Areas of Research and Expertiese
Biodosimetry for determining exposure to ionizing radiation retrospectively – overall aspects. There are a number of circumstances, especially related to accidents or terrorism where there is an urgent need to determine whether an individual has been exposed to radiation doses of a magnitude where medical intervention is desirable to reduce the probability of adverse outcomes. I first established the potential of using EPR for such dosimetry in 1968, then led the team that established that such measurements could be made in vivo in teeth and in nails, and I have continued to have a leading role in the application and evaluation of biodosimetry, especially for large-scale radiation events. We also have provided analyses of the challenges and possibilities for applications to specific populations (military VS. general civilian population VS. radiation workers).
Brady JM, Aarestad NO, and Swartz HM. In Vivo Dosimetry by Electron Spin Resonance Spectroscopy. Health Phys. 15: 43-47 (1968).
Swartz HM, Williams BB, Nicolalde RJ, Demidenko E, and Flood AB. Overview of Biodosimetry for Management of Unplanned Exposures to Ionizing Radiation. Radiat Meas 46: 742-748 (2011).
Swartz HM, Flood AB, Williams BB, Nicolalde RJ, and Shapiro A. Overview of Methods for Establishing Dose to Individuals for Managing Unplanned, Clinically Significant Exposures to Ionizing Radiation. Pp 91-108 in The Medical Basis for Radiation-Accident Preparedness: Medical Management. Christensen DM, Sugarman SL and O’Hara, Jr FM (Eds). Oak Ridge TN: Oak Ridge Associated Universities (2014)
Swartz HM, Flood AB, Williams BB, Meineke V, Dorr H. Comparison of the needs for biodosimetry for large-scale radiation events for military versus civilian populations. Health Phys 106(6):755-763 (2014)
Williams BB, Flood AB, Demidenko E, Swartz HM. ROC Analysis for Evaluation of Radiation Biodosimetry Technologies. Radiat Prot Dosim 172 (1-3): 145-151 (2016), doi:10.1093/rpd/ ncw168. PMC5225982
Biodosimetry for determining exposure to ionizing radiation retrospectively – tooth dosimetry. I have led the development of the use of teeth for retrospective dosimetry, starting with a demonstration of ability to make such measurements in intact teeth in vitro and then showing that these measurements could be made non-invasively in vivo. I have led the research that demonstrated that in vivo teeth measurements can be made quickly and effectively in remote locations with a device that does not require trained operators.
Miyake M, Liu KJ, Walczak T, and Swartz HM. In Vivo EPR Dosimetry of Accidental Exposures to Radiation: Experimental Results Indicating the Feasibility of Practical Use in Human Subjects. Appl Rad Isot 52: 1031-1038 (2000).
Williams BB, Dong R, Flood AB, Grinberg OY, Kmiec M, Lesniewski PN, Matthews TP, Nicolalde RJ, Raynolds T, Salikhov I, and Swartz HM. A Deployable In Vivo EPR Tooth Dosimeter for Triage after a Radiation Event Involving Large Populations. Radiat Meas 46(9): 772-777 (2011). PMC3182096
Williams BB, Flood AB, Salikhov I, Kobayashi K, Dong R, Rychert K, Du G, Schreiber W, Swartz HM. In vivo EPR tooth dosimetry for triage after a radiation event involving large populations. Radiat Environ Biophys 53(2):334-346 (2014) (DOI 10.1007/s00411-014-0534-9).
Flood AB, Williams BB, Schreiber W, Du G, Wood VA, Kmiec MM, Petryakov SV, Demidenko E, Swartz HM and Members of the EPR Center Tooth Dosimetry Project Team. Advances in in vivo EPR tooth biodosimetry: Meeting the targets for initial triage following a large-scale radiation event. Radiat Prot Dosim 172 (1-3): 72-80 (2016). PMC5225975
Biodosimetry for determining exposure to ionizing radiation retrospectively –nail dosimetry. In collaboration with several other investigators (e.g., Steve Swarts, François Trompier, and Alex Romanyukha), I have been involved in the development of the use of nails as potential radiation dosimeters. While the EPR signals induced by clipping the fingernails have impeded the widespread use of clipped nails for emergency dosimetry, we have overcome this challenge by developing a technique to make the measurements in vivo, in collaboration with the Medical College of Wisconsin who responded to our challenge to design and build a safe and effective resonator that could be used on nails in vivo. This approach now has the potential to become an important tool for addressing the significant need to evaluate the clinical risk of potentially exposed individuals, because it has the unique capability to rapidly provide spatially-resolved biodosimetry. Because its measurements can be made independently on all four limbs, this technique can provide unique and clinically crucial information, both about whether the dose was heterogeneous as well as assessing the magnitude of exposures to critical organs.
He X, Swarts SG, Demidenko E, Flood AB, Grinberg O, Gui J, Mariani M, Marsh SD, Ruuge AE, Sidabras JW, Tipikin D, Wilcox DE, and Swartz HM. Development and Validation of an Ex Vivo Electron Paramagnetic Resonance Fingernail Biodosimetric Method. Radiat Prot Dosim 159(1-4):172-181 (2014) (doi: 10. 1093/rpd/ncu129). PMC4095917
Khailov AM, Ivannikov AI, Skortsov VG, Stepanenko VF, Orlenko SP, Flood AB, Williams BB, Swartz HM. Calculation of dose conversion factors for doses in the fingernails to organ doses at external gamma irradiation in air. Radiat Meas 82:1-7 (2015) DOI: 10.1016/radmeas.2015.07.004 PMC4559862
Grinberg OY, Sidabras JW, Tipikin DS, Krymov V, Marian Mi, Feldman N, Kmiec M, Petryakov S, Brugger S, Carr B, Schreiber W, Swarts SG and Swartz HM. Dielectric-Backed Aperture Resonators for X-Band In Vivo EPR Nail Dosimetry. Radiat Prot Dosimetry (2016) 172 (1-3): 121-126 doi:10.1093/rpd/ncw163. PMC5225980
Swarts SG, Sidabras JW, Grinberg OY, Tipikin DS, Kmiec M, Petryakov S, Schreiber W, Wood VA, Williams BB, Flood AB, Swartz HM. Developments in Biodosimetry Methods for Triage, with a Focus on X-band Electron Paramagnetic Resonance In Vivo Fingernail Dosimetry. Health Phys 115(1):140–150 (2018).
