapped-proton and the galactic cosmic radiation components of the doses. A tissue-equivalent proportional counter (TEPC) and a charged-particle directional spectrometer (CPDS) were flown next to the phantom torso to provide data on the incident internal radiation environment. Accurate models of the shielding distributions at the site of the TEPC, the CPDS and a scalable Computerized Anatomical Male (CAM) model of the phantom torso were developed. These measurements provided a comprehensive data set to map the dose distribution inside a human phantom, and to assess the accuracy and validity of radiation transport models throughout the human body. The results show that for the conditions in the International Space Station (ISS) orbit during periods near the solar minimum, the ratio of the blood-forming organ dose rate to the skin absorbed dose rate is about 80%, and the ratio of the dose equivalents is almost one. The results show that the GCR model dose-rate predictions are 20% lower than the observations. Assuming that the trapped-belt models lead to a correct orbit-averaged energy spectrum, the measurements of dose rates inside the phantom cannot be fully understood. Passive measurements using 6Li- and 7Li-based detectors on the astronauts and inside the brain and thyroid of the phantom show the presence of a significant contribution due to thermal neutrons, an area requiring additional study.

A Collaborative Support Approach on UML Sequence Diagrams for Aspect-Oriented Software

NASA Astrophysics Data System (ADS)

de Almeida Naufal, Rafael; Silveira, Fábio F.; Guerra, Eduardo M.

AOP and its broader application on software projects brings the importance to provide the separation between aspects and OO components at design time, to leverage the understanding of AO systems, promote aspects' reuse and obtain the benefits of AO modularization. Since the UML is a standard for modeling OO systems, it can be applied to model the decoupling between aspects and OO components. The application of UML to this area is the subject of constant study and is the focus of this paper. In this paper it is presented an extension based on the default UML meta-model, named MIMECORA-DS, to show object-object, object-aspect and aspect-aspect interactions applying the UML's sequence diagram. This research also presents the application of MIMECORA-DS in a case example, to assess its applicability.

Methods for Probabilistic Radiological Dose Assessment at a High-Level Radioactive Waste Repository.

NASA Astrophysics Data System (ADS)

Maheras, Steven James

Methods were developed to assess and evaluate the uncertainty in offsite and onsite radiological dose at a high-level radioactive waste repository to show reasonable assurance that compliance with applicable regulatory requirements will be achieved. Uncertainty in offsite dose was assessed by employing a stochastic precode in conjunction with Monte Carlo simulation using an offsite radiological dose assessment code. Uncertainty in onsite dose was assessed by employing a discrete-event simulation model of repository operations in conjunction with an occupational radiological dose assessment model. Complementary cumulative distribution functions of offsite and onsite dose were used to illustrate reasonable assurance. Offsite dose analyses were performed for iodine -129, cesium-137, strontium-90, and plutonium-239. Complementary cumulative distribution functions of offsite dose were constructed; offsite dose was lognormally distributed with a two order of magnitude range. However, plutonium-239 results were not lognormally distributed and exhibited less than one order of magnitude range. Onsite dose analyses were performed for the preliminary inspection, receiving and handling, and the underground areas of the repository. Complementary cumulative distribution functions of onsite dose were constructed and exhibited less than one order of magnitude range. A preliminary sensitivity analysis of the receiving and handling areas was conducted using a regression metamodel. Sensitivity coefficients and partial correlation coefficients were used as measures of sensitivity. Model output was most sensitive to parameters related to cask handling operations. Model output showed little sensitivity to parameters related to cask inspections.

Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olson, J.J.; Friedman, R.; Orr, K.

1990-05-01

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose,more » a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.« less

An investigation of the effect of aspect and compression ratios on sediment dispersion using discrete element modelling

NASA Astrophysics Data System (ADS)

Wang, Dong; Tan, Danielle S.

2017-12-01

We use discrete element modelling to simulate a system of sand being released underwater, similar to the process of releasing sediment tailings back into the sea in nodule harvesting, in 2D. The force model includes concentration-dependent drag, buoyancy, `added mass' and Stokeslet disturbance. For a fixed number of uniform-sized particles, we vary the aspect ratio and the compression ratio of the rectangular mass of granular media pre-release. We observed that the spreading leads to a nonlinear increase with aspect ratio. On the other hand, when the compression ratio is increased, the total spreading increases; however the spread of the bulk of the sand decreases at small aspect ratios and increases at large aspect ratios. We proposed a simple theoretical model for the horizontal spreading which depends on both the aspect and compression ratios.

Tense or Aspect?: Effects of L1 Tense/Aspect Prominence in L2 Acquisition

ERIC Educational Resources Information Center

Martinovic-Zic, Aida

2009-01-01

This study introduces a typological model of the "conceptual language-specific approach" to the L2 research on the acquisition of tense-aspect. The model is based on the typological notion of prominence, classifying languages into tense-prominent and aspect-prominent (Bhat 1999) and the L1 research proposal that language-specific…

SHEDS-PM: A POPULATION EXPOSURE MODEL FOR PREDICTING DISTRIBUTIONS OF PM EXPOSURE AND DOSE FROM BOTH OUTDOOR AND INDOOR SOURCES

EPA Science Inventory

The US EPA National Exposure Research Laboratory (NERL) has developed a population exposure and dose model for particulate matter (PM), called the Stochastic Human Exposure and Dose Simulation (SHEDS) model. SHEDS-PM uses a probabilistic approach that incorporates both variabi...

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

PubMed

Teunis, P F M; Ogden, I D; Strachan, N J C

2008-06-01

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

Dependence of normal brain integral dose and normal tissue complication probability on the prescription isodose values for γ-knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun

2001-11-01

A recent multi-institutional clinical study suggested possible benefits of lowering the prescription isodose lines for stereotactic radiosurgery procedures. In this study, we investigate the dependence of the normal brain integral dose and the normal tissue complication probability (NTCP) on the prescription isodose values for γ-knife radiosurgery. An analytical dose model was developed for γ-knife treatment planning. The dose model was commissioned by fitting the measured dose profiles for each helmet size. The dose model was validated by comparing its results with the Leksell gamma plan (LGP, version 5.30) calculations. The normal brain integral dose and the NTCP were computed and analysed for an ensemble of treatment cases. The functional dependence of the normal brain integral dose and the NCTP versus the prescribing isodose values was studied for these cases. We found that the normal brain integral dose and the NTCP increase significantly when lowering the prescription isodose lines from 50% to 35% of the maximum tumour dose. Alternatively, the normal brain integral dose and the NTCP decrease significantly when raising the prescribing isodose lines from 50% to 65% of the maximum tumour dose. The results may be used as a guideline for designing future dose escalation studies for γ-knife applications.

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

NASA Astrophysics Data System (ADS)

El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

2006-11-01

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

Atmospheric radiation modeling of galactic cosmic rays using LRO/CRaTER and the EMMREM model with comparisons to balloon and airline based measurements

NASA Astrophysics Data System (ADS)

Joyce, C. J.; Schwadron, N. A.; Townsend, L. W.; deWet, W. C.; Wilson, J. K.; Spence, H. E.; Tobiska, W. K.; Shelton-Mur, K.; Yarborough, A.; Harvey, J.; Herbst, A.; Koske-Phillips, A.; Molina, F.; Omondi, S.; Reid, C.; Reid, D.; Shultz, J.; Stephenson, B.; McDevitt, M.; Phillips, T.

2016-09-01

We provide an analysis of the galactic cosmic ray radiation environment of Earth's atmosphere using measurements from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) aboard the Lunar Reconnaissance Orbiter (LRO) together with the Badhwar-O'Neil model and dose lookup tables generated by the Earth-Moon-Mars Radiation Environment Module (EMMREM). This study demonstrates an updated atmospheric radiation model that uses new dose tables to improve the accuracy of the modeled dose rates. Additionally, a method for computing geomagnetic cutoffs is incorporated into the model in order to account for location-dependent effects of the magnetosphere. Newly available measurements of atmospheric dose rates from instruments aboard commercial aircraft and high-altitude balloons enable us to evaluate the accuracy of the model in computing atmospheric dose rates. When compared to the available observations, the model seems to be reasonably accurate in modeling atmospheric radiation levels, overestimating airline dose rates by an average of 20%, which falls within the uncertainty limit recommended by the International Commission on Radiation Units and Measurements (ICRU). Additionally, measurements made aboard high-altitude balloons during simultaneous launches from New Hampshire and California provide an additional comparison to the model. We also find that the newly incorporated geomagnetic cutoff method enables the model to represent radiation variability as a function of location with sufficient accuracy.

Comparison of Models for Bubonic Plague Reveals Unique Pathogen Adaptations to the Dermis.

PubMed

Gonzalez, Rodrigo J; Weening, Eric H; Lane, M Chelsea; Miller, Virginia L

2015-07-01

Vector-borne pathogens are inoculated in the skin of mammals, most likely in the dermis. Despite this, subcutaneous (s.c.) models of infection are broadly used in many fields, including Yersinia pestis pathogenesis. We expand on a previous report where we implemented intradermal (i.d.) inoculations to study bacterial dissemination during bubonic plague and compare this model with an s.c. We found that i.d. inoculations result in faster kinetics of infection and that bacterial dose influenced mouse survival after i.d. but not s.c. inoculation. Moreover, a deletion mutant of rovA, previously shown to be moderately attenuated in the s.c. model, was severely attenuated in the i.d. Lastly, based on previous observations where a population bottleneck from the skin to lymph nodes was observed after i.d., but not after s.c., inoculations, we used the latter model as a strategy to identify an additional bottleneck in bacterial dissemination from lymph nodes to the bloodstream. Our data indicate that the more biologically relevant i.d. model of bubonic plague differs significantly from the s.c. model in multiple aspects of infection. These findings reveal adaptations of Y. pestis to the dermis and how these adaptations can define the progression of disease. They also emphasize the importance of using a relevant route of infection when addressing host-pathogen interactions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Three-Dimensional Electron Beam Dose Calculations.

NASA Astrophysics Data System (ADS)

Shiu, Almon Sowchee

The MDAH pencil-beam algorithm developed by Hogstrom et al (1981) has been widely used in clinics for electron beam dose calculations for radiotherapy treatment planning. The primary objective of this research was to address several deficiencies of that algorithm and to develop an enhanced version. Two enhancements have been incorporated into the pencil-beam algorithm; one models fluence rather than planar fluence, and the other models the bremsstrahlung dose using measured beam data. Comparisons of the resulting calculated dose distributions with measured dose distributions for several test phantoms have been made. From these results it is concluded (1) that the fluence-based algorithm is more accurate to use for the dose calculation in an inhomogeneous slab phantom, and (2) the fluence-based calculation provides only a limited improvement to the accuracy the calculated dose in the region just downstream of the lateral edge of an inhomogeneity. The source of the latter inaccuracy is believed primarily due to assumptions made in the pencil beam's modeling of the complex phantom or patient geometry. A pencil-beam redefinition model was developed for the calculation of electron beam dose distributions in three dimensions. The primary aim of this redefinition model was to solve the dosimetry problem presented by deep inhomogeneities, which was the major deficiency of the enhanced version of the MDAH pencil-beam algorithm. The pencil-beam redefinition model is based on the theory of electron transport by redefining the pencil beams at each layer of the medium. The unique approach of this model is that all the physical parameters of a given pencil beam are characterized for multiple energy bins. Comparisons of the calculated dose distributions with measured dose distributions for a homogeneous water phantom and for phantoms with deep inhomogeneities have been made. From these results it is concluded that the redefinition algorithm is superior to the conventional, fluence-based, pencil-beam algorithm, especially in predicting the dose distribution downstream of a local inhomogeneity. The accuracy of this algorithm appears sufficient for clinical use, and the algorithm is structured for future expansion of the physical model if required for site specific treatment planning problems.

TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, J; Wu, Q.J.; Yin, F

2014-06-15

Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into fivemore » groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant #R21CA161389 and a master research grant by Varian Medical System.« less

A dual two dimensional electronic portal imaging device transit dosimetry model based on an empirical quadratic formalism

PubMed Central

Metwaly, M; Glegg, M; Baggarley, S P; Elliott, A

2015-01-01

Objective: This study describes a two dimensional electronic portal imaging device (EPID) transit dosimetry model that can predict either: (1) in-phantom exit dose, or (2) EPID transit dose, for treatment verification. Methods: The model was based on a quadratic equation that relates the reduction in intensity to the equivalent path length (EPL) of the attenuator. In this study, two sets of quadratic equation coefficients were derived from calibration dose planes measured with EPID and ionization chamber in water under reference conditions. With two sets of coefficients, EPL can be calculated from either EPID or treatment planning system (TPS) dose planes. Consequently, either the in-phantom exit dose or the EPID transit dose can be predicted from the EPL. The model was tested with two open, five wedge and seven sliding window prostate and head and neck intensity-modulated radiation therapy (IMRT) fields on phantoms. Results were analysed using absolute gamma analysis (3%/3 mm). Results: The open fields gamma pass rates were >96.8% for all comparisons. For wedge and IMRT fields, comparisons between predicted and TPS-computed in-phantom exit dose resulted in mean gamma pass rate of 97.4% (range, 92.3–100%). As for the comparisons between predicted and measured EPID transit dose, the mean gamma pass rate was 97.5% (range, 92.6–100%). Conclusion: An EPID transit dosimetry model that can predict in-phantom exit dose and EPID transit dose was described and proven to be valid. Advances in knowledge: The described model is practical, generic and flexible to encourage widespread implementation of EPID dosimetry for the improvement of patients' safety in radiotherapy. PMID:25969867

A dose error evaluation study for 4D dose calculations

NASA Astrophysics Data System (ADS)

Milz, Stefan; Wilkens, Jan J.; Ullrich, Wolfgang

2014-10-01

Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms. The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms. The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex programming structure. The study discloses disadvantages for the bETM and for the DIM. DIM yielded insufficient results for large voxel sizes, while bETM is prone to errors for small voxel sizes.

A dose error evaluation study for 4D dose calculations.

PubMed

Milz, Stefan; Wilkens, Jan J; Ullrich, Wolfgang

2014-11-07

Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms.The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms.The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm; 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex programming structure. The study discloses disadvantages for the bETM and for the DIM. DIM yielded insufficient results for large voxel sizes, while bETM is prone to errors for small voxel sizes.

An analytic linear accelerator source model for GPU-based Monte Carlo dose calculations.

PubMed

Tian, Zhen; Li, Yongbao; Folkerts, Michael; Shi, Feng; Jiang, Steve B; Jia, Xun

2015-10-21

Recently, there has been a lot of research interest in developing fast Monte Carlo (MC) dose calculation methods on graphics processing unit (GPU) platforms. A good linear accelerator (linac) source model is critical for both accuracy and efficiency considerations. In principle, an analytical source model should be more preferred for GPU-based MC dose engines than a phase-space file-based model, in that data loading and CPU-GPU data transfer can be avoided. In this paper, we presented an analytical field-independent source model specifically developed for GPU-based MC dose calculations, associated with a GPU-friendly sampling scheme. A key concept called phase-space-ring (PSR) was proposed. Each PSR contained a group of particles that were of the same type, close in energy and reside in a narrow ring on the phase-space plane located just above the upper jaws. The model parameterized the probability densities of particle location, direction and energy for each primary photon PSR, scattered photon PSR and electron PSR. Models of one 2D Gaussian distribution or multiple Gaussian components were employed to represent the particle direction distributions of these PSRs. A method was developed to analyze a reference phase-space file and derive corresponding model parameters. To efficiently use our model in MC dose calculations on GPU, we proposed a GPU-friendly sampling strategy, which ensured that the particles sampled and transported simultaneously are of the same type and close in energy to alleviate GPU thread divergences. To test the accuracy of our model, dose distributions of a set of open fields in a water phantom were calculated using our source model and compared to those calculated using the reference phase-space files. For the high dose gradient regions, the average distance-to-agreement (DTA) was within 1 mm and the maximum DTA within 2 mm. For relatively low dose gradient regions, the root-mean-square (RMS) dose difference was within 1.1% and the maximum dose difference within 1.7%. The maximum relative difference of output factors was within 0.5%. Over 98.5% passing rate was achieved in 3D gamma-index tests with 2%/2 mm criteria in both an IMRT prostate patient case and a head-and-neck case. These results demonstrated the efficacy of our model in terms of accurately representing a reference phase-space file. We have also tested the efficiency gain of our source model over our previously developed phase-space-let file source model. The overall efficiency of dose calculation was found to be improved by ~1.3-2.2 times in water and patient cases using our analytical model.

On-line photolithography modeling using spectrophotometry and Prolith/2

NASA Astrophysics Data System (ADS)

Engstrom, Herbert L.; Beacham, Jeanne E.

1994-05-01

Spectrophotometry has been applied to optimizing photolithography processes in semiconductor manufacturing. For many years thin film measurement systems have been used in manufacturing for controlling film deposition processes. The combination of film thickness mapping with photolithography modeling has expanded the applications of this technology. Experimental measurements of dose-to-clear, the minimum light exposure dose required to fully develop a photoresist, are described. It is shown how dose-to-clear and photoresist contrast may be determined rapidly and conveniently from measurements of a dose exposure matrix on a monitor wafer. Such experimental measurements may underestimate the dose-to- clear because of thickness variations of the photoresist and underlying layers on the product wafer. Online modeling of the photolithographic process together with film thickness maps of the entire wafer can overcome this problem. Such modeling also provides maps of dose-to- clear and resist linewidth that can be used to estimate and optimize yield.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moignier, Alexandra, E-mail: alexandra.moignier@irsn.fr; Derreumaux, Sylvie; Broggio, David

Purpose: Current retrospective cardiovascular dosimetry studies are based on a representative patient or simple mathematic phantoms. Here, a process of patient modeling was developed to personalize the anatomy of the thorax and to include a heart model with coronary arteries. Methods and Materials: The patient models were hybrid computational phantoms (HCPs) with an inserted detailed heart model. A computed tomography (CT) acquisition (pseudo-CT) was derived from HCP and imported into a treatment planning system where treatment conditions were reproduced. Six current patients were selected: 3 were modeled from their CT images (A patients) and the others were modelled from 2more » orthogonal radiographs (B patients). The method performance and limitation were investigated by quantitative comparison between the initial CT and the pseudo-CT, namely, the morphology and the dose calculation were compared. For the B patients, a comparison with 2 kinds of representative patients was also conducted. Finally, dose assessment was focused on the whole coronary artery tree and the left anterior descending coronary. Results: When 3-dimensional anatomic information was available, the dose calculations performed on the initial CT and the pseudo-CT were in good agreement. For the B patients, comparison of doses derived from HCP and representative patients showed that the HCP doses were either better or equivalent. In the left breast radiation therapy context and for the studied cases, coronary mean doses were at least 5-fold higher than heart mean doses. Conclusions: For retrospective dose studies, it is suggested that HCP offers a better surrogate, in terms of dose accuracy, than representative patients. The use of a detailed heart model eliminates the problem of identifying the coronaries on the patient's CT.« less

Depth dependence of absorbed dose, dose equivalent and linear energy transfer spectra of galactic and trapped particles in polyethylene and comparison with calculations of models

NASA Technical Reports Server (NTRS)

Badhwar, G. D.; Cucinotta, F. A.; Wilson, J. W. (Principal Investigator)

1998-01-01

A matched set of five tissue-equivalent proportional counters (TEPCs), embedded at the centers of 0 (bare), 3, 5, 8 and 12-inch-diameter polyethylene spheres, were flown on the Shuttle flight STS-81 (inclination 51.65 degrees, altitude approximately 400 km). The data obtained were separated into contributions from trapped protons and galactic cosmic radiation (GCR). From the measured linear energy transfer (LET) spectra, the absorbed dose and dose-equivalent rates were calculated. The results were compared to calculations made with the radiation transport model HZETRN/NUCFRG2, using the GCR free-space spectra, orbit-averaged geomagnetic transmission function and Shuttle shielding distributions. The comparison shows that the model fits the dose rates to a root mean square (rms) error of 5%, and dose-equivalent rates to an rms error of 10%. Fairly good agreement between the LET spectra was found; however, differences are seen at both low and high LET. These differences can be understood as due to the combined effects of chord-length variation and detector response function. These results rule out a number of radiation transport/nuclear fragmentation models. Similar comparisons of trapped-proton dose rates were made between calculations made with the proton transport model BRYNTRN using the AP-8 MIN trapped-proton model and Shuttle shielding distributions. The predictions of absorbed dose and dose-equivalent rates are fairly good. However, the prediction of the LET spectra below approximately 30 keV/microm shows the need to improve the AP-8 model. These results have strong implications for shielding requirements for an interplanetary manned mission.

Remediation mechanisms of mercapto-grafted palygorskite for cadmium pollutant in paddy soil.

PubMed

Liang, Xuefeng; Qin, Xu; Huang, Qingqing; Huang, Rong; Yin, Xiuling; Cai, Yanming; Wang, Lin; Sun, Yuebing; Xu, Yingming

2017-10-01

The immobilization agent was the key factor that determined the success of remediation of heavy metal polluted soil. In this study, mercapto-grafted palygorskite (MP) as a novel and efficient immobilization agent was utilized for the remediation of Cd-polluted paddy soil in pot trials, and the remediation mechanisms were investigated in the aspect of soil chemistry and plant physiology with different rice cultivars as model plants. Mercapto-grafted palygorskite at applied doses of 0.1-0.3% could reduce Cd contents of brown rice and straws of different cultivars significantly. Both reduced DTPA-extractable Cd contents in rhizosphere and non-rhizosphere soil and decreasing Cd contents in iron plaques on rice root surfaces confirmed that MP was an efficient immobilization agent for Cd pollutant in paddy soil. In the aspect of soil chemistry, the pH values of rhizosphere and non-rhizosphere soils had no statistical changes in the MP treatment groups, but their zeta potentials decreased obviously, indicating that MP could enhance the fixation or sorption of Cd on soil compositions. In the aspect of antioxidant system, MP could increase POD activity of rice roots significantly to alleviate the stress of Cd to roots, and resulted in the decrease of T-AOC, SOD, and CAT activities of rice roots of the selected cultivars. MP had no inhabitation or enhancement effects on TSH of rice roots but enhance the contents of MTs and NPT to binding Cd to complete detoxification process. MP as a novel and efficient immobilization agent could complete the remediation effects through soil chemistry and plant physiological mechanisms.

