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Within this special issue, many eminent investigators report on measurements of oxygen (O 2 ) levels in tissues. Given the complexities of spatial and temporal heterogeneities of O 2 in tissues and its many sources, this commentary draws attention to what such measurements do and do not actually assess regarding O 2 levels in tissues. Given this limitation, it also discusses how these results can be used most effectively. To provide a convenient mechanism to discuss these issues more fully, this analysis focuses on measurements using EPR oximetry, but these considerations apply to all other techniques. The nature of the delivery of O 2 to tissues and the mechanisms by which O 2 is consumed necessarily result in very different levels of O 2 within the volume of each voxel of a measurement. Better spatial resolution cannot fully resolve the problem because the variations include O 2 gradients within each cell. Improved resolution of the time-dependent variation in O 2 is also very challenging because O 2 levels within tissues can have fluctuations of O 2 levels in the range of milliseconds, while most methods require longer times to acquire the data from each voxel. Based on these issues, we argue that the values obtained inevitably are complex aggregates of averages of O 2 levels across space and time in the tissue. These complexities arise from the complex physiology of tissues and are compounded by the limitations of the technique and its ability to acquire data. However, one often can obtain very meaningful and useful results if these complexities and limitations are taken into account. We illustrate this, using results obtained with in vivo EPR oximetry, especially utilizing its capacity to make repeated measurements to follow changes in O 2 levels that occur with interventions and/or over time., (© 2024. The Author(s), under exclusive licence to World Molecular Imaging Society.)

The development of effective uses of biodosimetry in large-scale events has been hampered by residual, i.e., "legacy" thinking based on strategies that scale up from biodosimetry in small accidents. Consequently, there remain vestiges of unrealistic assumptions about the likely magnitude of victims in "large" radiation events and incomplete analyses of the logistics for making biodosimetry measurements/assessments in the field for primary triage. Elements remain from an unrealistic focus on developing methods to use biodosimetry in the initial stage of triage for a million or more victims. Based on recent events and concomitant increased awareness of the potential for large-scale events as well as increased sophistication in planning and experience in the development of biodosimetry, a more realistic assessment of the most effective roles of biodosimetry in large-scale events is urgently needed. We argue this leads to a conclusion that the most effective utilization of biodosimetry in very large events would occur in a second stage of triage, after initially winnowing the population by identifying those most in need of acute medical attention, based on calculations of geographic sites where significant exposures could have occurred. Understanding the potential roles and limitations of biodosimetry in large-scale events involving significant radiation exposure should lead to development of the most effective and useful biodosimetric techniques for each stage of triage for acute radiation syndrome injuries, i.e., based on more realistic assumptions about the underlying event and the logistics for carrying out biodosimetry for large populations., (©2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Purpose: Electron paramagnetic resonance (EPR) biodosimetry, used to triage large numbers of individuals incidentally exposed to unknown doses of ionizing radiation, is based on detecting a stable physical response in the body that is subject to quantifiable variation after exposure. In vivo measurement is essential to fully characterize the radiation response relevant to a living tooth measured in situ. The purpose of this study was to verify EPR spectroscopy in vivo by estimating the radiation dose received in participants' teeth., Methods and Materials: A continuous wave L-band spectrometer was used for EPR measurements. Participants included healthy volunteers and patients undergoing head and neck and total body irradiation treatments. Healthy volunteers completed 1 measurement each, and patients underwent measurement before starting treatment and between subsequent fractions. Optically stimulated luminescent dosimeters and diodes were used to determine the dose delivered to the teeth to validate EPR measurements., Results: Seventy measurements were acquired from 4 total body irradiation and 6 head and neck patients over 15 months. Patient data showed a linear increase of EPR signal with delivered dose across the dose range tested. A linear least-squares weighted fit of the data gave a statistically significant correlation between EPR signal and absorbed dose (P < .0001). The standard error of inverse prediction (SEIP), used to assess the usefulness of fits, was 1.92 Gy for the dose range most relevant for immediate triage (≤7 Gy). Correcting for natural background radiation based on patient age reduced the SEIP to 1.51 Gy., Conclusions: This study demonstrated the feasibility of using spectroscopic measurements from radiation therapy patients to validate in vivo EPR biodosimetry. The data illustrated a statistically significant correlation between the magnitude of EPR signals and absorbed dose. The SEIP of 1.51 Gy, obtained under clinical conditions, indicates the potential value of this technique in response to large radiation events., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Measuring oxygen (O 2 ) in tissues has been a central theme of the International Society on Oxygen Transport to Tissue (ISOTT) since its founding 50 years ago in 1973. The initial presentations by many distinguished members reflect this focus and demonstrate the importance of the contributions of the members of ISOTT. This paper considers their work and its legacy in the context of the continuing challenges of making meaningful measurements of O 2 in tissue. Because many technical, physiological, and pathophysiological factors are directly or implicitly involved in obtaining any measured value of O 2 in living tissues, interpretations of what the measured value represents and its biological implications need to take these factors into account. The challenges arise from two very simple but painfully true factors that make it challenging to obtain measurements of O 2 in tissues in vivo that are useful for the understanding of physiological and pathophysiological processes. First, throughout the volume of functioning tissue that is assessed by any technique, there is a complex spatial heterogeneity of O 2 levels. No technique can usually fully represent this complexity in a given measurement, because the heterogeneity extends from the environment in the tissue surrounding cells to variations within the cell. Therefore, the value of the output from a measurement inevitably consists of a complex, averaged summary of O 2 in the tissue. Second, the levels of O 2 are constantly changing in living tissues (variations occur in seconds, minutes, hours, and/or days and differ by location) at rates that are difficult to resolve for available techniques, because they occur faster than data acquisition time and/or cannot be used as frequently as needed to follow the longer-term changes. However, as demonstrated in research reported in the publications from ISOTT, studies of O 2 in tissue, in spite of the potential ambiguities in the measured values, can provide very valuable insights into physiology and pathophysiology. This is most likely to occur if researchers explicitly recognise why and how their measurement does not fully portray the complexity of O 2 . When measurements can be repeated, the resulting change between measurements provides information about the dynamics of the physiology and pathophysiology. Assessing change in O 2 levels can also provide evidence about responses to treatments. Similarly, finding evidence of hypoxia, even though it does not capture the heterogeneity and dynamics actually happening in the tissue, can still inform clinical care if the measurement is well-understood., (© 2024. Oxygen Transport to Tissue International.)