Clinical Applications of EPR. EPR is a very powerful technique in terms of the types of information that can be obtained using paramagnetic molecules that are introduced as probes or generated by pathophysiological processes. The technical challenges for leveraging these capabilities into useful studies have been successfully carried out in several laboratories including ours. Our more unique contribution has been to conceptualize how to make such measurements in human subjects in ways that provide robust data obtained from human subjects Such applications are significant additions to clinical use that range from diagnosis to therapy and have been designed in ways that are compatible with usual clinical practice. We have developed such capabilities and applied them successfully for clinical measurements of tissue oxygen and radiation dosimetry. These studies have been supported by significant external funding from NIH [PPG from NCI (2015-20) and U19-CMCR from NIAID (2010–17)].
Caston RM, Schreiber W, Hou H, Williams BB, Chen EY, Schaner PE, Jarvis LA, Flood AB, Petryakov SV, Kmiec MM, Kuppusamy P, Swartz HM. Development of the Implantable Resonator System for Clinical EPR oximetry. Cell Biochem Biophys 2017 Dec;75(3-4):275-283. doi: 10.1007/s12013-017-0809-2. PMC5972368
Swartz HM, Williams BB, Zaki BI, Hartford AC, Jarvis LA, Chen EY, Comi RJ, Ernstoff MS, H. Hou H, Khan N, Swarts SG, Flood AB, P. Kuppusamy P. Clinical EPR: Unique Opportunities and Challenges. Acad Radiol 21(2):197-206 (2014). PMC3921887
Hou H, Dong R, Li H, Williams BB, Lariviere JP, Hekmatyar S, Kauppinen R, Khan N, and Swartz HM. Dynamic Changes in Oxygenation of Intracranial Tumor and Contralateral Brain During Tumor Growth and Carbogen Breathing: A Multi-Site EPR Oximetry with Implantable Resonators. J Magn Reson 214(1):22-28 (2012). PMC3730127
Hou HG, Li HB, Dong R, Mupparaju SP, Khan N, and Swartz HM. Cerebral Oxygenation of the Cortex and Caudate Putamen Following Normobaric Hyperoxia and Mild Hypoxia in the Rats-EPR Oximetry with Multi-Probe Implantable Resonators. Adv Exp Med Biol 915: 61-67 (2011). PMC3955716
Measurement of oxygen under biologically pertinent conditions and their application to medically significant problems. Molecular oxygen plays a large and critically important role in cells, tissues, and whole animals in many aspects of pathophysiology and physiology. By leveraging the capabilities of EPR probes including their chemical versatility and stability, we have used EPR oximetry to investigate aspects that cannot be measured as readily by other techniques. Specific areas in which we have made significant contributions include: measurements of intracellular oxygen (demonstrating the existence of significant intracellular gradients and their origin in the properties of membranes and showing significant gradients related to cholesterol content), direct and repeated measurements of oxygen in tumors (useful for understanding and altering therapy to increase its effectiveness), direct and repeated measurements of oxygen in ischemia in the brain, and measurements to determine the effect of anesthetics on tissue pO2.
Khan K, Shen J, Chang TY, Chang CY, Fung PCW, Grinberg OY, Demidenko E and Swartz HM. Plasma Membrane Cholesterol: A Possible Barrier to Intracellular Oxygen in Normal and Mutant CHO Cells Defective in Cholesterol Metabolism. Biochem. 42: 23-29 (2003).
Hou H, Dong D, Li H, Williams BB, Lariviere JP, Hekmatyar S, Kauppinen R, Khan N, and Swartz HM. Dynamic Changes in Oxygenation of Intracranial Tumor and Contralateral Brain During Tumor Growth and Carbogen Breathing: A Multi-Site EPR Oximetry With Implantable Resonators. J Magn Reson 214(1):22-28 (2012) PMC3730127
Hou H, Li H, Dong R, Khan N, Swartz HM. Real-time monitoring of ischemic and contralateral brain pO2 during stroke by variable length multisite resonators. Magn Reson Imaging 32(5):563-569 (2014). PMC4297608
Hou H, Grinberg OY, Taie S, Leichtweis S, Miyake M, Grinberg S, Xie H, Csete M and Swartz HM. Electron Paramagnetic Resonance (EPR) Assessment of Brain Tissue Oxygen Tension in Anesthetized Rats. Anesth Analg 96: 1467-1472 (2003).
Metabolically-Sensitive contrast agents. The emergence of magnetic resonance as a clinically effective tool has been remarkable and has profoundly enhanced the ability to detect and characterize pathophysiology. The use of contrast agents has had an important and positive effect on this field. I have made a significant contribution to this field by developing and demonstrating the concept of using contrast agents that add an additional dimension: to reflect metabolic and pathophysiological functions. The basis for the field was summarized below in 1 and 2 and its applicability using EPR is summarized in 3.
Swartz HM, Chen K, Hu H, and Hideg K. Contrast Agents for Magnetic Resonance Spectroscopy: A Method to Obtain Increased Information in In Vivo and In Vitro Spectroscopy. Magn Reson Med 22: 372-377 (1991).
Swartz HM and Khan N. EPR Spectroscopy of Function In Vivo: Origins, Achievements, and Future Possibilities. Pp 197-228 in Biomedical ESR, Part A: Free Radicals, Metals, Medicine, and Physiology. Series: Biological Magnetic Resonance, vol. 23. Springer, Boston, MA. Eaton SS, Eaton GR, Berliner LJ (eds.) (2005). DOI: https://doi.org/10.1007/0-387-26741-7_9.
Chen K, Lutz NW, Wehrle JP, Glickson JD, Swartz HM. Selective Suppression of Lipid Resonances by Lipid-Soluble Nitroxides in NMR Spectroscopy. Magn ResON Med 25: 120-127 (1992).