A Consumer's Guide to Benchmark Dose Models: Results of U.S. EPA Testing of 14 Dichotomous, 8 Continuous, and 6 Developmental Models (Presentation)

EPA Science Inventory

Benchmark dose risk assessment software (BMDS) was designed by EPA to generate dose-response curves and facilitate the analysis, interpretation and synthesis of toxicological data. Partial results of QA/QC testing of the EPA benchmark dose software (BMDS) are presented. BMDS pr...

Vitamins and Nutrients as Primary Treatments in Experimental Brain Injury: Clinical Implications for Nutraceutical Therapies

PubMed Central

Haar, Cole Vonder; Peterson, Todd C.; Martens, Kris M.; Hoane, Michael R.

2016-01-01

With the numerous failures of pharmaceuticals to treat traumatic brain injury in humans, more researchers have become interested in combination therapies. This is largely due to the multimodal nature of damage from injury, which causes excitotoxicity, oxidative stress, edema, neuroinflammation and cell death. Polydrug treatments have the potential to target multiple aspects of the secondary injury cascade, while many previous therapies focused on one particular aspect. Of specific note are vitamins, minerals and nutrients that can be utilized to supplement other therapies. Many of these have low toxicity, are already FDA approved and have minimal interactions with other drugs, making them attractive targets for therapeutics. Over the past 20 years, interest in supplementation and supraphysiologic dosing of nutrients for brain injury has increased and indeed many vitamins and nutrients now have a considerable body of literature backing their use. Here, we review several of the prominent therapies in the category of nutraceutical treatment for brain injury in experimental models, including vitamins (B2, B3, B6, B9, C, D, E), herbs and traditional medicines (ginseng, gingko biloba), flavonoids, and other nutrients (magnesium, zinc, carnitine, omega-3 fatty acids). While there is still much work to be done, several of these have strong potential for clinical therapies, particularly with regard to polydrug regimens. PMID:26723564

[Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen].

PubMed

Viguier, F; Roessle, C; Zerhouni, L; Rouleau, A; Benmelouka, C; Chevallier, A; Chast, F; Conort, O

2016-11-01

The recommended daily dose of acetaminophen is limited to 60mg/kg/day with a maximum of 3g daily dose in adults weighing less than 50kg or in patients undergoing certain risk factors. This study aimed at assessing the fulfillment of those recommendations and the possible impact on the liver dysfunction at supra-therapeutic doses of acetaminophen. This study was performed one day in 9 services. Patients characteristics, acetaminophen dose, daily dose administered, physiopathological aspects, markers of liver damage were collected. Among 542 prescriptions analyzed, 343 of them contained acetaminophen. The median age of patients studied was 81 years and one third weighed less than 50kg. The main risk factor of supra-therapeutic prescriptions was the lack of dose acetaminophen based on weight with 14% patients concerned and this risk raised at 17% when the pathophysiological conditions were included. The presence of pharmacists in medicals departments was more effective than the use of informatics programs limiting the dose systematically to 3g/day, or a distant pharmaceutical validation from care services to reduce the risk of acetaminophen overdose. According to the statement of administrations, only 4 of 49 patients received doses above 60mg/kg/day with a low impact on liver function tests. The continuous presence in pharmaceutical care services was the most effective measure to ensure effective implementation of acetaminophen recommendations. Copyright © 2016 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Melatonin Therapy in Patients with Alzheimer's Disease.

PubMed

Cardinali, Daniel P; Vigo, Daniel E; Olivar, Natividad; Vidal, María F; Brusco, Luis I

2014-04-10

Alzheimer's disease (AD) is a major health problem and a growing recognition exists that efforts to prevent it must be undertaken by both governmental and non-governmental organizations. In this context, the pineal product, melatonin, has a promising significance because of its chronobiotic/cytoprotective properties potentially useful for a number of aspects of AD. One of the features of advancing age is the gradual decrease in circulating melatonin levels. A limited number of therapeutic trials have indicated that melatonin has a therapeutic value as a neuroprotective drug in the treatment of AD and minimal cognitive impairment (which may evolve to AD). Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects, which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100 mg/day are urgently needed to assess its therapeutic validity in neurodegenerative disorders such as AD.

[Gastroprotective and antisecretory effect of a phytochemical made from matico leaves (Piper aduncum)].

PubMed

Arroyo, Jorge; Bonilla, Pablo; Moreno-Exebio, Luis; Ronceros, Gerardo; Tomás, Gloria; Huamán, Juana; Raez, Ernesto; Quino, Mariano; Rodriguez-Calzado, Javier

2013-01-01

To determine the gastroprotective and antisecretory effect of ethanol extract from matico leaves (Piper aduncum) in animal models. To evaluate the gastroprotective effect, 220 mice of the Balb C57 strain were used. They were randomized in 22 groups of ten animals each, in which the formation of gastric ulcers was induced with indomethacin. Gastroprotection was determined by evaluating three aspects: inflammation, number of hemorrhagic shocks and number of ulcers. To evaluate the antisecretory effect, 64 white male Holtzman rats were used, which were randomized in eight groups of eight animals, one control and seven groups of treatment with one extract dose level and two phytochemical dose levels. Antisecretion was obtained through the pylorus ligation. Regarding gastroprotection, dichloromethane, chloroform, hexane and methanol extracts decreased inflammation to over 66% (p<0,05). The ethanolic extract shows 100% activity in reducing the number of hemorrhagic bands (p<0,05). The chloroform extract shows antiulcer activity at 75% (p<0,05). In terms of antisecretion, the phytochemical in capsules containing the ethanolic extract achieved 72% reduction of the gastric secretion volume (p<0,01) and 104,3% (p<0,01) PH increase. In experimental conditions, ethanolic extracts, their fractions and phytochemicals have a gastroprotective effect in mice and antisecretory effect in rats.

Strategies for delivering bone morphogenetic protein for bone healing.

PubMed

Begam, Howa; Nandi, Samit Kumar; Kundu, Biswanath; Chanda, Abhijit

2017-01-01

Bone morphogenetic proteins (BMPs) are the most significant growth factors that belong to the Transforming Growth Factor Beta (TGF-β) super-family. Though more than twenty members of this family have been identified so far in humans, Food and Drug Administration (FDA) approved two growth factors: BMP-2 and BMP-7 for treatments of spinal fusion and long-bone fractures with collagen carriers. Currently BMPs are clinically used in spinal fusion, oral and maxillofacial surgery and also in the repair of long bone defects. The efficiency of BMPs depends a lot on the selection of suitable carriers. At present, different types of carrier materials are used: natural and synthetic polymers, calcium phosphate and ceramic-polymer composite materials. Number of research articles has been published on the minute intricacies of the loading process and release kinetics of BMPs. Despite the significant evidence of its potential for bone healing demonstrated in animal models, future clinical investigations are needed to define dose, scaffold and route of administration. The efficacy and application of BMPs in various levels with a proper carrier and dose is yet to be established. The present article collates various aspects of success and limitation and identifies the prospects and challenges associated with the use of BMPs in orthopaedic surgery. Copyright © 2016 Elsevier B.V. All rights reserved.

World Association for the Advancement of Veterinary Parasitology (WAAVP): Guideline for the evaluation of drug efficacy against non-coccidial gastrointestinal protozoa in livestock and companion animals.

PubMed

Geurden, T; Olson, M E; O'Handley, R M; Schetters, T; Bowman, D; Vercruysse, J

2014-08-29

The current guideline was written to aid in the design, implementation and interpretation of studies for the assessment of drug efficacy against non-coccidial gastrointestinal protozoan parasites, with Giardia spp. as the leading example. The information provided in this guideline deals with aspects of how to conduct controlled studies using experimental infection models (dose determination and dose confirmation) and efficacy studies in commercial facilities (field effectiveness studies). Furthermore, the selection of suitable animals, housing, infection procedure, choice of diagnostic technique and data analysis are discussed. This guideline is intended to assist investigators in conducting specific studies, to provide specific information for registration authorities involved in the decision-making process, to assist in the approval and registration of new drugs and to facilitate the worldwide adoption of uniform procedures. The primary parameter for drug efficacy is the reduction in either parasite excretion or parasite counts and a minimum efficacy of 90% is required against non-coccidial gastrointestinal protozoa. A supporting efficacy parameter is a significant difference in the proportion of infected animals between treated and non-treated groups. Persistent efficacy is considered as an additional claim to therapeutic efficacy. Copyright © 2014 Elsevier B.V. All rights reserved.

Cognitive outcome in adolescents and young adults after repeat courses of antenatal corticosteroids.

PubMed

Stålnacke, Johanna; Diaz Heijtz, Rochellys; Norberg, Hanna; Norman, Mikael; Smedler, Ann-Charlotte; Forssberg, Hans

2013-08-01

To investigate whether repeat courses of antenatal corticosteroids have long-term effects on cognitive and psychological functioning. In a prospective cohort study, 58 adolescents and young adults (36 males) who had been exposed to 2-9 weekly courses of betamethasone in utero were assessed with neuropsychological tests and behavior self-reports. Unexposed subjects (n = 44, 25 males) matched for age, sex, and gestational age at birth served as a comparison group. In addition, individuals exposed in utero to a single course (n = 25, 14 males) were included for dose-response analysis. Group differences were investigated using multilevel linear modeling. Mean scores obtained in 2 measures of attention and speed were significantly lower in subjects exposed to 2 or more antenatal corticosteroids courses (Symbol Search, P = .009; Digit Span Forward, P = .02), but these were not dose-dependent. Exposure to repeat courses of antenatal corticosteroids was not associated with general deficits in higher cognitive functions, self-reported attention, adaptability, or overall psychological function. Although this study indicates that repeat exposure to antenatal corticosteroids may have an impact on aspects of executive functioning, it does not provide support for the prevailing concern that such fetal exposure will have a major adverse impact on cognitive functions and psychological health later in life. Copyright © 2013 Mosby, Inc. All rights reserved.

A review: Development of a microdose model for analysis of adaptive response and bystander dose response behavior.

PubMed

Leonard, Bobby E

2008-02-27

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type (125)I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite primary unresolved questions regarding adaptive response behavior and bystander behavior. The five features of major significance provided by the Microdose Model so far are 1. Single Specific Energy Hits initiate Adaptive Response. 2. Mammogram and diagnostic X-rays induce a protective Bystander Effect as well as Adaptive Response radio-protection. 3. For mammogram X-rays the Adaptive Response protection is retained at high primer dose levels. 4. The dose range of the AR protection depends on the value of the Specific Energy per Hit, 1 >. 5. Alpha particle induced deleterious Bystander damage is modulated by low LET radiation.