This paper briefly examines electron paramagnetic resonance (EPR) techniques to measure dose from exposure to external radiation, assessing their current status, potential future uses and the challenges impacting their progress. We conclude the uses and potential value of different EPR techniques depend on the number of victims and whether they characterize short- or long-term risks from exposure. For large populations, EPR biodosimetry based on in vivo measurements or using co-located inanimate objects offer the greatest promise for assessing acute, life-threatening risk and the magnitude and extent of such risk. To assess long-term risk, ex vivo EPR methods using concentrated enamel from exfoliated teeth are most impactful. For small groups, ex vivo EPR biodosimetry based on available samples of teeth, nails and/or bones are most useful. The most important challenges are common to all approaches: improve the technique's technical capabilities and advance recognition by planning groups of the relative strengths EPR techniques offer for each population size. The most useful applications are likely to be for triage and medical guidance in large events and for radiation epidemiology to evaluate long-term risks., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Extremely high dose rate radiation delivery (FLASH) for cancer treatment has been shown to produce less damage to normal tissues while having the same radiotoxic effect on tumor tissue (referred to as the FLASH effect). Research on the FLASH effect has two very pertinent implications for the field of biodosimetry: (1) FLASH is a good model to simulate delivery of prompt radiation from the initial moments after detonating a nuclear weapon and (2) the FLASH effect elucidates how dose rate impacts the biological mechanisms that underlie most types of biological biodosimetry. The impact of dose rate will likely differ for different types of biodosimetry, depending on the specific underlying mechanisms. The greatest impact of FLASH effects is likely to occur for assays based on biological responses to radiation damage, but the consequences of differential effects of dose rates on the accuracy of dose estimates has not been taken into account., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Following large-scale radiation events, an overwhelming number of people will potentially need mitigators or treatment for radiation-induced injuries. This necessitates having methods to triage people based on their dose and its likely distribution, so life-saving treatment is directed only to people who can benefit from such care. Using estimates of victims following an improvised nuclear device striking a major city, we illustrate a two-tier approach to triage. At the second tier, after first removing most who would not benefit from care, biodosimetry should provide accurate dose estimates and determine whether the dose was heterogeneous. We illustrate the value of using in vivo electron paramagnetic resonance nail biodosimetry to rapidly assess dose and determine its heterogeneity using independent measurements of nails from the hands and feet. Having previously established its feasibility, we review the benefits and challenges of potential improvements of this method that would make it particularly suitable for tier 2 triage. Improvements, guided by a user-centered approach to design and development, include expanding its capability to make simultaneous, independent measurements and improving its precision and universality., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this review is to stimulate readers to undertake appropriate investigations of the mechanism for a possible oxygen effect in FLASH. FLASH is a method of delivery of radiation that empirically, in animal models, appears to decrease the impact of radiation on normal tissues while retaining full effect on tumors. This has the potential for achieving a significantly increased effectiveness of radiation therapy. The mechanism is not known but, especially in view of the prominent role that oxygen has in the effects of radiation, investigations of mechanisms of FLASH have often focused on impacts of FLASH on oxygen levels. We and others have previously shown that simple differential depletion of oxygen directly changing the response to radiation is not a likely mechanism. In this review we consider how time-varying changes in oxygen levels could account for the FLASH effect by changing oxygen-dependent signaling in cells. While the methods of delivering FLASH are still evolving, current approaches for FLASH can differ from conventional irradiation in several ways that can impact the pattern of oxygen consumption: the rate of delivery of the radiation (40 Gy/s vs. 0.1 Gy/s), the time over which each fraction is delivered (e.g., <0.5 s. vs. 300 s), the delivery in pulses, the number of fractions, the size of the fractions, and the total duration of treatment. Taking these differences into account and recognizing that cell signaling is an intrinsic component of the need for cells to maintain steady-state conditions and, therefore, is activated by small changes in the environment, we delineate the potential time dependent changes in oxygen consumption and overview the cell signaling pathways whose differential activation by FLASH could account for the observed biological effects of FLASH. We speculate that the most likely pathways are those involved in repair of damaged DNA., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The delivery of radiation at an ultra-high dose rate (FLASH) is an important new approach to radiotherapy (RT) that appears to be able to improve the therapeutic ratio by diminishing damage to normal tissues. While the mechanisms by which FLASH improves outcomes have not been established, a role involving molecular oxygen (O 2 ) is frequently mentioned. In order to effectively determine if the protective effect of FLASH RT occurs via a differential direct depletion of O 2 (compared to conventional radiation), it is essential to consider the known role of O 2 in modifying the response of cells and tissues to ionising radiation (known as 'the oxygen effect'). Considerations include: (1) The pertinent reaction involves an unstable intermediate of radiation-damaged DNA, which either undergoes chemical repair to restore the DNA or reacts with O 2 , resulting in an unrepairable lesion in the DNA, (2) These reactions occur in the nuclear DNA, which can be used to estimate the distance needed for O 2 to diffuse through the cell to reach the intermediates, (3) The longest lifetime that the reactive site of the DNA is available to react with O 2 is 1-10 μsec, (4) Using these lifetime estimates and known diffusion rates in different cell media, the maximal distance that O 2 could travel in the cytosol to reach the site of the DNA (i.e., the nucleus) in time to react are 60-185 nm. This calculation defines the volume of oxygen that is pertinent for the direct oxygen effect, (5) Therefore, direct measurements of oxygen to determine if FLASH RT operates through differential radiochemical depletion of oxygen will require the ability to measure oxygen selectively in a sphere of <200 nm, with a time resolution of the duration of the delivery of FLASH, (6) It also is possible that alterations of oxygen levels by FLASH could occur more indirectly by affecting oxygen-dependent cell signalling and/or cellular repair., (© 2022. Springer Nature Switzerland AG.)

Objective: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the 'OxyChip', as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing., Methods: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO 2 ) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry., Results: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4-128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO 2 values were variable with overall median 15.7 mmHg (range 0.6-73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO 2 was 31.8 mmHg (range 1.5-144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation., Conclusions: Measurement of baseline pO 2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes., Competing Interests: PK has multiple patents issued for OxyChip; but declares no competing interest. AF and HS are co-owners of Clin-EPR, a company that sells EPR spectrometers for research use in human subjects. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schaner, Williams, Chen, Pettus, Schreiber, Kmiec, Jarvis, Pastel, Zuurbier, DiFlorio-Alexander, Paydarfar, Gosselin, Barth, Rosenkranz, Petryakov, Hou, Tse, Pletnev, Flood, Wood, Hebert, Mosher, Demidenko, Swartz and Kuppusamy.)