Melanoma – impact of oxygen and melanin. Melanomas differ from other malignant tumors in a number of ways that are clinically significant. They have a greater tendency to be influenced by immune responses. They are sometimes rather resistant to radiation therapy. The melanin within them may have roles in these and other clinical aspects of melanomas. We have used EPR to characterize the melanin and its interactions with oxygen and metal ions and free radicals because such knowledge could inform improved ways to treat melanoma and determine its aggressive potential. WE also demonstrated, for probably the first time, that immunotherapy can impact other concentration in tumors
O'Hara JA, Blumenthal RD, Grinberg OY, Demidenko E, Grinberg S, Wilmot CM, Taylor AM, Goldenberg DM, Swartz HM (2001). Response to radioimmunotherapy correlates with tumor pO2 measured by EPR oximetry in human tumor xenografts. Radiat Res 155(3):466-473.
Sarna T, Duleba A, Korytowski W, Swartz H (1980). Interaction of melanin with oxygen. Arch Biochem Biophys 200(1):140-148.
Nilges MJ, Swartz HM (1984). "Quinone and semiquinone intermediates in the reaction of 4-hydroxyanisole and tyrosinase." In Reily P (Ed.): Hydroxyanisole: Recent Advances in Melanoma Therapy, IRL Press, Oxford, pp 26-33.
Hopwood LE, Swartz HM, Pajak S (1985). Effect of melanin on radiation response of CHO cells. Int J Radiat Biol Relat Stud Phys Chem Med 47(5):531-537.
Sarna T, Swartz HM (1993). "Interactions of Melanin with Oxygen (and Related Species)." In Scott G (Ed.): Atmospheric Oxidation and Antioxidants Elsevier Science Publishers, Amsterdam, Vol. III, Chapter 5, pp 129-169.
Sarna T, Swartz HM (2006). “Physical Properties of Melanins.” In Nordlund JJ, Boissy RE, Hearing VJ, King RA, Oetting W, Ortonne JP (Eds.): The Pigmentary System: Physiology and Pathophysiology (Book), 2nd Edition. Oxford University Press, New York, Chap. 16, pp 311-341.
Free Radicals and other paramagnetic species in functioning biological systems. Using the unique capabilities of EPR to directly measure unpaired electrons, especially those in free radicals, we have carried out a series of studies on free radicals in biological systems that have brought solid quantitative data to a field that has had problems with the rigor of the experimental studies. The following is a sampling of the topics in which our group has made significant contributions.
Roles in carcinogenesis: H. M. Swartz, "Electron Spin Resonance Studies of Carcinogenesis," in Advances in Cancer Research, G. Klein and S. Weinhouse, (Eds.), Academic Press, New York, pp. 227-252 (1972).
Roles in melanin: R. C. Sealy, C. C. Felix, J. S. Hyde, and H. M. Swartz, "Structure and Reactivity of Melanins: Influence of Free Radicals and Metals Ions," Free Radic. Biol. Med. 4: 210-251 (1980).
Roles in radiation protection and sensitization: H. M. Swartz, E. C. Richardson, E. S. Copeland, R. T. Lofberg, and R. J. Jandacek, "Structure Function Studies of the Aminothiol Radio-Protectants," in Radiation Protection and Sensitization, W. L. Moroson and M. Quintiliani, (Eds.), Taylor and Francis, Ltd., London, pp. 121-131 (1970)
Detection in vivo: G.S. Timmins, K.J. Liu, E. J.H. Bechara, Y. Kotake, and H.M. Swartz, “Trapping of Free Radicals with Direct In Vivo EPR Detection: A Comparison of 5,5-Dimethyl-1-Pyrroline-N-oxide (DMPO) and 5-Diethoxyphosphoryl-5-Methyl-1-Pyrroline-N-oxide (DEPMPO) as Spin Traps for HO• and SO4•-, Free Rad. Biol. Med. 27: 329-333 (1999).
Selected List of Published Work in MyBibliography:
Areas of Research and Expertiese
Clinical and human factors issues in clinical oximetry of tissues for improving cancer treatment: From 2010-2018, I served as Associate Director for Clinical Studies and Human Factors at the EPR Center at Dartmouth. Since 2014, I have been working with the EPR oximetry team to evaluate the instrument and have led the regulatory and practical aspects of conducting the clinical studies involving India ink as sensors for assessing the level of oxygen in tumor tissues. This work has great clinical importance because EPR oximetry has the potential to directly measure pO2 in tissue repeatedly and noninvasively (after initially placing the sensor material in the tissue). Low levels of oxygen in cancer tumors (hypoxia) have been well established to be an independent and powerful predictor of tumor responsiveness to cancer therapies including radiation therapy, chemotherapy and surgery. EPR oximetry can also measure whether the tumor is responsive to hyperoxic treatments (such as breathing 100% oxygen for a few minutes). Responsiveness to hyperoxic treatment as well as understanding the baseline hypoxic levels offer an important opportunity to personalize treatments, thereby improving outcomes. I have taken the lead to conduct comparative effectiveness studies and a framework suitable for comparing clinical oximetry methods as well as an analysis of India ink used for marking in medical applications. I have taken the lead on evaluating the human-instrument interface and practical conduct of the studies, presenting and publishing on practical and statistical considerations in the interpretation of the data and the translation of bench-ready instruments into practical medical devices. I have taken a lead in preparing reports of benchmark studies using EPR, materials to obtain FDA approval for investigational use of the implantable resonator, and performed risk analyses on several sensors.