[Occlusion treatment for amblyopia. Age dependence and dose-response relationship].

PubMed

Fronius, M

2016-04-01

Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.

RADIOACTIVE CONTAMINATION OF FOODS. PROBLEMS IN THE FOOD CONSUMPTION OF THE ITALIAN POPULATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferro-Luzzi, A.; Mariani, A.

The aspects of health physics that are basically applications of physics are reviewed. Units of radiation measurement, RBE, permissible doses, personnel monitoring, applications of radiation spectrometry, and measurement of body activity are considered, as well as the release, dispersion, and deposition of radioactive material in reactor accidents. 140 references. (D.C.W.)

Underestimation of Low-Dose Radiation in Treatment Planning of Intensity-Modulated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, Si Young; Liu, H. Helen; Mohan, Radhe

2008-08-01

Purpose: To investigate potential dose calculation errors in the low-dose regions and identify causes of such errors for intensity-modulated radiotherapy (IMRT). Methods and Materials: The IMRT treatment plans of 23 patients with lung cancer and mesothelioma were reviewed. Of these patients, 15 had severe pulmonary complications after radiotherapy. Two commercial treatment-planning systems (TPSs) and a Monte Carlo system were used to calculate and compare dose distributions and dose-volume parameters of the target volumes and critical structures. The effect of tissue heterogeneity, multileaf collimator (MLC) modeling, beam modeling, and other factors that could contribute to the differences in IMRT dose calculationsmore » were analyzed. Results: In the commercial TPS-generated IMRT plans, dose calculation errors primarily occurred in the low-dose regions of IMRT plans (<50% of the radiation dose prescribed for the tumor). Although errors in the dose-volume histograms of the normal lung were small (<5%) above 10 Gy, underestimation of dose <10 Gy was found to be up to 25% in patients with mesothelioma or large target volumes. These errors were found to be caused by inadequate modeling of MLC transmission and leaf scatter in commercial TPSs. The degree of low-dose errors depends on the target volumes and the degree of intensity modulation. Conclusions: Secondary radiation from MLCs contributes a significant portion of low dose in IMRT plans. Dose underestimation could occur in conventional IMRT dose calculations if such low-dose radiation is not properly accounted for.« less

An empirical model for calculation of the collimator contamination dose in therapeutic proton beams

NASA Astrophysics Data System (ADS)

Vidal, M.; De Marzi, L.; Szymanowski, H.; Guinement, L.; Nauraye, C.; Hierso, E.; Freud, N.; Ferrand, R.; François, P.; Sarrut, D.

2016-02-01

Collimators are used as lateral beam shaping devices in proton therapy with passive scattering beam lines. The dose contamination due to collimator scattering can be as high as 10% of the maximum dose and influences calculation of the output factor or monitor units (MU). To date, commercial treatment planning systems generally use a zero-thickness collimator approximation ignoring edge scattering in the aperture collimator and few analytical models have been proposed to take scattering effects into account, mainly limited to the inner collimator face component. The aim of this study was to characterize and model aperture contamination by means of a fast and accurate analytical model. The entrance face collimator scatter distribution was modeled as a 3D secondary dose source. Predicted dose contaminations were compared to measurements and Monte Carlo simulations. Measurements were performed on two different proton beam lines (a fixed horizontal beam line and a gantry beam line) with divergent apertures and for several field sizes and energies. Discrepancies between analytical algorithm dose prediction and measurements were decreased from 10% to 2% using the proposed model. Gamma-index (2%/1 mm) was respected for more than 90% of pixels. The proposed analytical algorithm increases the accuracy of analytical dose calculations with reasonable computation times.

Embracing model-based designs for dose-finding trials

PubMed Central

Love, Sharon B; Brown, Sarah; Weir, Christopher J; Harbron, Chris; Yap, Christina; Gaschler-Markefski, Birgit; Matcham, James; Caffrey, Louise; McKevitt, Christopher; Clive, Sally; Craddock, Charlie; Spicer, James; Cornelius, Victoria

2017-01-01

Background: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). Methods: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. Results: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators’ preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. Conclusions: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia. PMID:28664918

The development and validation of a Monte Carlo model for calculating the out-of-field dose from radiotherapy treatments

NASA Astrophysics Data System (ADS)

Kry, Stephen

Introduction. External beam photon radiotherapy is a common treatment for many malignancies, but results in the exposure of the patient to radiation away from the treatment site. This out-of-field radiation irradiates healthy tissue and may lead to the induction of secondary malignancies. Out-of-field radiation is composed of photons and, at high treatment energies, neutrons. Measurement of this out-of-field dose is time consuming, often difficult, and is specific to the conditions of the measurements. Monte Carlo simulations may be a viable approach to determining the out-of-field dose quickly, accurately, and for arbitrary irradiation conditions. Methods. An accelerator head, gantry, and treatment vault were modeled with MCNPX and 6 MV and 18 MV beams were simulated. Photon doses were calculated in-field and compared to measurements made with an ion chamber in a water tank. Photon doses were also calculated out-of-field from static fields and compared to measurements made with thermoluminescent dosimeters in acrylic. Neutron fluences were calculated and compared to measurements made with gold foils. Finally, photon and neutron dose equivalents were calculated in an anthropomorphic phantom following intensity-modulated radiation therapy and compared to previously published dose equivalents. Results. The Monte Carlo model was able to accurately calculate the in-field dose. From static treatment fields, the model was also able to calculate the out-of-field photon dose within 16% at 6 MV and 17% at 18 MV and the neutron fluence within 19% on average. From the simulated IMRT treatments, the calculated out-of-field photon dose was within 14% of measurement at 6 MV and 13% at 18 MV on average. The calculated neutron dose equivalent was much lower than the measured value but is likely accurate because the measured neutron dose equivalent was based on an overestimated neutron energy. Based on the calculated out-of-field doses generated by the Monte Carlo model, it was possible to estimate the risk of fatal secondary malignancy, which was consistent with previous estimates except for the neutron discrepancy. Conclusions. The Monte Carlo model developed here is well suited to studying the out-of-field dose equivalent from photons and neutrons under a variety of irradiation configurations, including complex treatments on complex phantoms. Based on the calculated dose equivalents, it is possible to estimate the risk of secondary malignancy associated with out-of-field doses. The Monte Carlo model should be used to study, quantify, and minimize the out-of-field dose equivalent and associated risks received by patients undergoing radiation therapy.

Monte Carlo evaluation of Acuros XB dose calculation Algorithm for intensity modulated radiation therapy of nasopharyngeal carcinoma

NASA Astrophysics Data System (ADS)

Yeh, Peter C. Y.; Lee, C. C.; Chao, T. C.; Tung, C. J.

2017-11-01

Intensity-modulated radiation therapy is an effective treatment modality for the nasopharyngeal carcinoma. One important aspect of this cancer treatment is the need to have an accurate dose algorithm dealing with the complex air/bone/tissue interface in the head-neck region to achieve the cure without radiation-induced toxicities. The Acuros XB algorithm explicitly solves the linear Boltzmann transport equation in voxelized volumes to account for the tissue heterogeneities such as lungs, bone, air, and soft tissues in the treatment field receiving radiotherapy. With the single beam setup in phantoms, this algorithm has already been demonstrated to achieve the comparable accuracy with Monte Carlo simulations. In the present study, five nasopharyngeal carcinoma patients treated with the intensity-modulated radiation therapy were examined for their dose distributions calculated using the Acuros XB in the planning target volume and the organ-at-risk. Corresponding results of Monte Carlo simulations were computed from the electronic portal image data and the BEAMnrc/DOSXYZnrc code. Analysis of dose distributions in terms of the clinical indices indicated that the Acuros XB was in comparable accuracy with Monte Carlo simulations and better than the anisotropic analytical algorithm for dose calculations in real patients.

Reliability of Current Biokinetic and Dosimetric Models for Radionuclides: A Pilot Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leggett, Richard Wayne; Eckerman, Keith F; Meck, Robert A.

2008-10-01

This report describes the results of a pilot study of the reliability of the biokinetic and dosimetric models currently used by the U.S. Nuclear Regulatory Commission (NRC) as predictors of dose per unit internal or external exposure to radionuclides. The study examines the feasibility of critically evaluating the accuracy of these models for a comprehensive set of radionuclides of concern to the NRC. Each critical evaluation would include: identification of discrepancies between the models and current databases; characterization of uncertainties in model predictions of dose per unit intake or unit external exposure; characterization of variability in dose per unit intakemore » or unit external exposure; and evaluation of prospects for development of more accurate models. Uncertainty refers here to the level of knowledge of a central value for a population, and variability refers to quantitative differences between different members of a population. This pilot study provides a critical assessment of models for selected radionuclides representing different levels of knowledge of dose per unit exposure. The main conclusions of this study are as follows: (1) To optimize the use of available NRC resources, the full study should focus on radionuclides most frequently encountered in the workplace or environment. A list of 50 radionuclides is proposed. (2) The reliability of a dose coefficient for inhalation or ingestion of a radionuclide (i.e., an estimate of dose per unit intake) may depend strongly on the specific application. Multiple characterizations of the uncertainty in a dose coefficient for inhalation or ingestion of a radionuclide may be needed for different forms of the radionuclide and different levels of information of that form available to the dose analyst. (3) A meaningful characterization of variability in dose per unit intake of a radionuclide requires detailed information on the biokinetics of the radionuclide and hence is not feasible for many infrequently studied radionuclides. (4) The biokinetics of a radionuclide in the human body typically represents the greatest source of uncertainty or variability in dose per unit intake. (5) Characterization of uncertainty in dose per unit exposure is generally a more straightforward problem for external exposure than for intake of a radionuclide. (6) For many radionuclides the most important outcome of a large-scale critical evaluation of databases and biokinetic models for radionuclides is expected to be the improvement of current models. Many of the current models do not fully or accurately reflect available radiobiological or physiological information, either because the models are outdated or because they were based on selective or uncritical use of data or inadequate model structures. In such cases the models should be replaced with physiologically realistic models that incorporate a wider spectrum of information.« less

Radiation dose rate affects the radiosensitization of MCF-7 and HeLa cell lines to X-rays induced by dextran-coated iron oxide nanoparticles.

