Cooperative Regulatory Functions of miR858 and MYB83 during Cyst Nematode Parasitism

MicroRNAs (miRNAs) recently have been established as key regulators of transcriptome reprogramming that define cell function and identity. Nevertheless, the molecular functions of the greatest number of miRNA genes remain to be determined. Here, we report cooperative regulatory functions of miR858 and its MYB83 transcription factor target gene in transcriptome reprogramming during Heterodera cyst nematode parasitism of Arabidopsis (Arabidopsis thaliana). Gene expression analyses and promoter-GUS fusion assays documented a role of miR858 in posttranscriptional regulation of MYB83 in the Heterodera schachtii-induced feeding sites, the syncytia. Constitutive overexpression of miR858 interfered with H. schachtii parasitism of Arabidopsis, leading to reduced susceptibility, while reduced miR858 abundance enhanced plant susceptibility. Similarly, MYB83 expression increases were conducive to nematode infection because overexpression of a noncleavable coding sequence of MYB83 significantly increased plant susceptibility, whereas a myb83 mutation rendered the plants less susceptible. In addition, RNA-seq analysis revealed that genes involved in hormone signaling pathways, defense response, glucosinolate biosynthesis, cell wall modification, sugar transport, and transcriptional control are the key etiological factors by which MYB83 facilitates nematode parasitism of Arabidopsis. Furthermore, we discovered that miR858-mediated silencing of MYB83 is tightly regulated through a feedback loop that might contribute to fine-tuning the expression of more than a thousand of MYB83-regulated genes in the H. schachtii-induced syncytium. Together, our results suggest a role of the miR858-MYB83 regulatory system in finely balancing gene expression patterns during H. schachtii parasitism of Arabidopsis to ensure optimal cellular function

A Single-Particle Trigger for Time-of-Flight Measurements in Prompt-Gamma Imaging

[EN] Tracking of single particles accelerated by synchrotrons is a subject that crosses several physics fields. The high clinical intensities used in particle therapy that can exceed 10(9)p/s make this task very challenging. The tracking of the arrival time of single particles in the ion beam is fundamental for the verification of the particle range and dose delivered to the patient. We present a prototype made of scintillating fibers which has been used to provide time-of-flight (TOF) information for three beam species currently accelerated at the Heidelberg Ion-Beam Therapy Center (HIT). We have demonstrated a time-tracker for a prompt-gamma spectroscopy system that allows for a background TOF rejection with a sub-nanosecond time resolution.PM was supported by a research fellowship for postdoctoral researchers from the Alexander von Humboldt Foundation, Bonn, Germany. RD was supported by the International Max Planck Research School for Quantum Dynamics in Physics, Chemistry and Biology, Heidelberg, Germany.Martins, PM.; Dal Bello, R.; Seimetz, M.; Hermann, G.; Kihm, T.; Seco, J. (2020). A Single-Particle Trigger for Time-of-Flight Measurements in Prompt-Gamma Imaging. Frontiers in Physics. 8:1-13. https://doi.org/10.3389/fphy.2020.00169S1138Parodi, K., Crespo, P., Eickhoff, H., Haberer, T., Pawelke, J., Schardt, D., & Enghardt, W. (2005). Random coincidences during in-beam PET measurements at microbunched therapeutic ion beams. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 545(1-2), 446-458. doi:10.1016/j.nima.2005.02.002Crespo, P., Barthel, T., Frais-Kolbl, H., Griesmayer, E., Heidel, K., Parodi, K., … Enghardt, W. (2005). Suppression of random coincidences during in-beam PET measurements at ion beam radiotherapy facilities. IEEE Transactions on Nuclear Science, 52(4), 980-987. doi:10.1109/tns.2005.852637Testa, E., Bajard, M., Chevallier, M., Dauvergne, D., Le Foulher, F., Freud, N., … Testa, M. (2008). Monitoring the Bragg peak location of 73MeV∕u carbon ions by means of prompt γ-ray measurements. Applied Physics Letters, 93(9), 093506. doi:10.1063/1.2975841Biegun, A. K., Seravalli, E., Lopes, P. C., Rinaldi, I., Pinto, M., Oxley, D. C., … Schaart, D. R. (2012). Time-of-flight neutron rejection to improve prompt gamma imaging for proton range verification: a simulation study. Physics in Medicine and Biology, 57(20), 6429-6444. doi:10.1088/0031-9155/57/20/6429Smeets, J., Roellinghoff, F., Prieels, D., Stichelbaut, F., Benilov, A., Busca, P., … Dubus, A. (2012). Prompt gamma imaging with a slit camera for real-time range control in proton therapy. Physics in Medicine and Biology, 57(11), 3371-3405. doi:10.1088/0031-9155/57/11/3371Verburg, J. M., Riley, K., Bortfeld, T., & Seco, J. (2013). Energy- and time-resolved detection of prompt gamma-rays for proton range verification. Physics in Medicine and Biology, 58(20), L37-L49. doi:10.1088/0031-9155/58/20/l37Golnik, C., Hueso-González, F., Müller, A., Dendooven, P., Enghardt, W., Fiedler, F., … Pausch, G. (2014). Range assessment in particle therapy based on promptγ-ray timing measurements. Physics in Medicine and Biology, 59(18), 5399-5422. doi:10.1088/0031-9155/59/18/5399Cambraia Lopes, P., Clementel, E., Crespo, P., Henrotin, S., Huizenga, J., Janssens, G., … Schaart, D. R. (2015). Time-resolved imaging of prompt-gamma rays for proton range verification using a knife-edge slit camera based on digital photon counters. Physics in Medicine and Biology, 60(15), 6063-6085. doi:10.1088/0031-9155/60/15/6063Petzoldt, J., Roemer, K. E., Enghardt, W., Fiedler, F., Golnik, C., Hueso-González, F., … Pausch, G. (2016). Characterization of the microbunch time structure of proton pencil beams at a clinical treatment facility. Physics in Medicine and Biology, 61(6), 2432-2456. doi:10.1088/0031-9155/61/6/2432Verburg, J. M., & Seco, J. (2014). Proton range verification through prompt gamma-ray spectroscopy. Physics in Medicine and Biology, 59(23), 7089-7106. doi:10.1088/0031-9155/59/23/7089Hueso-González, F., Enghardt, W., Fiedler, F., Golnik, C., Janssens, G., Petzoldt, J., … Pausch, G. (2015). First test of the prompt gamma ray timing method with heterogeneous targets at a clinical proton therapy facility. Physics in Medicine and Biology, 60(16), 6247-6272. doi:10.1088/0031-9155/60/16/6247Martins, P. M., Dal Bello, R., Rinscheid, A., Roemer, K., Werner, T., Enghardt, W., … Seco, J. (2017). Prompt gamma spectroscopy for range control with CeBr3. Current Directions in Biomedical Engineering, 3(2), 113-117. doi:10.1515/cdbme-2017-0023Gil, E. C., Albarrán, E. M., Minucci, E., Nüssle, G., Padolski, S., Petrov, P., … Kozhuharov, V. (2017). The beam and detector of the NA62 experiment at CERN. Journal of Instrumentation, 12(05), P05025-P05025. doi:10.1088/1748-0221/12/05/p05025Schüttauf, A. (2004). Timing RPCs in FOPI. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 533(1-2), 65-68. doi:10.1016/j.nima.2004.07.002Alici, A. (2012). Status and performance of the ALICE MRPC-based Time-Of-Flight detector. Journal of Instrumentation, 7(10), P10024-P10024. doi:10.1088/1748-0221/7/10/p10024Blanco, A., Fonte, P., Garzon, J. A., Koenig, W., Kornakov, G., & Lopes, L. (2013). Performance of the HADES-TOF RPC wall in a Au + Au beam at 1.25 AGeV. Journal of Instrumentation, 8(01), P01004-P01004. doi:10.1088/1748-0221/8/01/p01004Sadrozinski, H. F.-W., Ely, S., Fadeyev, V., Galloway, Z., Ngo, J., Parker, C., … Vinattieri, A. (2013). Ultra-fast silicon detectors. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 730, 226-231. doi:10.1016/j.nima.2013.06.033Cartiglia, N., Staiano, A., Sola, V., Arcidiacono, R., Cirio, R., Cenna, F., … Zavrtanik, M. (2017). Beam test results of a 16 ps timing system based on ultra-fast silicon detectors. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 850, 83-88. doi:10.1016/j.nima.2017.01.021Sadrozinski, H. F.-W., Seiden, A., & Cartiglia, N. (2017). 