Comparing the effectiveness of methods to measure oxygen in tissues for prognosis and treatment of cancer. Flood AB, Satinsky VA, Swartz HM. Adv Exp Med Biol.923:113-120 (2016): doi: 10.1007/978-3-319-38810-6_15. PMID: 275261
Direct and repeated clinical measurements of p02 for enhancing cancer therapy and other applications. Swartz HM, Williams BB, Hou H, Khan N, Jarvis LA, Chen EY, Schaner PE, Ali AN, Gallez B, Kuppusamy P, Flood AB. Adv Exp Med Biol. 923: 95-104 (2016) doi: 10.1007/978-3-319-38810-6_13. PMID: 27526130
Using India ink as a sensor for oximetry: Evidence of its safety as a medical device. Flood AB, Wood VA, and Swartz HM. Adv Exp Med Biol 977:297-312, 2017 PMID: 28685459
Development of the implantable resonator system for clinical EPR oximetry. Caston RM, Schreiber W, Hou H, Williams BB, Chen EY, Schaner PE, Jarvis LA, Flood AB, Petryakov SV, Kmiec MM, Kuppusamy P, Swartz HM. Cell Biochem and Biophy, 75(3-4): 275-283, 2017 PMID: 28687906
Guidance for Academics to Transfer ‘Bench-ready’ Medical Technology into Usual Clinical Practice. Case Study: Sensors and Spectrometer used in EPR Oximetry. Flood AB, Wood VA, Schreiber W, Williams BB, Gallez B, Swartz HS. Adv Exp Med Biol. 2018;1072:233-239. doi: 10.1007/978-3-319-91287-5_37.PMID: 30178351
Clinical and human factors issues in biodosimetry for large-scale radiation disasters: In my role as Associate Director, I have supervised the evaluation of human factors in the development of the EPR devices (in vivo tooth dosimetry, in vivo nail dosimetry, and clipped nail dosimetry) for use as a field-deployed point-of-care biodosimetry method to rapidly evaluate up to one million people potentially exposed to life threatening ionizing radiation in a terrorist event or major accident involving radiation. I have taken the lead in developing a comparative effectiveness framework adapted to public disaster healthcare and have reported simulations of the feasibility and timeliness of six major methods for biodosimetry (one of which is EPR in vivo tooth dosimetry). I have been invited to present this work at workshops held by the FDA and NIAID as well as many international conferences on biodosimetry for large scale disasters.
A framework for comparative evaluation of dosimetric methods to triage a large population following a radiological event. Flood AB, Nicolalde RJ, Demidenko E, Williams BB, Shapiro A, et al. Radiation measurements. 2011; 46(9):916-922. NIHMSID: NIHMS282532 PMID: 21949481 PMCID: PMC3178340
Advances in a framework to compare bio-dosimetry methods for triage in large-scale radiation events. Flood AB, Boyle HK, Du G, Demidenko E, Nicolalde RJ, et al. Radiat Prot Dosimetry. 2014; 159(1-4):77-86. PMID: 24729594 PMCID: PMC4067227
Evaluating the Special Needs of the Military for Radiation Biodosimetry for Tactical Warfare against Deployed Troops: Comparing Military to Civilian Needs for Biodosimetry Methods. Flood AB, Ali AN, Boyle HK, Du G, Satinsky VA, Swarts SG, Williams BB, Demidenko E, Schreiber W, Swartz HM. Health Phys. 111(2):169-182; 2016. DOI: 10.1097/HP.0000000000000538. PMID: 27356061
Advances in in vivo EPR tooth biodosimetry: Meeting the targets for initial triage following a large-scale radiation event. Flood AB, Williams BB, Schreiber W, Du G, Wood VA, Kmiec MM, Petryakov SV, Demidenko E, Swartz HM and Members of the EPR Center Tooth Dosimetry Project Team.. Radiat Prot Dosimetry (2016) 172 (1-3): 72-80 PMID: 27421468
Organizational and professional determinants of quality of care in US hospitals: My initial research was part of a major national study of the quality of surgical care in the United States, originally funded by an award from the National Academy of Sciences and then by two major grants from the predecessor of the DHH Agency for Healthcare Research and Quality (AHRQ). It was the first major study of hospital care using a combination of computerized medical records (>600,000 patients in 1224 hospitals) and an intense study of ~10,000 surgical patients in 17 hospitals chosen to be representative of US hospitals. We developed strategies to evaluate quality of care based on outcomes (death and major morbidities after surgery) that led to the development of federal reports of quality indicators of hospitals in the 1980s. I worked with the team studying organizational and professional factors that were expected to influence quality of care. From that work, several publications drew many editorials, comments, and two highly influential papers reported on the influence of having a large volume of surgical cases on achieving better outcomes.
Professional power and professional effectiveness: The power of the surgical staff and the quality of surgical care in hospitals. Flood AB, Scott WR. J Health Soc Behav. 1978; 19(3):240-54. PMID: 568155
Effectiveness in professional organizations: The impact of surgeons and surgical staff organizations on the quality of care in hospitals. Flood AB, Scott WR, Ewy W, Forrest WH Jr. Health Serv Res. 1982; 17(4):341-66. PMID: 7152960 PMCID: PMC1068694
Does practice make perfect? Part I: The relation between hospital volume and outcomes for selected diagnostic categories. Flood AB, Scott WR, Ewy W. Medical care. 1984; 22(2): 98-114. PMID: 6700280
Hospital Structure and Performance Flood A, Scott W. Baltimore, MD: Johns Hopkins U Press; 1987.
Understanding how financial incentives impact utilization of healthcare: A continuation of my work on how organizations and policies can influence the utilization and quality of healthcare, I studied how financial incentives within an organization and external to it (such as insurance policies) can impact the type and amount of utilization of services patients receive and the quality of their outcomes. The article on ‘through the lens’ cited below was awarded the ASA’s Eliot Freidson award for best paper of the year in medical sociology. This work has also been applied to cancer care (including an examination of the influence of policy on the continuum of cancer care) and to technology assessments of surgical care as well as to evaluating privacy and security issues in the use of electronic medical records.
Through the lenses of organizational sociology: The role of organizational theory and research in conceptualizing and examining our health care system. Flood AB, Fennell ML. J Health Soc Behav. 1995; Spec No:154-69. PMID: 7560846
How do HMOs achieve savings? The effectiveness of one organization's strategies. Flood AB, Fremont AM, Jin K, Bott DM, Ding J, et al. Health Serv Res. 1998; 33(1):79-99. PMID: 9566179 PMCID: PMC1070248.
The promise and pitfalls of explicitly rewarding physicians based on patient insurance. Flood AB, Bott DM, Goodrick E. J Ambul Care Manage. 2000; 23(1):55-70. PMID: 11184896
Health reforms as examples of multilevel interventions in cancer care. Flood AB, Fennell ML, Devers KJ. J of Nat Can Instit. Monographs. 2012; 2012(44):80-5. PMID: 22623600 PMCID: PMC3482967
Shared decision making by patients and doctors: My research has also been used to understand decision making by patients, especially in the context of trying to develop effective aids to help patients engage in shared decision making when there are several medically acceptable treatment options available. This work has been influential in both evaluating and improving patient aids as well as contributing to the theoretical understanding of patient decisions.