PubMed

Khoshgard, Karim; Kiani, Parvaneh; Haghparast, Abbas; Hosseinzadeh, Leila; Eivazi, Mohammad Taghi

2017-08-01

The aim of radiotherapy is to deliver lethal damage to cancerous tissue while preserving adjacent normal tissues. Radiation absorbed dose of the tumoral cells can increase when high atomic nanoparticles are present in them during irradiation. Also, the dose rate is an important aspect in radiation effects that determines the biological results of a given dose. This in vitro study investigated the dose-rate effect on the induced radiosensitivity by dextran-coated iron oxide in cancer cells. HeLa and MCF-7 cells were cultured in vitro and incubated with different concentrations of dextran-coated iron oxide nanoparticles. They were then irradiated with 6 MV photons at dose rates of 43, 185 and 370 cGy/min. The MTT test was used to obtain the cells' survival after 48 h of irradiations. Incubating the cells with the nanoparticles at concentrations of 10, 40 and 80 μg/ml showed no significant cytotoxicity effect. Dextran-coated iron oxide nanoparticles showed more radiosensitivity effect by increasing the dose rate and nanoparticles concentration. Radiosensitization enhancement factors of MCF-7 and HeLa cells at a dose-rate of 370 cGy/min and nanoparticles' concentration of 80 μg/ml were 1.21 ± 0.06 and 1.19 ± 0.04, respectively. Increasing the dose rate of 6 MV photons irradiation in MCF-7 and HeLa cells increases the radiosensitization induced by the dextran-coated iron nanoparticles in these cells.

Occupational radiation exposure in vascular interventional radiology: A complete evaluation of different body regions.

PubMed

Bacchim Neto, Fernando Antonio; Alves, Allan Felipe Fattori; Mascarenhas, Yvone Maria; Nicolucci, Patrícia; Pina, Diana Rodrigues de

2016-08-01

To perform a complete evaluation on radiation doses, received by primary and assistant medical staff, while performing different vascular interventional radiology procedures. We evaluated dose received in different body regions during three categories of vascular procedures: lower limb angiography (Angiography), lower limb percutaneous transluminal angioplasty (Angioplasty) and stent graft placement for abdominal aortic aneurysm treatment (A. A. A. Treatment). We positioned the dosimeters near the eye lens, thyroid, chest, abdomen, hands, and feet of the interventional physicians. Equivalent dose was compared with annual dose limits for workers in order to determine the maximum number of procedures per year that each physician could perform. We assessed 90 procedures. We found the highest equivalent doses in the A. A. A. Treatment, in which 90% of the evaluations indicated at least one region receiving more than 1mSv per procedure. Angioplasty was the only procedural modality that provided statistically different doses for different professionals, which is an important aspect on regards to radiological protection strategies. In comparison with the dose limits, the most critical region in all procedures was the eye lens. Since each body region of the interventionist is exposed to different radiation levels, dose distribution measurements are essential for radiological protection strategies. These results indicate that dosimeters placed in abdomen instead of chest may represent more accurately the whole body doses received by the medical staff. Additional dosimeters and a stationary shield for the eye lens are strongly recommended. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Standard and reduced radiation dose liver CT images: adaptive statistical iterative reconstruction versus model-based iterative reconstruction-comparison of findings and image quality.

PubMed

Shuman, William P; Chan, Keith T; Busey, Janet M; Mitsumori, Lee M; Choi, Eunice; Koprowicz, Kent M; Kanal, Kalpana M

2014-12-01

To investigate whether reduced radiation dose liver computed tomography (CT) images reconstructed with model-based iterative reconstruction ( MBIR model-based iterative reconstruction ) might compromise depiction of clinically relevant findings or might have decreased image quality when compared with clinical standard radiation dose CT images reconstructed with adaptive statistical iterative reconstruction ( ASIR adaptive statistical iterative reconstruction ). With institutional review board approval, informed consent, and HIPAA compliance, 50 patients (39 men, 11 women) were prospectively included who underwent liver CT. After a portal venous pass with ASIR adaptive statistical iterative reconstruction images, a 60% reduced radiation dose pass was added with MBIR model-based iterative reconstruction images. One reviewer scored ASIR adaptive statistical iterative reconstruction image quality and marked findings. Two additional independent reviewers noted whether marked findings were present on MBIR model-based iterative reconstruction images and assigned scores for relative conspicuity, spatial resolution, image noise, and image quality. Liver and aorta Hounsfield units and image noise were measured. Volume CT dose index and size-specific dose estimate ( SSDE size-specific dose estimate ) were recorded. Qualitative reviewer scores were summarized. Formal statistical inference for signal-to-noise ratio ( SNR signal-to-noise ratio ), contrast-to-noise ratio ( CNR contrast-to-noise ratio ), volume CT dose index, and SSDE size-specific dose estimate was made (paired t tests), with Bonferroni adjustment. Two independent reviewers identified all 136 ASIR adaptive statistical iterative reconstruction image findings (n = 272) on MBIR model-based iterative reconstruction images, scoring them as equal or better for conspicuity, spatial resolution, and image noise in 94.1% (256 of 272), 96.7% (263 of 272), and 99.3% (270 of 272), respectively. In 50 image sets, two reviewers (n = 100) scored overall image quality as sufficient or good with MBIR model-based iterative reconstruction in 99% (99 of 100). Liver SNR signal-to-noise ratio was significantly greater for MBIR model-based iterative reconstruction (10.8 ± 2.5 [standard deviation] vs 7.7 ± 1.4, P < .001); there was no difference for CNR contrast-to-noise ratio (2.5 ± 1.4 vs 2.4 ± 1.4, P = .45). For ASIR adaptive statistical iterative reconstruction and MBIR model-based iterative reconstruction , respectively, volume CT dose index was 15.2 mGy ± 7.6 versus 6.2 mGy ± 3.6; SSDE size-specific dose estimate was 16.4 mGy ± 6.6 versus 6.7 mGy ± 3.1 (P < .001). Liver CT images reconstructed with MBIR model-based iterative reconstruction may allow up to 59% radiation dose reduction compared with the dose with ASIR adaptive statistical iterative reconstruction , without compromising depiction of findings or image quality. © RSNA, 2014.

Normal tissue complication probability modelling of tissue fibrosis following breast radiotherapy

NASA Astrophysics Data System (ADS)

Alexander, M. A. R.; Brooks, W. A.; Blake, S. W.

2007-04-01

Cosmetic late effects of radiotherapy such as tissue fibrosis are increasingly regarded as being of importance. It is generally considered that the complication probability of a radiotherapy plan is dependent on the dose uniformity, and can be reduced by using better compensation to remove dose hotspots. This work aimed to model the effects of improved dose homogeneity on complication probability. The Lyman and relative seriality NTCP models were fitted to clinical fibrosis data for the breast collated from the literature. Breast outlines were obtained from a commercially available Rando phantom using the Osiris system. Multislice breast treatment plans were produced using a variety of compensation methods. Dose-volume histograms (DVHs) obtained for each treatment plan were reduced to simple numerical parameters using the equivalent uniform dose and effective volume DVH reduction methods. These parameters were input into the models to obtain complication probability predictions. The fitted model parameters were consistent with a parallel tissue architecture. Conventional clinical plans generally showed reducing complication probabilities with increasing compensation sophistication. Extremely homogenous plans representing idealized IMRT treatments showed increased complication probabilities compared to conventional planning methods, as a result of increased dose to areas receiving sub-prescription doses using conventional techniques.

Patient- and cohort-specific dose and risk estimation for abdominopelvic CT: a study based on 100 patients

NASA Astrophysics Data System (ADS)

Tian, Xiaoyu; Li, Xiang; Segars, W. Paul; Frush, Donald P.; Samei, Ehsan

2012-03-01

The purpose of this work was twofold: (a) to estimate patient- and cohort-specific radiation dose and cancer risk index for abdominopelvic computer tomography (CT) scans; (b) to evaluate the effects of patient anatomical characteristics (size, age, and gender) and CT scanner model on dose and risk conversion coefficients. The study included 100 patient models (42 pediatric models, 58 adult models) and multi-detector array CT scanners from two commercial manufacturers (LightSpeed VCT, GE Healthcare; SOMATOM Definition Flash, Siemens Healthcare). A previously-validated Monte Carlo program was used to simulate organ dose for each patient model and each scanner, from which DLP-normalized-effective dose (k factor) and DLP-normalized-risk index values (q factor) were derived. The k factor showed exponential decrease with increasing patient size. For a given gender, q factor showed exponential decrease with both increasing patient size and patient age. The discrepancies in k and q factors across scanners were on average 8% and 15%, respectively. This study demonstrates the feasibility of estimating patient-specific organ dose and cohort-specific effective dose and risk index in abdominopelvic CT requiring only the knowledge of patient size, gender, and age.

Learning the Lexical Aspects of a Second Language at Different Proficiencies: A Neural Computational Study

ERIC Educational Resources Information Center

Cuppini, Cristiano; Magosso, Elisa; Ursino, Mauro

2013-01-01

We present an original model designed to study how a second language (L2) is acquired in bilinguals at different proficiencies starting from an existing L1. The model assumes that the conceptual and lexical aspects of languages are stored separately: conceptual aspects in distinct topologically organized Feature Areas, and lexical aspects in a…

Evaluation of radiation dose to anthropomorphic paediatric models from positron-emitting labelled tracers

NASA Astrophysics Data System (ADS)

Xie, Tianwu; Zaidi, Habib

2014-03-01

PET uses specific molecules labelled with positron-emitting radionuclides to provide valuable biochemical and physiological information. However, the administration of radiotracers to patients exposes them to low-dose ionizing radiation, which is a concern in the paediatric population since children are at a higher cancer risk from radiation exposure than adults. Therefore, radiation dosimety calculations for commonly used positron-emitting radiotracers in the paediatric population are highly desired. We evaluate the absorbed dose and effective dose for 19 positron-emitting labelled radiotracers in anthropomorphic paediatric models including the newborn, 1-, 5-, 10- and 15-year-old male and female. This is achieved using pre-calculated S-values of positron-emitting radionuclides of UF-NCI paediatric phantoms and published biokinetic data for various radiotracers. The influence of the type of anthropomorphic model, tissue weight factors and direct human- versus mouse-derived biokinetic data on the effective dose for paediatric phantoms was also evaluated. In the case of 18F-FDG, dosimetry calculations of reference paediatric patients from various dose regimens were also calculated. Among the considered radiotracers, 18F-FBPA and 15O-water resulted in the highest and lowest effective dose in the paediatric phantoms, respectively. The ICRP 103 updated tissue-weighting factors decrease the effective dose in most cases. Substantial differences of radiation dose were observed between direct human- versus mouse-derived biokinetic data. Moreover, the effect of using voxel- versus MIRD-type models on the calculation of the effective dose was also studied. The generated database of absorbed organ dose and effective dose for various positron-emitting labelled radiotracers using new generation computational models and the new ICRP tissue-weighting factors can be used for the assessment of radiation risks to paediatric patients in clinical practice. This work also contributes to a better understanding of the factors influencing patient-specific radiation dose calculation.

Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bakhshandeh, Mohsen; Hashemi, Bijan, E-mail: bhashemi@modares.ac.ir; Mahdavi, Seied Rabi Mehdi

Purpose: To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Methods and Materials: Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-basedmore » treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with {alpha}/{beta} = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Results: Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D{sub 50} estimated from the models was approximately 44 Gy. Conclusions: The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.« less

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Current modeling practice may lead to falsely high benchmark dose estimates.