During a first-in-humans clinical trial investigating electron paramagnetic resonance tumor oximetry, a patient injected with the particulate oxygen sensor Printex ink was found to have unexpected fluorodeoxyglucose (FDG) uptake in a dermal nodule via positron emission tomography (PET). This nodule co-localized with the Printex ink injection; biopsy of the area, due to concern for malignancy, revealed findings consistent with ink and an associated inflammatory reaction. Investigations were subsequently performed to assess the impact of oxygen sensors on FDG-PET/CT imaging. A retrospective analysis of three clinical tumor oximetry trials involving two oxygen sensors (charcoal particulates and LiNc-BuO microcrystals) in 22 patients was performed to evaluate FDG imaging characteristics. The impact of clinically used oxygen sensors (carbon black, charcoal particulates, LiNc-BuO microcrystals) on FDG-PET/CT imaging after implantation in rat muscle (n = 12) was investigated. The retrospective review revealed no other patients with FDG avidity associated with particulate sensors. The preclinical investigation found no injected oxygen sensor whose mean standard uptake values differed significantly from sham injections. The risk of a false-positive FDG-PET/CT scan due to oxygen sensors appears low. However, in the right clinical context the potential exists that an associated inflammatory reaction may confound interpretation.

The effectiveness of blood transfusions can be impacted by storage and extensive processing techniques that involve treatment of red blood cells (RBCs) with pathogen reduction technologies (e.g., UV-light and chemical treatment), ex vivo stem cell derivation/maturation methods, and bioengineering of RBCs using nanotechnology. Therefore, there is a need to have methods that assess the evaluation of the effectiveness of transfusions to achieve their intended purpose: to increase oxygenation of critical tissues. Consequently, there has been intense interest in the development of techniques targeted at optimizing the assessment of RBC quality in preclinical and clinical settings. We provide a critical assessment of the ability of currently used methods to provide unambiguous information on oxygen levels in tissues and conclude that they cannot do this. This is because they are based on surrogates for the true goal of transfusion, which is to increase oxygenation of critical organs. This does not mean that they are valueless, but it does indicate that other methods are needed to provide direct measurements of oxygen in tissues. We report here on the initial results of a method that can provide direct assessment of the impact of the transfusion on tissue oxygen: EPR oximetry. It has the potential to provide such information in both preclinical and clinical settings for the assessment of blood quality posttransfusion.

Clinical measurements of O 2 in tissues will inevitably provide data that are at best aggregated and will not reflect the inherent heterogeneity of O 2 in tissues over space and time. Additionally, the nature of all existing techniques to measure O 2 results in complex sampling of the volume that is sensed by the technique. By recognizing these potential limitations of the measures, one can focus on the very important and useful information that can be obtained from these techniques, especially data about factors that can change levels of O 2 and then exploit these changes diagnostically and therapeutically. The clinical utility of such data ultimately needs to be verified by careful studies of outcomes related to the measured changes in levels of O 2 .

Introduction: Tumor hypoxia confers both a poor prognosis and increased resistance to oncologic therapies, and therefore, hypoxia modification with reliable oxygen profiling during anticancer treatment is desirable. The OxyChip is an implantable oxygen sensor that can detect tumor oxygen levels using electron paramagnetic resonance (EPR) oximetry. We report initial safety and feasibility outcomes after OxyChip implantation in a first-in-humans clinical trial (NCT02706197, www.clinicaltrials.gov). Materials and Methods: Twenty-four patients were enrolled. Eligible patients had a tumor ≤ 3 cm from the skin surface with planned surgical resection as part of standard-of-care therapy. Most patients had a squamous cell carcinoma of the skin (33%) or a breast malignancy (33%). After an initial cohort of six patients who received surgery alone, eligibility was expanded to patients receiving either chemotherapy or radiotherapy prior to surgical resection. The OxyChip was implanted into the tumor using an 18-G needle; a subset of patients had ultrasound-guided implantation. Electron paramagnetic resonance oximetry was carried out using a custom-built clinical EPR scanner. Patients were evaluated for associated toxicity using the Common Terminology Criteria for Adverse Events (CTCAE); evaluations started immediately after OxyChip placement, occurred during every EPR oximetry measurement, and continued periodically after removal. The OxyChip was removed during standard-of-care surgery, and pathologic analysis of the tissue surrounding the OxyChip was performed. Results: Eighteen patients received surgery alone, while five underwent chemotherapy and one underwent radiotherapy prior to surgery. No unanticipated serious adverse device events occurred. The maximum severity of any adverse event as graded by the CTCAE was 1 (least severe), and all were related to events typically associated with implantation. After surgical resection, 45% of the patients had no histopathologic findings specifically associated with the OxyChip. All tissue pathology was "anticipated" excepting a patient with greater than expected inflammatory findings, which was assessed to be related to the tumor as opposed to the OxyChip. Conclusion: This report of the first-in-humans trial of OxyChip implantation and EPR oximetry demonstrated no significant clinical pathology or unanticipated serious adverse device events. Use of the OxyChip in the clinic was thus safe and feasible., (Copyright © 2020 Schaner, Pettus, Flood, Williams, Jarvis, Chen, Pastel, Zuurbier, diFlorio-Alexander, Swartz and Kuppusamy.)

It is well understood that the level of molecular oxygen (O 2 ) in tissue is a very important factor impacting both physiology and pathological processes as well as responsiveness to some treatments. Data on O 2 in tissue could be effectively utilized to enhance precision medicine. However, the nature of the data that can be obtained using existing clinically applicable techniques is often misunderstood, and this can confound the effective use of the information. Attempts to make clinical measurements of O 2 in tissues will inevitably provide data that are aggregated over time and space and therefore will not fully represent the inherent heterogeneity of O 2 in tissues. Additionally, the nature of existing techniques to measure O 2 may result in uneven sampling of the volume of interest and therefore may not provide accurate information on the "average" O 2 in the measured volume. By recognizing the potential limitations of the O 2 measurements, one can focus on the important and useful information that can be obtained from these techniques. The most valuable clinical characterizations of oxygen are likely to be derived from a series of measurements that provide data about factors that can change levels of O 2 , which then can be exploited both diagnostically and therapeutically. The clinical utility of such data ultimately needs to be verified by careful studies of outcomes related to the measured changes in levels of O 2 ., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