The role of expectations in patients' reports of post-operative outcomes and improvement following therapy. Flood AB, Lorence DP, Ding J, McPherson K, Black NA. Med Care. 1993; 31(11):1043-56. PMID: 7694013
The importance of patient preference in the decision to screen for prostate cancer. Prostate Patient Outcomes Research Team. Flood AB, Wennberg JE, Nease RF Jr, Fowler FJ Jr, Ding J, et al. J Gen Int Med. 1996; 11(6):342-9. PMID: 8803740
Making evidence-based decisions in medicine: (or more importantly) using evidence when the case doesn't quite fit. Flood AB. Women Health Iss. 2004; 14(1):3-6. PMID: 15001181
Modifying unwarranted variations in health care: shared decision making using patient decision aids. O'Connor AM, Llewellyn-Thomas HA, Flood AB. Health Aff. 2004; Suppl: VAR63-72. PMID: 15471770
Selected List of Published Work in MyBibliography:
Areas of Research and Expertiese
Development of resonators for in vivo biodosimetry for determining exposure to ionizing radiation retrospectively I have played a key engineering role in the design, development, documentation and testing of resonators capable of being used in vivo for retrospective biodosimetry in the event of a largescale event involving accidental exposures or via terrorists events with ionizing radiation. The following references show my contributions to making resonators that are sensitive but also capable of meeting the particular challenges of in vivo use, e.g., lossiness of tissues, movement of the subject, positioning of the sample (such as for in vivo measurements of nails or teeth or the diabetic foot).
Wilson Schreiber, Sergey Petryakov, Maciej M. Kmiec, Matthew A. Feldman, Paul M. Meaney, Victoria A. Wood, Holly K. Boyle, Ann B. Flood, Benjamin B. Williams, Harold M. Swartz. Flexible, wireless, inductively coupled surface coil resonator for EPR tooth dosimetry – Radiation Protection Dosimetry 2016; doi: 10.1093/rpd/ncw153
Oleg Grinberg, Jason W. Sidabras, Dmitriy Tipikin, Vladimir Krymov, Michael Mariani, Matthew Feldman, Maciej Kmiec, Sergey Petryakov, Spencer Brugger, Brandon Carr, Wilson Schreiber, Steven G. Swarts, Harold M. Swartz. Dielectric-backed aperture resonators for X-band in vivo EPR nail Dosimetry – Radiation Protection Dosimetry 2016; doi: 10.1093/rpd/ncw163
Sergey Petryakov, Wilson Schreiber, Maciej Kmiec, Benjamin B. Williams, Harold M. Swartz Surface dielectric resonators for x-band EPR spectroscopy – Radiation Protection Dosimetry 2016; doi: 10.1093/rpd/ncw167
Caston RM, Schreiber W, Hou H, Williams BB, Chen EY, Schaner PE, Jarvis LA, Flood AB, Petryakov SV, Kmiec MM, Kuppusamy P, Swartz HM Development of the Implantable Resonator System for Clinical EPR oximetry - Cell Biochemistry and Biophysics, DOI: 10.1007/s12013-017-0809-2, July 7, 2017.
Making Applications of EPR dosimetry Practical and Effective. EPR is a robust technique in terms of the types of information that can be obtained using paramagnetic molecules that are introduced as probes or generated by pathophysiological processes. The technical challenges for leveraging these capabilities into useful studies have been successfully carried out in several laboratories. More unique contributions have been to conceptualize how to make such measurements in human subjects in ways that provide robust data obtained from human subjects under duress. I have made significant contributions in these developments, not only in the development of microwave bridges and resonators, but also in the software developments to automate the processing of data and the planning of human factors that are unique to these applications, such as the need to be operated by novice operators, to be transportable to disaster areas, and the need to be safe and comfortable for the operators and subjects to carry out measurements. The following papers provide examples of my overall and clinical/human factors contributions to in vivo EPR biodosimetry.
Steven G. Swarts, Jason W. Sidabras, Oleg Grinberg, Dmitriy S. Tipikin, Maciej Kmiec, Sergey Petryakov, Wilson Schreiber, Victoria A. Wood, Benjamin B. Williams, Ann Barry Flood, Harold M. Swartz. Developments in Biodosimetry Methods for Triage, with a Focus on X-band Electron Paramagnetic Resonance In vivo Fingernail Dosimetry – Health Physics Journal - 2018 Jul;115(1):140-150. doi: 10.1097/HP.0000000000000874
Ann Barry Flood; Benjamin B. Williams; Wilson Schreiber; Gaixin Du; Victoria A. Wood; Maciej M. Kmiec; Sergey V. Petryakov; Eugene Demidenko; Harold M. Swartz Advances in in vivo EPR Tooth Biodosimetry: Meeting the targets for initial triage following a large-scale radiation event – _Radiation Protection Dosimetry 2016; doi: 10.1093/rpd/ncw165
Ann Barry Flood, Holly K. Boyle, Gaixin Du, Victoria A. Satinsky, Steven G. Swarts, Benjamin B. Williams, Eugene Demidenko, Wilson Schreiber, Harold M. Swartz. Evaluating the Special Needs of the Military for Radiation Biodosimetry for Tactical Warfare Against Deployed Troops: Comparing Military to Civilian Needs for Biodosimetry Methods. – Health Physics 2016; doi: 10.1097/HP.0000000000000538
Benjamin B. Williams, Ann Barry Flood, Ildar Salikhov, Kyo Kobayashi, Ruhong Dong, Kevin Rychert, Gaixin Du, Wilson Schreiber, Harold M. Swartz. In vivo EPR tooth dosimetry for triage after a radiation event involving large populations. - Radiat Environ Biophys. 2014 May;53(2):335-46. doi: 10.1007/s00411-014-0534-9. PMID: 24711003
Applying EPR in vivo methods to Clinical Applications in Cancer and Immunotherapy Applications of EPR range from diagnosis to therapy and have been designed in ways that are compatible with usual clinical practice. Capabilities have been developed and applied successfully for clinical measurements of tissue oxygen and peripheral vascular disease. My contributions in this area include my efforts to develop software that can provide output that is useful to the clinical end-users of EPR oximetry:
Flood AB, Schaner PE, Vaupel P, Williams BB, Gallez B, Chen EY, Ali A, Liu T, Lawson VH, Schreiber W, Swartz HM. Clinical and statistical considerations when assessing oxygen levels in tumors: Illustrative results from clinical EPR oximetry studies – Adv Exp Med Bio (In Press)
L A Jarvis, B B Williams, P E Schaner, E Y Chen, C V Angeles, H Hou, W Schreiber, V A Wood, A B Flood, H M Swartz, P Kuppusamy. Phase 1 Clinical Trial of OxyChip, an Implantable Absolute pO2 Sensor for Tumor Oximetry - International Journal of Radiation Oncology Bio-Physics, 2016 Oct ;96(2S):S109-S110; doi: 10.1016/j.ijrobp.2016.06.268
I have more than 35 years of experience as a research scientist. My research activities and experience, using electron paramagnetic resonance (EPR) as the basis, are unique and distinctive. The specific area of research that is most pertinent to this application is my contributions to biodosimetry for determining exposure to ionizing radiation retrospectively using nails. My work on this project focused on developing a resonator that can make in vivo measurements in fingernails and toenails. To achieve this goal, the sensitivity of a resonator must be increased significantly. The solution I proposed was to develop a new structure - dielectric backed aperture resonator. It has been shown theoretically (by HFSS modeling) and experimentally that this newly invented resonator for EPR is quite promising for being able to use nails for biodosimetry in large scale events involving unexpected exposure to radiation. Similarly, I have been involved in developing novel resonators for measuring accidental exposure using in vivo measurements of teeth.