PubMed

Ringblom, Joakim; Johanson, Gunnar; Öberg, Mattias

2014-07-01

Benchmark dose (BMD) modeling is increasingly used as the preferred approach to define the point-of-departure for health risk assessment of chemicals. As data are inherently variable, there is always a risk to select a model that defines a lower confidence bound of the BMD (BMDL) that, contrary to expected, exceeds the true BMD. The aim of this study was to investigate how often and under what circumstances such anomalies occur under current modeling practice. Continuous data were generated from a realistic dose-effect curve by Monte Carlo simulations using four dose groups and a set of five different dose placement scenarios, group sizes between 5 and 50 animals and coefficients of variations of 5-15%. The BMD calculations were conducted using nested exponential models, as most BMD software use nested approaches. "Non-protective" BMDLs (higher than true BMD) were frequently observed, in some scenarios reaching 80%. The phenomenon was mainly related to the selection of the non-sigmoidal exponential model (Effect=a·e(b)(·dose)). In conclusion, non-sigmoid models should be used with caution as it may underestimate the risk, illustrating that awareness of the model selection process and sound identification of the point-of-departure is vital for health risk assessment. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Americium-241 Decorporation Model

DTIC Science & Technology

2014-10-01

doses compared Radiation Dose Convert mass to activity if needed Calculate critical organ doses/ effective whole body dose (Christy and Eckerman...compartments over time with and without treatment, excretion rates, and radiation doses to critical organs. Calculations from the model may be used to...268 x E + 2 newton-meter (N/m) pound-force/foot2 4.788 026 x E – 2 kilo pascal (kPa) pound-force/inch2 (psi) 6.894 757 kilo pascal (kPa) pound- mass

A measurement-based generalized source model for Monte Carlo dose simulations of CT scans

PubMed Central

Ming, Xin; Feng, Yuanming; Liu, Ransheng; Yang, Chengwen; Zhou, Li; Zhai, Hezheng; Deng, Jun

2018-01-01

The goal of this study is to develop a generalized source model (GSM) for accurate Monte Carlo dose simulations of CT scans based solely on the measurement data without a priori knowledge of scanner specifications. The proposed generalized source model consists of an extended circular source located at x-ray target level with its energy spectrum, source distribution and fluence distribution derived from a set of measurement data conveniently available in the clinic. Specifically, the central axis percent depth dose (PDD) curves measured in water and the cone output factors measured in air were used to derive the energy spectrum and the source distribution respectively with a Levenberg-Marquardt algorithm. The in-air film measurement of fan-beam dose profiles at fixed gantry was back-projected to generate the fluence distribution of the source model. A benchmarked Monte Carlo user code was used to simulate the dose distributions in water with the developed source model as beam input. The feasibility and accuracy of the proposed source model was tested on a GE LightSpeed and a Philips Brilliance Big Bore multi-detector CT (MDCT) scanners available in our clinic. In general, the Monte Carlo simulations of the PDDs in water and dose profiles along lateral and longitudinal directions agreed with the measurements within 4%/1mm for both CT scanners. The absolute dose comparison using two CTDI phantoms (16 cm and 32 cm in diameters) indicated a better than 5% agreement between the Monte Carlo-simulated and the ion chamber-measured doses at a variety of locations for the two scanners. Overall, this study demonstrated that a generalized source model can be constructed based only on a set of measurement data and used for accurate Monte Carlo dose simulations of patients’ CT scans, which would facilitate patient-specific CT organ dose estimation and cancer risk management in the diagnostic and therapeutic radiology. PMID:28079526

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCulloch, M; Polan, D; Feng, M

Purpose: Previous studies have shown that radiotherapy treatment for liver metastases causes marked liver hypertrophy in areas receiving low dose and atrophy/fibrosis in areas receiving high dose. The purpose of this work is to develop and evaluate a biomechanical model-based dose-response model to describe these liver responses to SBRT. Methods: In this retrospective study, a biomechanical model-based deformable registration algorithm, Morfeus, was expanded to include dose-based boundary conditions. Liver and tumor volumes were contoured on the planning images and CT/MR images three months post-RT and converted to finite element models. A thermal expansion-based relationship correlating the delivered dose and volumemore » response was generated from 22 patients previously treated. This coefficient, combined with the planned dose, was applied as an additional boundary condition to describe the volumetric response of the liver of an additional cohort of metastatic liver patients treated with SBRT. The accuracy of the model was evaluated based on overall volumetric liver comparisons and the target registration error (TRE) using the average deviations in positions of identified vascular bifurcations on each set of registered images, with a target accuracy of the 2.5mm isotropic dose grid (vector dimension 4.3mm). Results: The thermal expansion coefficient models the volumetric change of the liver to within 3%. The accuracy of Morfeus with dose-expansion boundary conditions a TRE of 5.7±2.8mm compared to 11.2±3.7mm using rigid registration and 8.9±0.28mm using Morfeus with only spatial boundary conditions. Conclusion: A biomechanical model has been developed to describe the volumetric and spatial response of the liver to SBRT. This work will enable the improvement of correlating functional imaging with delivered dose, the mapping of the delivered dose from one treatment onto the planning images for a subsequent treatment, and will further provide information to assist with the biological characterization of patients’ response to radiation.« less

A measurement-based generalized source model for Monte Carlo dose simulations of CT scans

NASA Astrophysics Data System (ADS)

Ming, Xin; Feng, Yuanming; Liu, Ransheng; Yang, Chengwen; Zhou, Li; Zhai, Hezheng; Deng, Jun

2017-03-01

The goal of this study is to develop a generalized source model for accurate Monte Carlo dose simulations of CT scans based solely on the measurement data without a priori knowledge of scanner specifications. The proposed generalized source model consists of an extended circular source located at x-ray target level with its energy spectrum, source distribution and fluence distribution derived from a set of measurement data conveniently available in the clinic. Specifically, the central axis percent depth dose (PDD) curves measured in water and the cone output factors measured in air were used to derive the energy spectrum and the source distribution respectively with a Levenberg-Marquardt algorithm. The in-air film measurement of fan-beam dose profiles at fixed gantry was back-projected to generate the fluence distribution of the source model. A benchmarked Monte Carlo user code was used to simulate the dose distributions in water with the developed source model as beam input. The feasibility and accuracy of the proposed source model was tested on a GE LightSpeed and a Philips Brilliance Big Bore multi-detector CT (MDCT) scanners available in our clinic. In general, the Monte Carlo simulations of the PDDs in water and dose profiles along lateral and longitudinal directions agreed with the measurements within 4%/1 mm for both CT scanners. The absolute dose comparison using two CTDI phantoms (16 cm and 32 cm in diameters) indicated a better than 5% agreement between the Monte Carlo-simulated and the ion chamber-measured doses at a variety of locations for the two scanners. Overall, this study demonstrated that a generalized source model can be constructed based only on a set of measurement data and used for accurate Monte Carlo dose simulations of patients’ CT scans, which would facilitate patient-specific CT organ dose estimation and cancer risk management in the diagnostic and therapeutic radiology.

Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

PubMed Central

Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.

2015-01-01

Experimental Data Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t>60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t<60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. Mathematical Modeling We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods. PMID:25993564

Coordination of frontline defense mechanisms under severe oxidative stress.

PubMed

Kaur, Amardeep; Van, Phu T; Busch, Courtney R; Robinson, Courtney K; Pan, Min; Pang, Wyming Lee; Reiss, David J; DiRuggiero, Jocelyne; Baliga, Nitin S

2010-07-01

Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism. Through experimental validation of interactions within the OSR regulatory network, we show that despite their inability to directly sense reactive oxygen species, general transcription factors have an important function in coordinating this response. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was earlier constructed from cellular responses to diverse environmental perturbations--this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of gamma rays.

Monte Carlo track structure for radiation biology and space applications

NASA Technical Reports Server (NTRS)

Nikjoo, H.; Uehara, S.; Khvostunov, I. G.; Cucinotta, F. A.; Wilson, W. E.; Goodhead, D. T.

2001-01-01

Over the past two decades event by event Monte Carlo track structure codes have increasingly been used for biophysical modelling and radiotherapy. Advent of these codes has helped to shed light on many aspects of microdosimetry and mechanism of damage by ionising radiation in the cell. These codes have continuously been modified to include new improved cross sections and computational techniques. This paper provides a summary of input data for ionizations, excitations and elastic scattering cross sections for event by event Monte Carlo track structure simulations for electrons and ions in the form of parametric equations, which makes it easy to reproduce the data. Stopping power and radial distribution of dose are presented for ions and compared with experimental data. A model is described for simulation of full slowing down of proton tracks in water in the range 1 keV to 1 MeV. Modelling and calculations are presented for the response of a TEPC proportional counter irradiated with 5 MeV alpha-particles. Distributions are presented for the wall and wall-less counters. Data shows contribution of indirect effects to the lineal energy distribution for the wall counters responses even at such a low ion energy.

Mycotoxins co-contamination: Methodological aspects and biological relevance of combined toxicity studies.

PubMed

Alassane-Kpembi, Imourana; Schatzmayr, Gerd; Taranu, Ionelia; Marin, Daniela; Puel, Olivier; Oswald, Isabelle Paule

2017-11-02

Mycotoxins are secondary fungal metabolites produced mainly by Aspergillus, Penicillium, and Fusarium. As evidenced by large-scale surveys, humans and animals are simultaneously exposed to several mycotoxins. Simultaneous exposure could result in synergistic, additive or antagonistic effects. However, most toxicity studies addressed the effects of mycotoxins separately. We present the experimental designs and we discuss the conclusions drawn from in vitro experiments exploring toxicological interactions of mycotoxins. We report more than 80 publications related to mycotoxin interactions. The studies explored combinations involving the regulated groups of mycotoxins, especially aflatoxins, ochratoxins, fumonisins, zearalenone and trichothecenes, but also the "emerging" mycotoxins beauvericin and enniatins. Over 50 publications are based on the arithmetic model of additivity. Few studies used the factorial designs or the theoretical biology-based models of additivity. The latter approaches are gaining increased attention. These analyses allow determination of the type of interaction and, optionally, its magnitude. The type of interaction reported for mycotoxin combinations depended on several factors, in particular cell models and the tested dose ranges. However, synergy among Fusarium toxins was highlighted in several studies. This review indicates that well-addressed in vitro studies remain valuable tools for the screening of interactive potential in mycotoxin mixtures.