An effective medical response to a large-scale radiation event requires prompt and effective initial triage so that appropriate care can be provided to individuals with significant risk for severe acute radiation injury. Arguably, it would be advantageous to use injury rather than radiation dose for the initial assessment; i.e., use bioassays of biological damage. Such assays would be based on changes in intrinsic biological response elements; e.g., up- or down-regulation of genes, proteins, metabolites, blood cell counts, chromosomal aberrations, micronuclei, micro-RNA, cytokines, or transcriptomes. Using a framework to evaluate the feasibility of biodosimetry for triaging up to a million people in less than a week following a major radiation event, Part 1 analyzes the logistical feasibility and clinical needs for ensuring that biomarkers of organ-specific injury could be effectively used in this context. We conclude that the decision to use biomarkers of organ-specific injury would greatly benefit by first having independent knowledge of whether the person's exposure was heterogeneous and, if so, what was the dose distribution (to determine which organs were exposed to high doses). In Part 2, we describe how these two essential needs for prior information (heterogeneity and dose distribution) could be obtained by using in vivo nail dosimetry. This novel physical biodosimetry method can also meet the needs for initial triage, providing non-invasive, point-of-care measurements made by non-experts with immediate dose estimates for four separate anatomical sites. Additionally, it uniquely provides immediate information as to whether the exposure was homogeneous and, if not, it can estimate the dose distribution. We conclude that combining the capability of methods such as in vivo EPR nail dosimetry with bioassays to predict organ-specific damage would allow effective use of medical resources to save lives.

The aim of the paper is to discuss what currently is feasible clinically to measure the level of oxygen and how that measurement can be clinically useful. Because oxygen in tissues is quite heterogeneous and all methods of measurement can only provide an average across heterogeneities at some spatial and temporal resolution, the values that are obtained may have limitations on their clinical utility. However, even if such limitations are significant, if one utilizes repeated measurements and focuses on changes in the measured levels, rather than 'absolute levels', it may be possible to obtain very useful clinical information. While these considerations are especially pertinent in cancer, they also pertain to most other types of pathology.

The success of treatment for malignancies, especially those undergoing radiation therapy or chemotherapy, has long been recognized to depend on the degree of hypoxia in the tumor. In addition to the prognostic value of knowing the tumor's initial level of hypoxia, assessing the tumor oxygenation during standard therapy or oxygen-related treatments (such as breathing oxygen-enriched gas mixtures or taking drugs that can increase oxygen supply to tissues) can provide valuable data to improve the efficacy of treatments. A series of early clinical studies of tumors in humans are ongoing at Dartmouth and Emory using electron paramagnetic resonance (EPR) oximetry to assess tumor oxygenation, initially and over time during either natural disease progression or treatment. This approach has the potential for reaching the long-sought goal of enhancing the effectiveness of cancer therapy. In order to effectively reach this goal, we consider the validity of the practical and statistical assumptions when interpreting the measurements made in vivo for patients undergoing treatment for cancer.

In May 2019, scholars in management and organization of health care organizations and systems met. The opening plenary was a moderated discussion with five distinguished scholars who have exemplified pushing the frontier of organizational theory and practice throughout their careers: Ann Barry Flood of Dartmouth College, John Kimberly of the University of Pennsylvania, Anthony (Tony) Kovner of New York University, Stephen (Steve) Shortell of University of California at Berkeley, and Jacqueline (Jackie) Zinn of Temple University. The discussion was moderated by Ingrid Nembhard of the University of Pennsylvania. The goal of the plenary was to provide an opportunity to hear from senior members of the health care management community how they think about organizational behavior and theory, changes that they have observed, research gaps that they see, and lessons for research and practice that they have learned. This article is the transcript of that plenary discussion. It is shared to capture the intellectual history of the field and help surface the critical advancements still needed in organizational theory and practice in health care. The closing remarks of the panelists summarize recommendations for both practice and scholarship in health care organization management.

Background: The goal of red blood cell transfusion is to improve tissue oxygenation. Assessment of red blood cell quality and individualised therapeutic needs can be optimised using direct oxygen (O 2 ) measurements to guide treatment. Electron paramagnetic resonance oximetry is capable of accurate, repeatable and minimally invasive measurements of tissue pO 2 . Here we present preclinical proof-of-concept of the utility of electron paramagnetic resonance oximetry in an experimental setting of acute blood loss, transfusion, and post-transfusion monitoring., Materials and Methods: Donor rat blood was collected, leucocyte-reduced, and stored at 4 °C in AS-3 for 1, 7 and 14 days. Red blood cell morphology, O 2 equilibrium, p50 and Hill numbers from O 2 binding and dissociation curves were evaluated in vitro. Recipient rats were bled and maintained at a mean arterial pressure of 30-40 mmHg and hind limb muscle (biceps femoris) pO 2 at 25-50% of baseline. Muscle pO 2 was monitored continuously over the course of experiments to assess the effectiveness of red blood cell preparations at different stages of blood loss and restoration., Results: Red blood cell morphology, O 2 equilibrium and p50 values of intra-erythrocyte haemoglobin were significantly altered by refrigerated storage for both 7 and 14 days. Transfusion of red blood cells stored for 7 or 14 days demonstrated an equivalently impaired ability to restore hind limb muscle pO 2 , consistent with in vitro observations and transfusion with albumin. Red blood cells refrigerated for 1 day demonstrated normal morphology, in vitro oxygenation and in vivo restoration of tissue pO 2 ., Discussion: Electron paramagnetic resonance oximetry represents a useful approach to assessing the quality of red blood cells and subsequent transfusion effectiveness.

In a large-scale radiation event, thousands may be exposed to unknown amounts of radiation, some of which may be life-threatening without immediate attention. In such situations, a method to quickly and reliably estimate dose would help medical responders triage victims to receive life-saving care. We developed such a method using electron paramagnetic resonance (EPR) to make in vivo measurements of the maxillary incisors. This report provides evidence that the use of in vitro studies can provide data that are fully representative of the measurements made in vivo. This is necessary because, in order to systematically test and improve the reliability and accuracy of the dose estimates made with our EPR dosimetry system, it is important to conduct controlled studies in vitro using irradiated human teeth. Therefore, it is imperative to validate whether our in vitro models adequately simulate the measurements made in vivo, which are intended to help guide decisions on triage after a radiation event. Using a healthy volunteer with a dentition gap that allows using a partial denture, human teeth were serially irradiated in vitro and then, using a partial denture, placed in the volunteer's mouth for measurements. We compared dose estimates made using in vivo measurements made in the volunteer's mouth to measurements made on the same teeth in our complex mouth model that simulates electromagnetic and anatomic properties of the mouth. Our results demonstrate that this mouth model can be used in in vitro studies to develop the system because these measurements appropriately model in vivo conditions.