More generally, I have made significant contributions to the theoretical and experimental developments of EPR to be able to make in vivo measurements in animals and humans. In particular I was instrumental to the advancements made in high-spatial resolution multisite EPR oximetry, which has been applied to humans to assess pO2 in tumors (to identify regions of hypoxia that are more resistant to therapies so that treatments can be modified to improve their effectiveness) and which has been used to date in animals to assess ischemia and measure oxygen in the heart (allowing studies of the effect of anesthesia and physiological responses to medications among others).
Some of my career highlights include: Problem solver and manager of research and development efforts in the invention of new EPR techniques; fabrication of the world's first high-frequency (superconductive magnetic system) EPR spectrometer for chemistry and biophysics; research involving cell biophysics, cardiovascular measurements on animal models, and skin EPR measurements; development of the high-resolution multi-site EPR oximetry-imaging. As a mark of distinction for my professional achievements, I was awarded the National State Prize of USSR in 1989.
Areas of Research and Expertiese
Biodosimetry for determining exposure to ionizing radiation retrospectively using nails. There are a number of circumstances, especially related to accidents or terrorism, where there is an urgent need to determine whether an individual has been exposed to radiation doses of a magnitude where medical intervention is desirable to reduce the probability of adverse outcomes. My first contributions in this field concentrated on using clipped nails to assess unknown exposure to radiation. While this technique has the potential advantage of slowing self-harvesting of a sample to be sent to a lab for analysis, the signals were made more complex to analyze due to signals induced by the clipping process that interfered with a direct assessment of the true radiation-induced signal. Subsequently, my work changed to the development of a new type of resonator that was adapted to making in vivo measurements in fingernails and toenails. This offered the advantages of being suitable for being deployable to the site nearby to where people were accidentally exposed, producing immediate results within minutes, and not requiring that nails be clippable. These innovations make the use of nails much more feasible for biodosimetry in large scale nuclear power accidents or terrorism involving radiation.
He X, J. Gui, T.P. Matthews, B.B. Williams, S.G. Swarts, O. Grinberg, J. Sidabras, D.E. Wilcox, and H.M. Swartz, “Advances Towards Using Finger/Toenail Dosimetry to Triage a Large Population After Potential Exposure to Ionizing Radiatio,” Radiat. Meas. 46: 882-887 (2011).
He X, Swarts SG, Demidenko E, Flood AB, Grinberg O, Gui J, Mariani M, Marsh SD, Ruuge AE, Sidabras JW, Tipikin D, Wilcox DE, and Swartz HM. “Development and Validation of an Ex Vivo Electron Paramagnetic Resonance Fingernail Biodosimetric Method.” Radiat. Prot. Dosim. 159(1-4):172-181 (2014) (doi:10.1093/rpd/ncu129)
Oleg Grinberg, Jason W. Sidabras, Dmitriy Tipikin, Vladimir Krymov, Michael Mariani, Matthew Feldman, Maciej Kmiec, Sergey Petryakov, Spencer Brugger, Brandon Carr, Wilson Schreiber, Steven G. Swarts and Harold M. Swartz. “Dielectric-Backed Aperture Resonators For X-Band In Vivo EPR Nail Dosimetry.” Radiat Prot Dosimetry (2016) 172 (1-3): 121-126 doi:10.1093/rpd/ncw163
Swarts, SG. Jason W. Sidabras, Oleg Grinberg, Dmitriy S. Tipikin, Maciej Kmiec, Sergey Petryakov, Wilson Schreiber, Victoria A. Wood, Benjamin B. Williams, Ann B. Flood, Harold M. Swartz. Developments in Biodosimetry Methods for Triage, with a Focus on X-band Electron Paramagnetic Resonance In Vivo Fingernail Dosimetry. Health Phys. 115(1):140–150; 2018.
Biodosimetry for determining exposure to ionizing radiation retrospectively using teeth. In parallel to the contributions described above, I have been involved in developing the resonators for using teeth in vivo to make rapid assessments of accidental exposure to radiation to triage victims in the field.
Galtsev VE, Grinberg OY, Lebedev YS, Galtseva EV, EPR dosimetry sensitivity enhancement by detection of rapid passage signal of the tooth enamel at low-temperature, Appl Magn Res, 4 (3): 331-333 (1993)
Gal'tsev VE, Gal'tseva EV, Grinberg OY, Lebedev YS, Sensitivity enhancement of the tooth enamel EPR-Dosimetry. Dokl Akad Nauk (Rus). 334 (5): 649-652 (1994)
Iwasaki, O. Grinberg, T. Walczak and H.M. Swartz, “In Vivo Measurements of EPR Signals in Whole Human Teeth,” Appl. Radiat. and Isotopes. 62:187-190 (2005).
Iwasaki, T. Walczak, O. Grinberg and H.M. Swartz, “Differentiation of the Observed Low Frequency (1200 MHz) EPR Signals in Whole Human Teeth,” Appl. Radiat. and Isotopes. 62:133-139 (2005).