4D tracking with ultra-fast silicon detectors. Reports on Progress in Physics, 81(2), 026101. doi:10.1088/1361-6633/aa94d3Beddar, A. S., Mackie, T. R., & Attix, F. H. (1992). Water-equivalent plastic scintillation detectors for high-energy beam dosimetry: I. Physical characteristics and theoretical considerations. Physics in Medicine and Biology, 37(10), 1883-1900. doi:10.1088/0031-9155/37/10/006Beddar, A. S., Mackie, T. R., & Attix, F. H. (1992). Water-equivalent plastic scintillation detectors for high-energy beam dosimetry: II. Properties and measurements. Physics in Medicine and Biology, 37(10), 1901-1913. doi:10.1088/0031-9155/37/10/007Beaulieu, L., & Beddar, S. (2016). Review of plastic and liquid scintillation dosimetry for photon, electron, and proton therapy. Physics in Medicine and Biology, 61(20), R305-R343. doi:10.1088/0031-9155/61/20/r305Beddar, S., & Beaulieu, L. (Eds.). (2016). Scintillation Dosimetry. Imaging in Medical Diagnosis and Therapy. doi:10.1201/b19491Marcatili, S., Collot, J., Curtoni, S., Dauvergne, D., Hostachy, J.-Y., Koumeir, C., … Yamouni, M. (2020). Ultra-fast prompt gamma detection in single proton counting regime for range monitoring in particle therapy. Physics in Medicine & Biology, 65(24), 245033. doi:10.1088/1361-6560/ab7a6cKirn, T. (2017). SciFi – A large scintillating fibre tracker for LHCb. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 845, 481-485. doi:10.1016/j.nima.2016.06.057Leverington, B. D., Dziewiecki, M., Renner, L., & Runze, R. (2018). A prototype scintillating fibre beam profile monitor for Ion Therapy beams. Journal of Instrumentation, 13(05), P05030-P05030. doi:10.1088/1748-0221/13/05/p05030Vignati, A., Monaco, V., Attili, A., Cartiglia, N., Donetti, M., Mazinani, M. F., … Cirio, R. (2017). Innovative thin silicon detectors for monitoring of therapeutic proton beams: preliminary beam tests. Journal of Instrumentation, 12(12), C12056-C12056. doi:10.1088/1748-0221/12/12/c12056Krimmer, J., Dauvergne, D., Létang, J. M., & Testa, É. (2018). Prompt-gamma monitoring in hadrontherapy: A review. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 878, 58-73. doi:10.1016/j.nima.2017.07.063Pausch, G., Berthold, J., Enghardt, W., Römer, K., Straessner, A., Wagner, A., … Kögler, T. (2020). Detection systems for range monitoring in proton therapy: Needs and challenges. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 954, 161227. doi:10.1016/j.nima.2018.09.062Hueso-Gonzalez, F., & Bortfeld, T. (2020). Compact Method for Proton Range Verification Based on Coaxial Prompt Gamma-Ray Monitoring: A Theoretical Study. IEEE Transactions on Radiation and Plasma Medical Sciences, 4(2), 170-183. doi:10.1109/trpms.2019.2930362Haberer, T., Debus, J., Eickhoff, H., Jäkel, O., Schulz-Ertner, D., & Weber, U. (2004). The heidelberg ion therapy center. Radiotherapy and Oncology, 73, S186-S190. doi:10.1016/s0167-8140(04)80046-xHara, K., Hata, K., Kim, S., Mishina, M., Sano, M., Seiya, Y., … Yasuoka, K. (1998). Radiation hardness and mechanical durability of Kuraray optical fibers. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 411(1), 31-40. doi:10.1016/s0168-9002(98)00281-2Joram, C., Haefeli, G., & Leverington, B. (2015). Scintillating Fibre Tracking at High Luminosity Colliders. Journal of Instrumentation, 10(08), C08005-C08005. doi:10.1088/1748-0221/10/08/c08005EkelhofRJ Studies for the LHCb SciFi Tracker - Development of Modules from Scintillating Fibres and Tests of their Radiation Hardness2016Online control of particle therapy - CLaRyS collaboration1825 DauvergneD Final MediNet Network Meeting2019Tessonnier, T., Mairani, A., Chen, W., Sala, P., Cerutti, F., Ferrari, A., … Parodi, K. (2018). Proton and helium ion radiotherapy for meningioma tumors: a Monte Carlo-based treatment planning comparison. Radiation Oncology, 13(1). doi:10.1186/s13014-017-0944-3Mein, S., Dokic, I., Klein, C., Tessonnier, T., Böhlen, T. T., Magro, G., … Mairani, A. (2019). Biophysical modeling and experimental validation of relative biological effectiveness (RBE) for 4He ion beam therapy. Radiation Oncology, 14(1). doi:10.1186/s13014-019-1295-zSchoemers, C., Feldmeier, E., Naumann, J., Panse, R., Peters, A., & Haberer, T. (2015). The intensity feedback system at Heidelberg Ion-Beam Therapy Centre. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 795, 92-99. doi:10.1016/j.nima.2015.05.054Werner, F., Bauer, C., Bernhard, S., Capasso, M., Diebold, S., Eisenkolb, F., … Zietara, K. (2017). Performance verification of the FlashCam prototype camera for the Cherenkov Telescope Array. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 876, 31-34. doi:10.1016/j.nima.2016.12.056Actis, M., Agnetta, G., Aharonian, F., Akhperjanian, A., Aleksić, J., … Antico, F. (2011). Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy. Experimental Astronomy, 32(3), 193-316. doi:10.1007/s10686-011-9247-0Dal Bello, R., Magalhaes Martins, P., Graça, J., Hermann, G., Kihm, T., & Seco, J. (2019). Results from the experimental evaluation of CeBr scintillators for He prompt gamma spectroscopy. Medical Physics, 46(8), 3615-3626. doi:10.1002/mp.13594Puehlhofer, G., Bauer, C., Bernhard, S., Capasso, M., Diebold, S., Eisenkolb, F., … Zietara, K. (2016). FlashCam: a fully-digital camera for the medium-sized telescopes of the Cherenkov Telescope Array. Proceedings of The 34th International Cosmic Ray Conference — PoS(ICRC2015). doi:10.22323/1.236.1039Testa, M., Bajard, M., Chevallier, M., Dauvergne, D., Freud, N., Henriquet, P., … Testa, E. (2010). Real-time monitoring of the Bragg-peak position in ion therapy by means of single photon detection. Radiation and Environmental Biophysics, 49(3), 337-343. doi:10.1007/s00411-010-0276-2Dal Bello, R., Magalhaes Martins, P., Brons, S., Hermann, G., Kihm, T., Seimetz, M., & Seco, J. (2020). Prompt gamma spectroscopy for absolute range verification of 12C ions at synchrotron-based facilities. Physics in Medicine & Biology, 65(9), 095010. doi:10.1088/1361-6560/ab797321768 LeoWR Techniques for Nuclear and Particle Physics Experiments: A How-to Approach1994Graeff, C., Weber, U., Schuy, C., Saito, N., Volz, L., Piersimoni, P., … Kraemer, M. (2018). [OA027] Helium as a range probe in carbon ion therapy. Physica Medica, 52, 11. doi:10.1016/j.ejmp.2018.06.099Mazzucconi, D., Agosteo, S., Ferrarini, M., Fontana, L., Lante, V., Pullia, M., & Savazzi, S. (2018). Mixed particle beam for simultaneous treatment and online range verification in carbon ion therapy: Proof‐of‐concept study. Medical Physics, 45(11), 5234-5243. doi:10.1002/mp.13219Scintillating Fiber Trackers: recent developments and applications204 BlancF 14th ICATPP Conference on Astroparticle, Particle, Space Physics and Detectors for Physics Applications2013JoramC UwerU LeveringtonBD KirnT BachmannS EkelhofRJ LHCb Scintillating Fibre Tracker Engineering Design Review Report: Fibres, Mats and Modules201

Prompt gamma spectroscopy for absolute range verification of 12C ions at synchroton-based facilities

[EN] The physical range uncertainty limits the exploitation of the full potential of charged particle therapy. In this work, we face this issue aiming to measure the absolute Bragg peak position in the target. We investigate p, He-4, C-12 and O-16 beams accelerated at the Heidelberg Ion-Beam Therapy Center. The residual range of the primary C-12 ions is correlated to the energy spectrum of the prompt gamma radiation. The prompt gamma spectroscopy method was demonstrated for proton beams accelerated by cyclotrons and is developed here for the first time for heavier ions accelerated by a synchrotron. We develop a detector system that includes (i) a spectroscopic unit based on cerium(III) bromide and bismuth germanium oxide scintillating crystals, (ii) a beam trigger based on an array of scintillating fibers and (iii) a data acquisition system based on a FlashADC. We test the system in two different scenarios. In the first series of experiments, we detect and identify 19 independent spectral lines over a wide gamma