Instrumentation and application methodologies for rapidly and accurately estimating individual ionizing radiation dose are needed for on-site triage in a radiological/nuclear event. One such methodology is an in vivo X-band, electron paramagnetic resonance, physically based dosimetry method to directly measure the radiation-induced signal in fingernails. The primary components under development are key instrument features, such as resonators with unique geometries that allow for large sampling volumes but limit radiation-induced signal measurements to the nail plate, and methodological approaches for addressing interfering signals in the nail and for calibrating dose from radiation-induced signal measurements. One resonator development highlighted here is a surface resonator array designed to reduce signal detection losses due to the soft tissues underlying the nail plate. Several surface resonator array geometries, along with ergonomic features to stabilize fingernail placement, have been tested in tissue-equivalent nail models and in vivo nail measurements of healthy volunteers using simulated radiation-induced signals in their fingernails. These studies demonstrated radiation-induced signal detection sensitivities and quantitation limits approaching the clinically relevant range of ≤ 10 Gy. Studies of the capabilities of the current instrument suggest that a reduction in the variability in radiation-induced signal measurements can be obtained with refinements to the surface resonator array and ergonomic features of the human interface to the instrument. Additional studies are required before the quantitative limits of the assay can be determined for triage decisions in a field application of dosimetry. These include expanded in vivo nail studies and associated ex vivo nail studies to provide informed approaches to accommodate for a potential interfering native signal in the nails when calculating the radiation-induced signal from the nail plate spectral measurements and to provide a method for calibrating dose estimates from the radiation-induced signal measurements based on quantifying experiments in patients undergoing total-body irradiation or total-skin electron therapy.

This paper considers the critical role that academics can have in the development of clinical innovations and especially how their impact can be optimized. The focus should be on establishing the safety and efficacy of new approaches while also incorporating human factors and human use considerations into the inventions. It is very advantageous to work in concert with the end-users (operators and clinicians) to help ensure that the innovation will be useful and feasible to be incorporated into actual clinical practice as intended. This strategy enables developments to tackle real clinical needs by providing novel strategies to improve patient care while using solutions that fit into clinical practice and that are welcomed by patients and clinical staff. These principles are illustrated by a case study of the development of clinical in vivo EPR oximetry.

Hypoxic tumors are more resistant to radiotherapy and chemotherapy, which decreases the efficacy of these common forms of treatment. We have been developing implantable paramagnetic particulates to measure oxygen in vivo using electron paramagnetic resonance. Once implanted, oxygen can be measured repeatedly and non-invasively in superficial tissues (<3 cm deep), using an electron paramagnetic resonance spectrometer and an external surface-loop resonator. To significantly extend the clinical applications of electron paramagnetic resonance oximetry, we developed an implantable resonator system to obtain measurements at deeper sites. This system has been used to successfully obtain oxygen measurements in animal studies for several years. We report here on recent developments needed to meet the regulatory requirements to make this technology available for clinical use. radio frequency heating is discussed and magnetic resonance compatibility testing of the device has been carried out by a Good Laboratory Practice-certified laboratory. The geometry of the implantable resonator has been modified to meet our focused goal of verifying safety and efficacy for the proposed use of intracranial measurements and also for future use in tissue sites other than the brain. We have encapsulated the device within a smooth cylindrical-shaped silicone elastomer to prevent tissues from adhering to the device and to limit perturbation of tissue during implantation and removal. We have modified the configuration for simultaneously measuring oxygen at multiple sites by developing a linear array of oxygen sensing probes, which each provide independent measurements. If positive results are obtained in additional studies which evaluate biocompatibility and chemical characterization, we believe the implantable resonator will be at a suitable stage for initial testing in human subjects.

Clinical EPR spectroscopy is emerging as an important modality, with the potential to be used in standard clinical practice to determine the extent of hypoxia in tissues and whether hypoxic tissues respond to breathing enriched oxygen during therapy. Oximetry can provide important information useful for prognosis and to improve patient outcomes. EPR oximetry has many potential advantages over other ways to measure oxygen in tissues, including directly measuring oxygen in tissues and being particularly sensitive to low oxygen, repeatable, and non-invasive after an initial injection of the EPR-sensing material is placed in the tumor. The most immediately available oxygen sensor is India ink, where two classes of carbon (carbon black and charcoal) have been identified as having acceptable paramagnetic properties for oximetry. While India ink has a long history of safe use in tattoos, a systematic research search regarding its safety for marking tissues for medical uses and an examination of the evidence that differentiates between ink based on charcoal or carbon black has not been conducted., Methods: Using systematic literature search techniques, we searched the PubMed and Food and Drug Administration databases, finding ~1000 publications reporting on adverse events associated with India/carbon based inks. The detailed review of outcomes was based on studies involving >16 patients, where the ink was identifiable as carbon black or charcoal., Results: Fifty-six studies met these criteria. There were few reports of complications other than transient and usually mild discomfort and bleeding at injection, and there was no difference in charcoal vs. carbon black India ink., Conclusions: India ink was generally well tolerated by patients and physicians reported that it was easy to use in practice and used few resources. The risk is low enough to justify its use as an oxygen sensor in clinical practice.