Monte Carlo dosimetry for {sup 103}Pd, {sup 125}I, and {sup 131}Cs ocular brachytherapy with various plaque models using an eye phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lesperance, Marielle; Martinov, M.; Thomson, R. M., E-mail: rthomson@physics.carleton.ca

Purpose: To investigate dosimetry for ocular brachytherapy for a range of eye plaque models containing{sup 103}Pd, {sup 125}I, or {sup 131}Cs seeds with model-based dose calculations. Methods: Five representative plaque models are developed based on a literature review and are compared to the standardized COMS plaque, including plaques consisting of a stainless steel backing and acrylic insert, and gold alloy backings with: short collimating lips and acrylic insert, no lips and silicone polymer insert, no lips and a thin acrylic layer, and individual collimating slots for each seed within the backing and no insert. Monte Carlo simulations are performed usingmore » the EGSnrc user-code BrachyDose for single and multiple seed configurations for the plaques in water and within an eye model (including nonwater media). Simulations under TG-43 assumptions are also performed, i.e., with the same seed configurations in water, neglecting interseed and plaque effects. Maximum and average doses to ocular structures as well as isodose contours are compared for simulations of each radionuclide within the plaque models. Results: The presence of the plaque affects the dose distribution substantially along the plaque axis for both single seed and multiseed simulations of each plaque design in water. Of all the plaque models, the COMS plaque generally has the largest effect on the dose distribution in water along the plaque axis. Differences between doses for single and multiple seed configurations vary between plaque models and radionuclides. Collimation is most substantial for the plaque with individual collimating slots. For plaques in the full eye model, average dose in the tumor region differs from those for the TG-43 simulations by up to 10% for{sup 125}I and {sup 131}Cs, and up to 17% for {sup 103}Pd, and in the lens region by up to 29% for {sup 125}I, 34% for {sup 103}Pd, and 28% for {sup 131}Cs. For the same prescription dose to the tumor apex, the lowest doses to critical ocular structures are generally delivered with plaques containing {sup 103}Pd seeds. Conclusions: The combined effects of ocular and plaque media on dose are significant and vary with plaque model and radionuclide, suggesting the importance of model-based dose calculations employing accurate ocular and plaque media and geometries for eye plaque brachytherapy.« less

Beyond Gaussians: a study of single spot modeling for scanning proton dose calculation

PubMed Central

Li, Yupeng; Zhu, Ronald X.; Sahoo, Narayan; Anand, Aman; Zhang, Xiaodong

2013-01-01

Active spot scanning proton therapy is becoming increasingly adopted by proton therapy centers worldwide. Unlike passive-scattering proton therapy, active spot scanning proton therapy, especially intensity-modulated proton therapy, requires proper modeling of each scanning spot to ensure accurate computation of the total dose distribution contributed from a large number of spots. During commissioning of the spot scanning gantry at the Proton Therapy Center in Houston, it was observed that the long-range scattering protons in a medium may have been inadequately modeled for high-energy beams by a commercial treatment planning system, which could lead to incorrect prediction of field-size effects on dose output. In the present study, we developed a pencil-beam algorithm for scanning-proton dose calculation by focusing on properly modeling individual scanning spots. All modeling parameters required by the pencil-beam algorithm can be generated based solely on a few sets of measured data. We demonstrated that low-dose halos in single-spot profiles in the medium could be adequately modeled with the addition of a modified Cauchy-Lorentz distribution function to a double-Gaussian function. The field-size effects were accurately computed at all depths and field sizes for all energies, and good dose accuracy was also achieved for patient dose verification. The implementation of the proposed pencil beam algorithm also enabled us to study the importance of different modeling components and parameters at various beam energies. The results of this study may be helpful in improving dose calculation accuracy and simplifying beam commissioning and treatment planning processes for spot scanning proton therapy. PMID:22297324

Fluence-to-absorbed-dose conversion coefficients for neutron beams from 0.001 eV to 100 GeV calculated for a set of pregnant female and fetus models

NASA Astrophysics Data System (ADS)

Taranenko, Valery; Xu, X. George

2008-03-01

Protection of fetuses against external neutron exposure is an important task. This paper reports a set of absorbed dose conversion coefficients for fetal and maternal organs for external neutron beams using the RPI-P pregnant female models and the MCNPX code. The newly developed pregnant female models represent an adult female with a fetus including its brain and skeleton at the end of each trimester. The organ masses were adjusted to match the reference values within 1%. For the 3 mm cubic voxel size, the models consist of 10-15 million voxels for 35 organs. External monoenergetic neutron beams of six standard configurations (AP, PA, LLAT, RLAT, ROT and ISO) and source energies 0.001 eV-100 GeV were considered. The results are compared with previous data that are based on simplified anatomical models. The differences in dose depend on source geometry, energy and gestation periods: from 20% up to 140% for the whole fetus, and up to 100% for the fetal brain. Anatomical differences are primarily responsible for the discrepancies in the organ doses. For the first time, the dependence of mother organ doses upon anatomical changes during pregnancy was studied. A maximum of 220% increase in dose was observed for the placenta in the nine months model compared to three months, whereas dose to the pancreas, small and large intestines decreases by 60% for the AP source for the same models. Tabulated dose conversion coefficients for the fetus and 27 maternal organs are provided.

Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, John M., E-mail: jrobertson@beaumont.ed; Soehn, Matthias; Yan Di

Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to developmore » a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.« less

Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.

PubMed

Yap, Christina; Billingham, Lucinda J; Cheung, Ying Kuen; Craddock, Charlie; O'Quigley, John

2017-12-15

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR . ©2017 American Association for Cancer Research.

SU-F-T-142: An Analytical Model to Correct the Aperture Scattered Dose in Clinical Proton Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, B; Liu, S; Zhang, T

2016-06-15

Purpose: Apertures or collimators are used to laterally shape proton beams in double scattering (DS) delivery and to sharpen the penumbra in pencil beam (PB) delivery. However, aperture-scattered dose is not included in the current dose calculations of treatment planning system (TPS). The purpose of this study is to provide a method to correct the aperture-scattered dose based on an analytical model. Methods: A DS beam with a non-divergent aperture was delivered using a single-room proton machine. Dose profiles were measured with an ion-chamber scanning in water and a 2-D ion chamber matrix with solid-water buildup at various depths. Themore » measured doses were considered as the sum of the non-contaminated dose and the aperture-scattered dose. The non-contaminated dose was calculated by TPS and subtracted from the measured dose. Aperture scattered-dose was modeled as a 1D Gaussian distribution. For 2-D fields, to calculate the scatter-dose from all the edges of aperture, a sum of weighted distance was used in the model based on the distance from calculation point to aperture edge. The gamma index was calculated between the measured and calculated dose with and without scatter correction. Results: For a beam with range of 23 cm and aperture size of 20 cm, the contribution of the scatter horn was ∼8% of the total dose at 4 cm depth and diminished to 0 at 15 cm depth. The amplitude of scatter-dose decreased linearly with the depth increase. The 1D gamma index (2%/2 mm) between the calculated and measured profiles increased from 63% to 98% for 4 cm depth and from 83% to 98% at 13 cm depth. The 2D gamma index (2%/2 mm) at 4 cm depth has improved from 78% to 94%. Conclusion: Using the simple analytical method the discrepancy between the measured and calculated dose has significantly improved.« less

Comparison of 2-Dose and 3-Dose 9-Valent Human Papillomavirus Vaccine Schedules in the United States: A Cost-effectiveness Analysis.

PubMed

Laprise, Jean-François; Markowitz, Lauri E; Chesson, Harrell W; Drolet, Mélanie; Brisson, Marc

2016-09-01

A recent clinical trial using the 9-valent human papillomavirus virus (HPV) vaccine has shown that antibody responses after 2 doses are noninferior to those after 3 doses, suggesting that 2 and 3 doses may have comparable vaccine efficacy. We used an individual-based transmission-dynamic model to compare the population-level effectiveness and cost-effectiveness of 2- and 3-dose schedules of 9-valent HPV vaccine in the United States. Our model predicts that if 2 doses of 9-valent vaccine protect for ≥20 years, the additional benefits of a 3-dose schedule are small as compared to those of 2-dose schedules, and 2-dose schedules are likely much more cost-efficient than 3-dose schedules. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Cytogenetic effect of low dose gamma-radiation in Hordeum vulgare seedlings: non-linear dose-effect relationship.

PubMed

Geras'kin, Stanislav A; Oudalova, Alla A; Kim, Jin Kyu; Dikarev, Vladimir G; Dikareva, Nina S

2007-03-01

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10-1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed.

Estimation of absorbed doses from paediatric cone-beam CT scans: MOSFET measurements and Monte Carlo simulations.

PubMed

Kim, Sangroh; Yoshizumi, Terry T; Toncheva, Greta; Frush, Donald P; Yin, Fang-Fang

2010-03-01

The purpose of this study was to establish a dose estimation tool with Monte Carlo (MC) simulations. A 5-y-old paediatric anthropomorphic phantom was computed tomography (CT) scanned to create a voxelised phantom and used as an input for the abdominal cone-beam CT in a BEAMnrc/EGSnrc MC system. An X-ray tube model of the Varian On-Board Imager((R)) was built in the MC system. To validate the model, the absorbed doses at each organ location for standard-dose and low-dose modes were measured in the physical phantom with MOSFET detectors; effective doses were also calculated. In the results, the MC simulations were comparable to the MOSFET measurements. This voxelised phantom approach could produce a more accurate dose estimation than the stylised phantom method. This model can be easily applied to multi-detector CT dosimetry.

Ecological Dose Modeling of Aquatic and Riparian Receptors to Strontium-90 with an Emphasis on Radiosensitive Organs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poston, Ted M.; Traub, Richard J.; Antonio, Ernest J.

2011-07-20

The 100-NR-2 site is the location of elevated releases of strontium-90 to the Columbia River via contaminated groundwater. The resulting dose to aquatic and riparian receptors was evaluated in 2005 (DOE 2009) and compared to U.S. Department of Energy (DOE) dose guidance values. We have conducted additional dose assessments for a broader spectrum of aquatic and riparian organisms using RESRAD Biota and specific exposure scenarios. Because strontium-90 accumulates in bone, we have also modeled the dose to the anterior kidney, a blood-forming and immune system organ that lies close to the spinal column of fish. The resulting dose is primarilymore » attributable to the yttrium-90 progeny of strontium-90 and very little of the dose is associated with the beta emission from strontium-90. All dose modeling results were calculated with an assumption of secular equilibrium between strontium-90 and yttrum-90.« less

Model-derived dose rates per unit concentration of radon in air in a generic plant geometry.

PubMed

Vives i Batlle, J; Smith, A; Vives-Lynch, S; Copplestone, D; Pröhl, G; Strand, T

2011-11-01

A model for the derivation of dose rates per unit radon concentration in plants was developed in line with the activities of a Task Group of the International Commission on Radiological Protection (ICRP), aimed at developing more realistic dosimetry for non-human biota. The model considers interception of the unattached and attached fractions of the airborne radon daughters by plant stomata, diffusion of radon gas through stomata, permeation through the plant's epidermis and translocation of deposited activity to plant interior. The endpoint of the model is the derivation of dose conversion coefficients relative to radon gas concentration at ground level. The model predicts that the main contributor to dose is deposition of (214)Po α-activity on the plant surface and that diffusion of radon daughters through the stomata is of relatively minor importance; hence, daily variations have a small effect on total dose.

A consistent two-mutation model of bone cancer for two data sets of radium-injected beagles.