Harold M. Swartz, Greg Burke, M. Coey, Eugene Demidenko, Ruhong Dong, Oleg Grinberg, James Hilton, Akinori Iwasaki, Piotr Lesniewski, Maciej Kmiec, Kai-Ming Lo, R. Javier Nicolalde, Andres Ruuge, Yasuko Sakata, Artur Sucheta, Tadeusz Walczak, Benjamin B. Williams, Chad Mitchell, Alex Romanyukha, David A. Schauer, "In Vivo EPR for Dosimetry." Radiation Measurements. 42 (6-7), Sp. Iss. SI:1075-1084 (2007).
Benjamin B. Williams, Artur Sucheta, Ruhong Dong, Yasuko Sakata, Akinori Iwasaki, Gregory Burke, Oleg Grinberg, Piotr Lesniewski, Maciej Kmiec, Harold M. Swartz. "Experimental Procedures for Sensitive and Reproducible In Situ EPR Tooth Dosimetry," Radiation Measurements. 42(6-7), Sp. Iss. SI:1094-1098 (2007)
H.M. Swartz, A.B. Flood, B.B. Williams, R. Dong, S.G. Swarts, X. He, O. Grinberg, J. Sidabras, E. Demidenko, J. Gui, D. J. Gladstone, L.A. Jarvis, M.M Kmiec, K. Kobayashi, P.N. Lesniewski, S.D. Marsh, T.P. Matthews, R.J. Nicolalde, P.M. Pennington, T. Raynolds, I. Salikhov, D.E. Wilcox, and B.I. Zaki, “Electron Paramagnetic Resonance Dosimetry for a Large-Scale Radiation Incident,” Health. Phys. 103(3): 255-267 (2012). PMID: 22850230
J.D. Pollock, B.B. Williams, J.W. Sidabras, O. Grinberg, I. Salikhov, P. Lesniewski, M. Kmiec, and H.M. Swartz, “Surface Loop Resonator Design for In Vivo EPR Tooth Dosimetry Using Finite Element Analysis,” Health Phys. 98(2): 339-344 (2010).
B.B. Williams, R. Dong, A.B. Flood, O. Grinberg, M. Kmiec, P.N. Lesniewski, T.P. Matthews, R.J. Nicolalde, T. Raynolds, I. Salikhov, and H.M. Swartz, “A Deployable In Vivo EPR Tooth Dosimeter for Triage After a Radiation Event Involving Large Populations. Radiat. Meas. 46(9): 772-777 (2011).
Tumor oximetry – impact of oxygen on effectiveness of therapy. There is a large and critically important role of molecular oxygen in cells, tissues, and whole animals in many aspects of pathophysiology and physiology. We have used EPR oximetry to investigate aspects that cannot be measured as readily by other techniques by leveraging the capabilities of EPR probes including chemical versatility and stability. Specific areas in which we made significant contributions include measurements of intracellular oxygen demonstrating the existence of significant intracellular gradients and their origin in the properties of membranes and showing significant gradients related to cholesterol content, and direct and repeated measurements of oxygen in tumors.
J.A. O'Hara, R.D. Blumenthal, O.Y. Grinberg, E. Demidenko, S. Grinberg, C.M. Wilmot, A.M. Taylor, D.M. Goldenberg and H.M. Swartz, “Response to Radioimmunotherapy Correlates with Tumor pO2 Measured by EPR Oximetry in Human Tumor Xenografts,” Radiat. Res. 155: 466-473 (2001).
N. Khan, J. Shen, T.Y. Chang, C.Y. Chang, P.C.W. Fung, O. Grinberg, E. Demidenko and H. Swartz, “Plasma Membrane Cholesterol: A Possible Barrier to Intracellular Oxygen in Normal and Mutant CHO Cells Defective in Cholesterol Metabolism.” Biochem. 42: 23-29 (2003).
H. Hou, O.Y. Grinberg, S. Taie, S. Leichtweis, M. Miyake, S. Grinberg, H. Xie, M. Csete and H.M. Swartz, “Electron Paramagnetic Resonance (EPR) Assessment of Brain Tissue Oxygen Tension in Anesthetized Rats,” Anesth. Analg. 96: 1467-1472 (2003).
H. Hou, N. Khan, J.A. O’Hara, O.Y. Grinberg, J.F. Dunn, M. A. Abajian, C.M. Wilmot, M. Makki, E. Demidenko, S.Y. Lu, R.P. Steffen and H.M. Swartz. Effect of RSR13, an Allosteric Hemoglobin Modifier, on Oxygenation in Murine Tumors: An In Vivo EPR Oximetry and BOLD MRI Study. Int. J. of Radiat. Onc. Biol. Phys. 59(3):834-843 (2004)
H. Hou, N. Khan, O. Grinberg, H. Yu, S.A. Grinberg, S. Lu, E. Demidenko, R.P. Steffen, H.M. Swartz. “The Effects of EFAPROXYN™ (efaproxiral) on Subcutaneous RIF-1 Tumor Oxygenation and Enhancement of Radiotherapy Mediated Tumor Growth Inhibition in Mice,” Radiat. Res. 168: 218-225 (2007).
H.M. Swartz, G. Burke, M. Coey, E. Demidenko, R. Dong, O. Grinberg, J. Hilton, A. Iwasaki, P. Lesniewski, M. Kmiec, K. Lo, R.J. Nicolalde, A. Ruuge, Y. Sakata, A. Sucheta, T. Walczak, B.B. Williams, C. Mitchell, A. Romanyukha, and D. Schauer, “ Use of EPR for Dosimetry After the Potential Exposure of Large Numbers of People to Doses of Radiation that are Potentially Life Threatening” in Treasures of Eureka, Electron Paramagnetic Resonance From Fundamental Research To Pioneering Applications & Zavoisky Award, Volume 1, Axas Publishing, New Zealand, pp. 178-179 (2009).