energy spectrum in the presence of the four ion species for different targets, including a water target with a titanium insert. In the second series of experiments, we introduce a collimator aiming to relate the spectral information to the range of the primary particles. We perform extensive measurements for a C-12 beam and demonstrate submillimetric precision for the measurement of its Bragg peak position in the experimental setup. The features of the energy and time spectra for gamma radiation induced by p, He-4 and O-16 are investigated upstream and downstream from the Bragg peak position. We conclude the analysis by extrapolating the required future developments, which would be needed to achieve range verification with a 2 mm accuracy during a single fraction delivery of D=2 Gy<i physical dose.The author R.D.B. is supported by the International Max Planck Research School for Quantum Dynamics in Physics, Chemistry and Biology, Heidelberg, Germany. P.M.M. is supported by a research fellowship for postdoctoral researchers from the Alexander von Humboldt Foundation, Bonn, Germany. The authors thank the Radiation Protection Department of the DKFZ, in particular Mechthild Kammer, for the support with calibration sources. The authors also thank the staff of the Department of Medical Physics in Radiation Oncology of the DKFZ, in particular Gernot Echner, Armin Runz and Peter Haring for the support with the experimental setup.Dal Bello, R.; Martins, PM.; Brons, S.; Hermann, G.; Kihm, T.; Seimetz, M.; Seco, J. (2020). Prompt gamma spectroscopy for absolute range verification of 12C ions at synchroton-based facilities. Physics in Medicine and Biology. 65(9):1-23. https://doi.org/10.1088/1361-6560/ab7973S123659Amaldi, U., & Kraft, G. (2005). Radiotherapy with beams of carbon ions. Reports on Progress in Physics, 68(8), 1861-1882. doi:10.1088/0034-4885/68/8/r04Aricò, G., Gehrke, T., Gallas, R., Mairani, A., Jäkel, O., & Martišíková, M. (2019). Investigation of single carbon ion fragmentation in water and PMMA for hadron therapy. Physics in Medicine & Biology, 64(5), 055018. doi:10.1088/1361-6560/aafa46Böhlen, T. T., Cerutti, F., Chin, M. P. W., Fassò, A., Ferrari, A., Ortega, P. G., … Vlachoudis, V. (2014). The FLUKA Code: Developments and Challenges for High Energy and Medical Applications. Nuclear Data Sheets, 120, 211-214. doi:10.1016/j.nds.2014.07.049Bragg, W. H., & Kleeman, R. (1905). XXXIX. On the α particles of radium, and their loss of range in passing through various atoms and molecules. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science, 10(57), 318-340. doi:10.1080/14786440509463378Brun, R., & Rademakers, F. (1997). ROOT — An object oriented data analysis framework. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 389(1-2), 81-86. doi:10.1016/s0168-9002(97)00048-xCastriconi, R., Ciocca, M., Mirandola, A., Sini, C., Broggi, S., Schwarz, M., … Russo, P. (2016). Dose–response of EBT3 radiochromic films to proton and carbon ion clinical beams. Physics in Medicine and Biology, 62(2), 377-393. doi:10.1088/1361-6560/aa5078Guttormsen, M., Tveter, T. ., Bergholt, L., Ingebretsen, F., & Rekstad, J. (1996). The unfolding of continuum γ-ray spectra. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 374(3), 371-376. doi:10.1016/0168-9002(96)00197-0Haberer, T., Debus, J., Eickhoff, H., Jäkel, O., Schulz-Ertner, D., & Weber, U. (2004). The heidelberg ion therapy center. Radiotherapy and Oncology, 73, S186-S190. doi:10.1016/s0167-8140(04)80046-xHueso-González, F., Rabe, M., Ruggieri, T. A., Bortfeld, T., & Verburg, J. M. (2018). A full-scale clinical prototype for proton range verification using prompt gamma-ray spectroscopy. Physics in Medicine & Biology, 63(18), 185019. doi:10.1088/1361-6560/aad513Kelleter, L., Wrońska, A., Besuglow, J., Konefał, A., Laihem, K., Leidner, J., … Tessonnier, T. (2017). Spectroscopic study of prompt-gamma emission for range verification in proton therapy. Physica Medica, 34, 7-17. doi:10.1016/j.ejmp.2017.01.003Knopf, A.