The aim of the study is to determine the average intensity and variation of the native background signal amplitude (NSA) and of the solar light-induced signal amplitude (LSA) in electron paramagnetic resonance (EPR) spectra of tooth enamel for different kinds of teeth and different groups of people. These values are necessary for determination of the intensity of the radiation-induced signal amplitude (RSA) by subtraction of the expected NSA and LSA from the total signal amplitude measured in L-band for in vivo EPR dosimetry. Variation of these signals should be taken into account when estimating the uncertainty of the estimated RSA. A new analysis of several hundred EPR spectra that were measured earlier at X-band in a large-scale examination of the population of the Central Russia was performed. Based on this analysis, the average values and the variation (standard deviation, SD) of the amplitude of the NSA for the teeth from different positions, as well as LSA in outer enamel of the front teeth for different population groups, were determined. To convert data acquired at X-band to values corresponding to the conditions of measurement at L-band, the experimental dependencies of the intensities of the RSA, LSA and NSA on the m.w. power, measured at both X and L-band, were analysed. For the two central upper incisors, which are mainly used in in vivo dosimetry, the mean LSA annual rate induced only in the outer side enamel and its variation were obtained as 10 ± 2 (SD = 8) mGy y -1 , the same for X- and L-bands (results are presented as the mean ± error of mean). Mean NSA in enamel and its variation for the upper incisors was calculated at 2.0 ± 0.2 (SD = 0.5) Gy, relative to the calibrated RSA dose-response to gamma radiation measured under non-power saturation conditions at X-band. Assuming the same value for L-band under non-power saturating conditions, then for in vivo measurements at L-band at 25 mW (power saturation conditions), a mean NSA and its variation correspond to 4.0 ± 0.4 (SD = 1.0) Gy., (© Crown copyright 2016.)

Several important recent advances in the development and evolution of in vivo Tooth Biodosimetry using Electron Paramagnetic Resonance (EPR) allow its performance to meet or exceed the U.S. targeted requirements for accuracy and ease of operation and throughput in a large-scale radiation event. Ergonomically based changes to the magnet, coupled with the development of rotation of the magnet and advanced software to automate collection of data, have made it easier and faster to make a measurement. From start to finish, measurements require a total elapsed time of 5 min, with data acquisition taking place in less than 3 min. At the same time, the accuracy of the data for triage of large populations has improved, as indicated using the metrics of sensitivity, specificity and area under the ROC curve. Applying these standards to the intended population, EPR in vivo Tooth Biodosimetry has approximately the same diagnostic accuracy as the purported 'gold standard' (dicentric chromosome assay). Other improvements include miniaturisation of the spectrometer, leading to the creation of a significantly lighter and more compact prototype that is suitable for transporting for Point of Care (POC) operation and that can be operated off a single standard power outlet. Additional advancements in the resonator, including use of a disposable sensing loop attached to the incisor tooth, have resulted in a biodosimetry method where measurements can be made quickly with a simple 5-step workflow and by people needing only a few minutes of training (which can be built into the instrument as a training video). In sum, recent advancements allow this prototype to meet or exceed the US Federal Government's recommended targets for POC biodosimetry in large-scale events., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Receiver operating characteristic (ROC) analysis is a fundamental tool used for the evaluation and comparison of diagnostic systems that provides estimates of the combinations of sensitivity and specificity that can be achieved with a given technique. Along with critical considerations of practical limitations, such as throughput and time to availability of results, ROC analyses can be applied to provide meaningful assessments and comparisons of available biodosimetry methods. Accordingly, guidance from the Food and Drug Administration to evaluate biodosimetry devices recommends using ROC analysis. However, the existing literature for the numerous biodosimetry methods that have been developed to address the needs for triage either do not contain ROC analyses or present ROC analyses where the dose distributions of the study samples are not representative of the populations to be screened. The use of non-representative sample populations can result in a significant spectrum bias, where estimated performance metrics do not accurately characterize the true performance under real-world conditions. Particularly, in scenarios where a large group of people is screened because they were potentially exposed in a large-scale radiation event, directly measured population data do not exist. However, a number of complex simulations have been performed and reported in the literature that provide estimates of the required dose distributions. Based on these simulations and reported data about the output and uncertainties of biodosimetry assays, we illustrate how ROC curves can be generated that incorporate a realistic representative sample. A technique to generate ROC curves for biodosimetry data is presented along with representative ROC curves, summary statistics and discussion based on published data for triage-ready electron paramagnetic resonance in vivo tooth dosimetry, the dicentric chromosome assay and quantitative polymerase chain reaction assay. We argue that this methodology should be adopted generally to evaluate the performance of radiation biodosimetry screening assays so that they can be compared in the context of their intended use., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Testing and verification are an integral part of any cycle to design, manufacture and improve a novel device intended for use in humans. In the case of testing Dartmouth's electron paramagnetic resonance (EPR) in vivo tooth dosimetry device, in vitro studies are needed throughout its development to test its performance, i.e. to verify its current capability for assessing dose in individuals potentially exposed to ionizing radiation. Since the EPR device uses the enamel of human teeth to assess dose, models that include human teeth have been an integral mechanism to carry out in vitro studies during development and testing its ability to meet performance standards for its ultimate intended in vivo use. As the instrument improves over time, new demands for in vitro studies change as well. This paper describes the tooth models used to perform in vitro studies and their evolution to meet the changing demands for testing in vivo EPR tooth dosimetry., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Managing radiation injuries following a catastrophic event where large numbers of people may have been exposed to life-threatening doses of ionizing radiation relies on the availability of biodosimetry to assess whether individuals need to be triaged for care. Electron Paramagnetic Resonance (EPR) tooth dosimetry is a viable method to accurately estimate the amount of ionizing radiation to which an individual has been exposed. In the intended measurement conditions and scenario, it is essential that the measurement process be fast, straightforward and provides meaningful and accurate dose estimations for individuals in the expected measurement conditions. The sensing component of a conventional L-band EPR spectrometer used for tooth dosimetry typically consists of a surface coil resonator that is rigidly, physically attached to the coupler. This design can result in cumbersome operation, limitations in teeth geometries that may be measured and hinder the overall utility of the dosimeter. A novel surface coil resonator has been developed for the currently existing L-band (1.15 GHz) EPR tooth dosimeter for the intended use as a point of care device by minimally trained operators. This resonator development provides further utility to the dosimeter, and increases the usability of the dosimeter by non-expert operators in the intended use scenario., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this paper is to delineate characteristics of biodosimetry most suitable for assessing individuals who have potentially been exposed to significant radiation from a nuclear device explosion when the primary population targeted by the explosion and needing rapid assessment for triage is civilians vs. deployed military personnel. The authors first carry out a systematic analysis of the requirements for biodosimetry to meet the military's needs to assess deployed troops in a warfare situation, which include accomplishing the military mission. Then the military's special capabilities to respond and carry out biodosimetry for deployed troops in warfare are compared and contrasted systematically, in contrast to those available to respond and conduct biodosimetry for civilians who have been targeted by terrorists, for example. Then the effectiveness of different biodosimetry methods to address military vs. civilian needs and capabilities in these scenarios was compared and, using five representative types of biodosimetry with sufficient published data to be useful for the simulations, the number of individuals are estimated who could be assessed by military vs. civilian responders within the timeframe needed for triage decisions. Analyses based on these scenarios indicate that, in comparison to responses for a civilian population, a wartime military response for deployed troops has both more complex requirements for and greater capabilities to use different types of biodosimetry to evaluate radiation exposure in a very short timeframe after the exposure occurs. Greater complexity for the deployed military is based on factors such as a greater likelihood of partial or whole body exposure, conditions that include exposure to neutrons, and a greater likelihood of combined injury. These simulations showed, for both the military and civilian response, that a very fast rate of initiating the processing (24,000 d) is needed to have at least some methods capable of completing the assessment of 50,000 people within a 2- or 6-d timeframe following exposure. This in turn suggests a very high capacity (i.e., laboratories, devices, supplies and expertise) would be necessary to achieve these rates. These simulations also demonstrated the practical importance of the military's superior capacity to minimize time to transport samples to offsite facilities and use the results to carry out triage quickly. Assuming sufficient resources and the fastest daily rate to initiate processing victims, the military scenario revealed that two biodosimetry methods could achieve the necessary throughput to triage 50,000 victims in 2 d (i.e., the timeframe needed for injured victims), and all five achieved the targeted throughput within 6 d. In contrast, simulations based on the civilian scenario revealed that no method could process 50,000 people in 2 d and only two could succeed within 6 d.