PubMed

Bijwaard, H; Brugmans, M J P; Leenhouts, H P

2002-09-01

A two-mutation carcinogenesis model has been applied to model osteosarcoma incidence in two data sets of beagles injected with 226Ra. Taking age-specific retention into account, the following results have been obtained: (1) a consistent and well-fitting solution for all age and dose groups, (2) mutation rates that are linearly dependent on dose rate, with an exponential decrease for the second mutation at high dose rates, (3) a linear-quadratic dose-effect relationship, which indicates that care should be taken when extrapolating linearly, (4) highest cumulative incidences for injection at young adult age, and highest risks for injection doses of a few kBq kg(-1) at these ages, and (5) when scaled appropriately, the beagle model compares fairly well with a description for radium dial painters, suggesting that a consistent model description of bone cancer induction in beagles and humans may be possible.

Modulation of some quantitative and qualitative characteristics in rice ( Oryza sativa L.) and mung ( Phaseolus mungo L.) by ionizing radiation

NASA Astrophysics Data System (ADS)

Maity, J. P.; Mishra, D.; Chakraborty, A.; Saha, A.; Santra, S. C.; Chanda, S.

2005-12-01

The present work describes radiation-induced effects on some morphological characters of a cereal and a pulse-producing crop in India. 60Co gamma source is used for irradiating (from 50 to 350 Gy) the rice ( Oryza sativa L., Cv-2233) and mung ( Phaseolus mungo L.). Irradiation at lower doses of gamma rays effectively influences improving the morphological traits like seedling/plant height, tiller number, panicle number, panicle length, seed per panicle, seed per pod, pod length, pod number, while exposure at higher doses results in depletion of such parameters. Effective stimulatory dose for Oryza sativa L. Cv-2233 is 50 Gy and that for Phaseolus mungo L. is 200 Gy. Significance of such stimulation correlated with yielding ability of the plant concerned is discussed in the light of newer aspects in agricultural research.

Low dosages: new chemotherapeutic weapons on the battlefield of immune-related disease

PubMed Central

Liu, Jing; Zhao, Jie; Hu, Liang; Cao, Yuchun; Huang, Bo

2011-01-01

Chemotherapeutic drugs eliminate tumor cells at relatively high doses and are considered weapons against tumors in clinics and hospitals. However, despite their ability to induce cellular apoptosis, chemotherapeutic drugs should probably be regarded more as a class of cell regulators than cell killers, if the dosage used and the fact that their targets are involved in basic molecular events are considered. Unfortunately, the regulatory properties of chemotherapeutic drugs are usually hidden or masked by the massive cell death induced by high doses. Recent evidence has begun to suggest that low dosages of chemotherapeutic drugs might profoundly regulate various intracellular aspects of normal cells, especially immune cells. Here, we discuss the immune regulatory roles of three kinds of chemotherapeutic drugs under low-dose conditions and propose low dosages as potential new chemotherapeutic weapons on the battlefield of immune-related disease. PMID:21423201

[Medical expert consensus in AH on the clinical use of triple fixed-dose antihypertensive therapy in Spain].

PubMed

Mazón, P; Galve, E; Gómez, J; Gorostidi, M; Górriz, J L; Mediavilla, J D

The opinion of experts (different specialties) on the triple fixed-dose antihypertensive therapy in clinical practice may differ. Online questionnaire with controversial aspects of the triple therapy answered by panel of experts in hypertension (HT) using two-round modified Delphi method. The questionnaire was completed by 158 experts: Internal Medicine (49), Nephrology (26), Cardiology (83). Consensus was reached (agreement) on 27/45 items (60%); 7 items showed differences statistically significant. Consensus was reached regarding: Predictive factors in the need for combination therapy and its efficacy vs. increasing the dose of a pretreatment, and advantage of triple therapy (prescription/adherence/cost/pressure control) vs. free combination. This consensus provides an overview of the clinical use of triple therapy in moderate-severe and resistant/difficult to control HT. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

EPA Science Inventory

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking infor...

Low-dose ionizing radiation limitations to seed germination: Results from a model linking physiological characteristics and developmental-dynamics simulation strategy.

PubMed

Liu, Hui; Hu, Dawei; Dong, Chen; Fu, Yuming; Liu, Guanghui; Qin, Youcai; Sun, Yi; Liu, Dianlei; Li, Lei; Liu, Hong

2017-08-01

There is much uncertainty about the risks of seed germination after repeated or protracted environmental low-dose ionizing radiation exposure. The purpose of this study is to explore the influence mechanism of low-dose ionizing radiation on wheat seed germination using a model linking physiological characteristics and developmental-dynamics simulation. A low-dose ionizing radiation environment simulator was built to investigate wheat (Triticum aestivum L.) seeds germination process and then a kinetic model expressing the relationship between wheat seed germination dynamics and low-dose ionizing radiation intensity variations was developed by experimental data, plant physiology, relevant hypotheses and system dynamics, and sufficiently validated and accredited by computer simulation. Germination percentages were showing no differences in response to different dose rates. However, root and shoot lengths were reduced significantly. Plasma governing equations were set up and the finite element analysis demonstrated H 2 O, CO 2 , O 2 as well as the seed physiological responses to the low-dose ionizing radiation. The kinetic model was highly valid, and simultaneously the related influence mechanism of low-dose ionizing radiation on wheat seed germination proposed in the modeling process was also adequately verified. Collectively these data demonstrate that low-dose ionizing radiation has an important effect on absorbing water, consuming O 2 and releasing CO 2 , which means the risk for embryo and endosperm development was higher. Copyright © 2017 Elsevier Ltd. All rights reserved.

Around Semipalatinsk nuclear test site: progress of dose estimations relevant to the consequences of nuclear tests (a summary of 3rd Dosimetry Workshop on the Semipalatinsk nuclear test site area, RIRBM, Hiroshima University, Hiroshima, 9-11 of March, 2005).

PubMed

Stepanenko, Valeriy F; Hoshi, Masaharu; Bailiff, Ian K; Ivannikov, Alexander I; Toyoda, Shin; Yamamoto, Masayoshi; Simon, Steven L; Matsuo, Masatsugu; Kawano, Noriyuki; Zhumadilov, Zhaxybay; Sasaki, Masao S; Rosenson, Rafail I; Apsalikov, Kazbek N

2006-02-01

The paper is an analytical overview of the main results presented at the 3rd Dosimetry Workshop in Hiroshima(9-11 of March 2005), where different aspects of the dose reconstruction around the Semipalatinsk nuclear test site(SNTS) were discussed and summarized. The results of the international intercomparison of the retrospective luminescence dosimetry(RLD) method for Dolon' village(Kazakhstan) were presented at the Workshop and good concurrence between dose estimations by different laboratories from 6 countries (Japan, Russia, USA, Germany, Finland and UK) was pointed out. The accumulated dose values in brick for a common depth of 10mm depth obtained independently by all participating laboratories were in good agreement for all four brick samples from Dolon' village, Kazakhstan, with the average value of the local gamma dose due to fallout (near the sampling locations) being about 220 mGy(background dose has been subtracted).Furthermore, using a conversion factor of about 2 to obtain the free-in-air dose, a value of local dose approximately 440 mGy is obtained, which supports the results of external dose calculations for Dolon': recently published soil contamination data, archive information and new models were used for refining dose calculations and the external dose in air for Dolon village was estimated to be about 500 mGy. The results of electron spin resonance(ESR) dosimetry with tooth enamel have demonstrated the notable progress in application of ESR dosimetry to the problems of dose reconstruction around the Semipalatinsk nuclear test site. At the present moment, dose estimates by the ESR method have become more consistent with calculated values and with retrospective luminescence dosimetry data, but differences between ESR dose estimates and RLD/calculation data were noted. For example mean ESR dose for eligible tooth samples from Dolon' village was estimated to be about 140 mGy(above background dose), which is less than dose values obtained by RLD and calculations. A possible explanation of the differences between ESR and RLD/calculations doses is the following: for interpretation of ESR data the "shielding and behaviour" factors for investigated persons should be taken into account. The "upper level" of the combination of "shielding and behaviour" factors of dose reduction for inhabitants of Dolon' village of about 0.28 was obtained by comparing the individual ESR tooth enamel dose estimates with the calculated mean dose for this settlement. The biological dosimetry data related to the settlements near SNTS were presented at the Workshop. A higher incidence of unstable chromosome aberrations, micronucleus in lymphocytes, nuclear abnormalities of thyroid follicular cells, T-cell receptor mutations in peripheral blood were found for exposed areas (Dolon', Sarjal) in comparison with unexposed ones(Kokpekty). The significant greater frequency of stable translocations (results of analyses of chromosome aberrations in lymphocytes by the FISH technique) was demonstrated for Dolon' village in comparison with Chekoman(unexposed village). The elevated level of stable translocations in Dolon' corresponds to a dose of about 180 mSv, which is close to the results of ESR dosimetry for this village. The importance of investigating specific morphological types of thyroid nodules for thyroid dosimetry studies was pointed out. In general the 3rd Dosimetry Workshop has demonstrated remarkable progress in developing an international level of common approaches for retrospective dose estimations around the SNTS and in understanding the tasks for the future joint work in this direction. In the framework of a special session the problems of developing a database and registry in order to support epidemiological studies around SNTS were discussed. The results of investigation of psychological consequences of nuclear tests, which are expressed in the form of verbal behaviour, were presented at this session as well.

Interactions of elevation, aspect, and slope in models of forest species composition and productivity

Treesearch

Albert R. Stage; Christian Salas

2007-01-01

We present a linear model for the interacting effects of elevation, aspect, and slope for use in predicting forest productivity or species composition. The model formulation we propose integrates interactions of these three factors in a mathematical expression representing their combined effect in terms of a cosine function of aspect with a phase shift and amplitude...

Development of a flattening filter free multiple source model for use as an independent, Monte Carlo, dose calculation, quality assurance tool for clinical trials.

PubMed

Faught, Austin M; Davidson, Scott E; Popple, Richard; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

2017-09-01

The Imaging and Radiation Oncology Core-Houston (IROC-H) Quality Assurance Center (formerly the Radiological Physics Center) has reported varying levels of compliance from their anthropomorphic phantom auditing program. IROC-H studies have suggested that one source of disagreement between institution submitted calculated doses and measurement is the accuracy of the institution's treatment planning system dose calculations and heterogeneity corrections used. In order to audit this step of the radiation therapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Varian flattening filter free (FFF) 6 MV and FFF 10 MV therapeutic x-ray beams were commissioned based on central axis depth dose data from a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open-field measurements in a water tank for field sizes ranging from 3 × 3 cm 2 to 40 × 40 cm 2 . The models were then benchmarked against IROC-H's anthropomorphic head and neck phantom and lung phantom measurements. Validation results, assessed with a ±2%/2 mm gamma criterion, showed average agreement of 99.9% and 99.0% for central axis depth dose data for FFF 6 MV and FFF 10 MV models, respectively. Dose profile agreement using the same evaluation technique averaged 97.8% and 97.9% for the respective models. Phantom benchmarking comparisons were evaluated with a ±3%/2 mm gamma criterion, and agreement averaged 90.1% and 90.8% for the respective models. Multiple source models for Varian FFF 6 MV and FFF 10 MV beams have been developed, validated, and benchmarked for inclusion in an independent dose calculation quality assurance tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.