Ischemia—Contributions of Measuring Oxygen for prognosis and treatment The role of oxygen in determining the physiological impact of ischemia is key to understanding several diseases and their treatments. My contributions include the development of novel methods to assess oxygen in tissues using EPR to make direct and repeated measurements of oxygen in ischemia in the brain and determining the effect of anesthetics on tissue pO2. Key publications include:
O.Y. Grinberg, H. Hou, S.A. Grinberg, K.L. Moodie, E. Demidenko, B.J. Friedman, M.J. Post, and H.M. Swartz. PO2 and Regional Blood Flow in a Rabbit Model of Limb Ischemia. Physiological Measurement, 25: 659 – 670 (2004)
Moodie KL, Grinberg OY, Hou H, Tomaszewski J, Grinberg SA, Demidenko E, Friedman BJ, Swartz HM, Post MJ. Repeated noninvasive measurement of pO2 by a novel electron paramagnetic resonance method in a rabbit model of hindlimb ischemia. J American College of Cardiology 43 (5): 472A-472A Suppl. A (2004)
Grinberg OY, Hou HG, Roche MA, Merlis J, Grinberg SA, Khan N, Swartz HM, Dunn JF Modeling of the response of p(t)O(2) in rat brain to changes in physiological parameters. Oxygen Transport to Tissue XXVI. Advances in Experimental Medicine and Biology 566: 111-118 (2005)
H. Hou, O.Y. Grinberg, S. Grinberg and H.M. Swartz. Cerebral Tissue Oxygenation in Reversible Focal Ischemia in Rats: EPR Oximetry Measurements. Physiol. Meas. 26:131-141 (2005).
O.Y. Grinberg, B.B. Williams, A.E. Ruuge, S.A. Grinberg, S.A. Grinberg, D.E. Wilcox, H.M. Swartz and J.F. Freed, " Oxygen effects on the EPR signals from wood charcoals: Experimental results and the development of a model”. J Phys Chem B, 111( 46):13316-13324 ( 2007)
H. Hou, O. Grinberg, B. Williams, S. Grinberg, H. Yu, D.L. Alvarenga, H. Wallach, J. Buckey and H.M. Swartz, “Effect of Oxygen Therapy on Brain Damage and Cerebral pO2 in Transient Focal Cerebral Ischemia in the Rat,” Physiol. Meas. 28: 963-976 (2007).
H.M. Swartz, N. Khan, B.B. Williams, A.C. Hartford, B. Zaki, M. Ernstoff, J.C. Buckey, F.F. Gubaidullin, H. Hou, P. Lesniewski, M. Kmiec, O.Y. Grinberg, A. Sucheta, and T. Walczak, “Clinical Applications of In Vivo EPR: EPR Oximetry” in Treasures of Eureka, Electron Paramagnetic Resonance From Fundamental Research To Pioneering Applications & Zavoisky Award, Volume 1, Axas Publishing, New Zealand, pp. 178-179 (2009).
J.F. Dunn, N.M. Khan, H.G. Hou, J. Merlis, M.A. Abajian, E. Demidenko, O.Y. Grinberg, and H.M. Swartz, “Cerebral Oxygenation in Awake Rats during Acclimation and Deacclimation to Hypoxia: An In Vivo Electron Paramagnetic Resonance Study,” High Alt. Med. Biol. 12: 71-77 (2011).
Cardiology—Oxygen Measurements in the Heart We succeeded to obtain very interesting results using EPR to make direct and repeated measurements of oxygen and determine the effect of different medications and physiological conditions on tissue pO2 in isolated rat heart.
B.J. Friedman, O.Y. Grinberg, K. Isaacs, E.K. Ruuge, and H.M. Swartz, “Effect of Repetitive Ischemia on Local Myocardial Oxygen Tension in Isolated Perfused and Hypoperfused Rat Hearts,” Magn. Reson. Med. 35: 214-220 (1996).
H. M. Swartz, G. Bacic, B. Friedman, F. Goda, O. Y. Grinberg, P. J. Hoopes, J. Jiang, K. J. Liu, T. Nakashima, J. O'Hara, and T. Walczak, “Measurement of pO2 In Vivo, Including Human Subjects by Electron Paramagnetic Resonance,” Adv. Exp. Med. Biol. 361: 119-128 (1995).
B.J. Friedman, O.Y. Grinberg, S.A. Grinberg, and H.M. Swartz, “Myocardial Oxygen Tension in Isolated Erythrocyte-Perfused Rat Hearts and Comparison with Crystalloid Media,” J. Mol. Cell Cardiol. 29: 2855-2858 (1997).
B. J. Friedman, O. Y. Grinberg, K. Isaacs, T. M. Walczak, and H. M. Swartz, "Myocardial Oxygen Tension and Relative Capillary Density in Isolated Perfused Rat Hearts," J. Mol. Cell. Cardiol. 27: 2551-2558 (1995)
O. Y. Grinberg, S. A. Grinberg, B. J. Friedman, and H. M. Swartz, “Myocardial Oxygen Tension and Capillary Density in the Isolated Perfused Rat Heart During Pharmacological Intervention,” Adv. Exp. Med. Biol. 411: 171-181 (1997)
B.J. Friedman, O.Y. Grinberg, N.R. Ratcliffe, H.M. Swartz, and W.F. Hickey, “Acute Hemodynamic and Coronary Circulatory Effects of Experimental Autoimmune Myocarditis,” Heart Vessels. 13: 58-62 (1998).
Grinberg O, Novozhilov B, Grinberg S, Friedman B, Swartz HM. Axial oxygen diffusion in the krogh model: Modifications to account for myocardial oxygen tension in isolated perfused rat hearts measured by EPR oximetry. Oxygen Transport to Tissue XXVI. Advances in Experimental Medicine and Biology. 566: 127-134 (2005)
High-Spatial-Resolution Multisite EPR Oximetry It is known that application of an external magnetic gradient allows the provision of spatial resolution of pO2 measurements in tissue. To improve this method significantly, I made major contributions to work to develop high spatial resolution multi-site EPR oximetry by use of a convolution-based fitting method.
Grinberg OY and Berliner LJ editors, “Very High Frequency (VHF) ESR/EPR" Biological Magnetic Resonance - Volume 22: Plenum Publishing Co., NY, (2004).
Grinberg VO, Smirnov AI, Grinberg OY, Grinberg SA, O'Hara JA, Swartz HM Practical conditions and limitations for high-spatial-resolution multisite EPR oximetry. Applied Magnetic Resonance 28 (1-2): 69-78 (2005)