Current radiation disaster manuals list the time-to-emesis (TE) as the key triage indicator of radiation dose. The data used to support TE recommendations were derived primarily from nearly instantaneous, high dose-rate exposures as part of variable condition accident databases. To date, there has not been a systematic differentiation between triage dose estimates associated with high and low dose rate (LDR) exposures, even though it is likely that after a nuclear detonation or radiologic disaster, many surviving casualties would have received a significant portion of their total exposure from fallout (LDR exposure) rather than from the initial nuclear detonation or criticality event (high dose rate exposure). This commentary discusses the issues surrounding the use of emesis as a screening diagnostic for radiation dose after LDR exposure. As part of this discussion, previously published clinical data on emesis after LDR total body irradiation (TBI) is statistically re-analyzed as an illustration of the complexity of the issue and confounding factors. This previously published data includes 107 patients who underwent TBI up to 10.5 Gy in a single fraction delivered over several hours at 0.02 to 0.04 Gy min. Estimates based on these data for the sensitivity of emesis as a screening diagnostic for the low dose rate radiation exposure range from 57.1% to 76.6%, and the estimates for specificity range from 87.5% to 99.4%. Though the original data contain multiple confounding factors, the evidence regarding sensitivity suggests that emesis appears to be quite poor as a medical screening diagnostic for LDR exposures.

We have incorporated LiNc-BuO, an oxygen-sensing paramagnetic material, in polydimethylsiloxane (PDMS), which is an oxygen-permeable, biocompatible, and stable polymer. We fabricated implantable and retrievable oxygen-sensing chips (40 % LiNc-BuO in PDMS) using a 20-G Teflon tubing to mold the chips into variable shapes and sizes for in vivo studies in rats. In vitro EPR measurements were used to test the chip's oxygen response. Oxygen induced linear and reproducible line broadening with increasing partial pressure (pO2). The oxygen response was similar to that of bare (unencapsulated) crystals and did not change significantly on sterilization by autoclaving. The chips were implanted in rat femoris muscle and EPR oximetry was performed repeatedly (weekly) for 12 weeks post-implantation. The measurements showed good reliability and reproducibility over the period of testing. These results demonstrated that the new formulation of OxyChip with 40 % LiNc-BuO will enable the applicability of EPR oximetry for long-term measurement of oxygen concentration in tissues and has the potential for clinical applications.

Given the clinical evidence that hypoxic tumors are more resistant to standard therapy and that adjusting therapies can improve the outcomes for the subpopulation with hypoxic tumors, in vivo methods to measure oxygen in tissue have important clinical potential. This paper provides the rationale for and methodological strategies to use comparative effectiveness research to evaluate oximetry for cancer care. Nine oximetry methods that have been used in vivo to measure oxygen in human tumors are evaluated on several clinically relevant criteria to illustrate the value of applying comparative effectiveness to oximetry.

The first systematic multi-center study of the clinical use of EPR oximetry has begun, with funding as a PPG from the NCI. Using particulate oxygen sensitive EPR, materials in three complementary forms (India Ink, "OxyChips", and implantable resonators) the clinical value of the technique will be evaluated. The aims include using repeated measurement of tumor pO2 to monitor the effects of treatments on tumor pO2, to use the measurements to select suitable subjects for the type of treatment including the use of hyperoxic techniques, and to provide data that will enable existing clinical techniques which provide data relevant to tumor pO2 but which cannot directly measure it to be enhanced by determining circumstances where they can give dependable information about tumor pO2.

Absorbed doses to fingernails and organs were calculated for a set of homogenous external gamma-ray irradiation geometries in air. The doses were obtained by stochastic modeling of the ionizing particle transport (Monte Carlo method) for a mathematical human phantom with arms and hands placed loosely along the sides of the body. The resulting dose conversion factors for absorbed doses in fingernails can be used to assess the dose distribution and magnitude in practical dose reconstruction problems. For purposes of estimating dose in a large population exposed to radiation in order to triage people for treatment of acute radiation syndrome, the calculated data for a range of energies having a width of from 0.05 to 3.5 MeV were used to convert absorbed doses in fingernails to corresponding doses in organs and the whole body as well as the effective dose. Doses were assessed based on assumed rates of radioactive fallout at different time periods following a nuclear explosion.

In an event where many thousands of people may have been exposed to levels of radiation that are sufficient to cause the acute radiation syndrome, we need technology that can estimate the absorbed dose on an individual basis for triage and meaningful medical decision making. Such dose estimates may be achieved using in vivo electron paramagnetic resonance (EPR) tooth biodosimetry, which measures the number of persistent free radicals that are generated in tooth enamel following irradiation. However, the accuracy of dose estimates may be impacted by individual variations in teeth, especially the amount and distribution of enamel in the inhomogeneous sensitive volume of the resonator used to detect the radicals. In order to study the relationship between interpersonal variations in enamel and EPR-based dose estimates, it is desirable to estimate these parameters nondestructively and without adding radiation to the teeth. Magnetic Resonance Imaging (MRI) is capable of acquiring structural and biochemical information without imparting additional radiation, which may be beneficial for many EPR dosimetry studies. However, the extremely short T2 relaxation time in tooth structures precludes tooth imaging using conventional MRI methods. Therefore, we used zero echo time (ZTE) MRI to image teeth ex vivo to assess enamel volumes and spatial distributions. Using these data in combination with the data on the distribution of the transverse radio frequency magnetic field from electromagnetic simulations, we then can identify possible sources of variations in radiation-induced signals detectable by EPR. Unlike conventional MRI, ZTE applies spatial encoding gradients during the RF excitation pulse, thereby facilitating signal acquisition almost immediately after excitation, minimizing signal loss from short T2 relaxation times. ZTE successfully provided volumetric measures of tooth enamel that may be related to variations that impact EPR dosimetry and facilitate the development of analytical procedures for individual dose estimates.

For purposes of biodosimetry in the event of a large scale radiation disaster, one major and very promising point-of contact device is assessing dose using tooth enamel. This technique utilizes the capabilities of electron paramagnetic resonance to measure free radicals and other unpaired electron species, and the fact that the deposition of energy from ionizing radiation produces free radicals in most materials. An important stipulation for this strategy is that the measurements, need to be performed on a central incisor that is basically intact, i.e. which has an area of enamel surface that is as large as the probing tip of the resonator that is without decay or restorative care that replaces the enamel. Therefore, an important consideration is how to quickly assess whether the tooth has sufficient enamel to be measured for dose and whether there is resin present on the tooth being measured and to be able to characterize the amount of surface that is impacted. While there is a relatively small commercially available dielectric probe which could be used in this context, it has several disadvantages for the intended use. Therefore, a smaller, 1.19mm diameter 50 ohm, open-ended, coaxial dielectric probe has been developed as an alternative. The performance of the custom probe was validated against measurement results of known standards. Measurements were taken of multiple teeth enamel and dental resin samples using both probes. While the probe contact with the teeth samples was imperfect and added to measurement variability, the inherent dielectric contrast between the enamel and resin was sufficient that the probe measurements could be used as a robust means of distinguishing the two material types. The smaller diameter probe produced markedly more definitive results in terms of distinguishing the two materials.

The aim of this paper is to compare and contrast the needs for biodosimetry for initial triage for military forces and civilian populations when there are radiation exposures that involve potentially a large number of persons. Several differences in the likely scenarios for exposure of military forces include a greater likelihood of having higher rates of significant exposures, inhomogeneous exposures, significant doses from neutrons, and combined injury. Measurements will be able to begin sooner than for exposures in civilian settings because medical facilities usually are an integral part of the way military forces are deployed. It also will be very feasible to have personnel that will be trained and equipped specifically for rapid deployment to assess dose. As a consequence, the most appropriate biodosimetry techniques will include features that are not present or are less important for civilian settings; i.e., the need for changes that become measureable very soon after the radiation is received, the ability to complete measurements in very close proximity to the subjects (so samples do not need to be transported out and results returned), increased capability of resolving homogeneity of the exposure, ability to be carried out in an injured person, capability of determining whether neutrons have made a significant contribution to dose, and the ability to rely on more sophisticated equipment and trained personnel to carry out the measurements at the point of care.

Planning and preparation for a large-scale nuclear event would be advanced by assessing the applicability of potentially available bio-dosimetry methods. Using an updated comparative framework the performance of six bio-dosimetry methods was compared for five different population sizes (100-1,000,000) and two rates for initiating processing of the marker (15 or 15,000 people per hour) with four additional time windows. These updated factors are extrinsic to the bio-dosimetry methods themselves but have direct effects on each method's ability to begin processing individuals and the size of the population that can be accommodated. The results indicate that increased population size, along with severely compromised infrastructure, increases the time needed to triage, which decreases the usefulness of many time intensive dosimetry methods. This framework and model for evaluating bio-dosimetry provides important information for policy-makers and response planners to facilitate evaluation of each method and should advance coordination of these methods into effective triage plans., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

There is an imperative need to develop methods that can rapidly and accurately determine individual exposure to radiation for screening (triage) populations and guiding medical treatment in an emergency response to a large-scale radiological/nuclear event. To this end, a number of methods that rely on dose-dependent chemical and/or physical alterations in biomaterials or biological responses are in various stages of development. One such method, ex vivo electron paramagnetic resonance (EPR) nail dosimetry using human nail clippings, is a physical biodosimetry technique that takes advantage of a stable radiation-induced signal (RIS) in the keratin matrix of fingernails and toenails. This dosimetry method has the advantages of ubiquitous availability of the dosimetric material, easy and non-invasive sampling, and the potential for immediate and rapid dose assessment. The major challenge for ex vivo EPR nail dosimetry is the overlap of mechanically induced signals and the RIS. The difficulties of analysing the mixed EPR spectra of a clipped irradiated nail were addressed in the work described here. The following key factors lead to successful spectral analysis and dose assessment in ex vivo EPR nail dosimetry: (1) obtaining a thorough understanding of the chemical nature, the decay behaviour, and the microwave power dependence of the EPR signals, as well as the influence of variation in temperature, humidity, water content, and O₂ level; (2) control of the variability among individual samples to achieve consistent shape and kinetics of the EPR spectra; (3) use of correlations between the multiple spectral components; and (4) use of optimised modelling and fitting of the EPR spectra to improve the accuracy and precision of the dose estimates derived from the nail spectra. In the work described here, two large clipped nail datasets were used to test the procedures and the spectral fitting model of the results obtained with it. A 15-donor nail set with 90 nail samples from 15 donors was used to validate the sample handling and spectral analysis methods that have been developed but without the interference of a native background signal. Good consistency has been obtained between the actual RIS and the estimated RIS computed from spectral analysis. In addition to the success in RIS estimation, a linear dose response has also been achieved for all individuals in this study, where the radiation dose ranges from 0 to 6 Gy. A second 16-donor nail set with 96 nail samples was used to test the spectral fitting model where the background signal was included during the fitting of the clipped nail spectra data. Although the dose response for the estimated and actual RIS calculated in both donor nail sets was similar, there was an increased variability in the RIS values that was likely due to the variability in the background signal between donors. Although the current methods of sample handling and spectral analysis show good potential for estimating the RIS in the EPR spectra of nail clippings, there is a remaining degree of variability in the RIS estimate that needs to be addressed; this should be achieved by identifying and accounting for demographic sources of variability in the background nail signal and the composition of the nail matrix., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)