-C., & Lomax, A. (2013). In vivoproton range verification: a review. Physics in Medicine and Biology, 58(15), R131-R160. doi:10.1088/0031-9155/58/15/r131Kozlovsky, B., Murphy, R. J., & Ramaty, R. (2002). Nuclear Deexcitation Gamma‐Ray Lines from Accelerated Particle Interactions. The Astrophysical Journal Supplement Series, 141(2), 523-541. doi:10.1086/340545Krimmer, J., Dauvergne, D., Létang, J. M., & Testa, É. (2018). Prompt-gamma monitoring in hadrontherapy: A review. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 878, 58-73. doi:10.1016/j.nima.2017.07.063Leverington, B. D., Dziewiecki, M., Renner, L., & Runze, R. (2018). A prototype scintillating fibre beam profile monitor for Ion Therapy beams. Journal of Instrumentation, 13(05), P05030-P05030. doi:10.1088/1748-0221/13/05/p05030Mein, S., Choi, K., Kopp, B., Tessonnier, T., Bauer, J., Ferrari, A., … Mairani, A. (2018). Fast robust dose calculation on GPU for high-precision 1H, 4He, 12C and 16O ion therapy: the FRoG platform. Scientific Reports, 8(1). doi:10.1038/s41598-018-33194-4Paganetti, H. (2012). Range uncertainties in proton therapy and the role of Monte Carlo simulations. Physics in Medicine and Biology, 57(11), R99-R117. doi:10.1088/0031-9155/57/11/r99Panaino, C., Taylor, M. J., MacKay, R., Merchant, M. J., Price, T., Pheonix, B., & Green, S. (2018). Abstract ID: 171 A Monte Carlo study to reduce range uncertainty in proton beam therapy via prompt gamma-ray detection. Physica Medica, 45, S2. doi:10.1016/j.ejmp.2017.11.027Pinto, M., Bajard, M., Brons, S., Chevallier, M., Dauvergne, D., Dedes, G., … Testa, M. (2014). Absolute prompt-gamma yield measurements for ion beam therapy monitoring. Physics in Medicine and Biology, 60(2), 565-594. doi:10.1088/0031-9155/60/2/565Quarati, F. G. A., Dorenbos, P., van der Biezen, J., Owens, A., Selle, M., Parthier, L., & Schotanus, P. (2013). Scintillation and detection characteristics of high-sensitivity CeBr3 gamma-ray spectrometers. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 729, 596-604. doi:10.1016/j.nima.2013.08.005Dal Bello, R., Magalhaes Martins, P., & Seco, J. (2018). CeBr3scintillators for4He prompt gamma spectroscopy: Results from a Monte Carlo optimization study. Medical Physics, 45(4), 1622-1630. doi:10.1002/mp.12795Dal Bello, R., Magalhaes Martins, P., Graça, J., Hermann, G., Kihm, T., & Seco, J. (2019). Results from the experimental evaluation of CeBr scintillators for He prompt gamma spectroscopy. Medical Physics, 46(8), 3615-3626. doi:10.1002/mp.13594Roemer, K., Pausch, G., Bemmerer, D., Berthel, M., Dreyer, A., Golnik, C., … Fiedler, F. (2015). Characterization of scintillator crystals for usage as prompt gamma monitors in particle therapy. Journal of Instrumentation, 10(10), P10033-P10033. doi:10.1088/1748-0221/10/10/p10033Testa, M., Bajard, M., Chevallier, M., Dauvergne, D., Freud, N., Henriquet, P., … Testa, E. (2010). Real-time monitoring of the Bragg-peak position in ion therapy by means of single photon detection. Radiation and Environmental Biophysics, 49(3), 337-343. doi:10.1007/s00411-010-0276-2Tommasino, F., Scifoni, E., & Durante, M. (2015). New Ions for Therapy. International Journal of Particle Therapy, 2(3), 428-438. doi:10.14338/ijpt-15-00027.1Vanstalle, M., Mattei, I., Sarti, A., Bellini, F., Bini, F., Collamati, F., … Tessa, C. L. (2017). Benchmarking Geant4 hadronic models for prompt‐ γ monitoring in carbon ion therapy. Medical Physics, 44(8), 4276-4286. doi:10.1002/mp.12348Verburg, J. M., Riley, K., Bortfeld, T., & Seco, J. (2013). Energy- and time-resolved detection of prompt gamma-rays for proton range verification. Physics in Medicine and Biology, 58(20), L37-L49. doi:10.1088/0031-9155/58/20/l37Verburg, J. M., & Seco, J. (2014). Proton range verification through prompt gamma-ray spectroscopy. Physics in Medicine and Biology, 59(23), 7089-7106. doi:10.1088/0031-9155/59/23/7089Werner, F., Bauer, C., Bernhard, S., Capasso, M., Diebold, S., Eisenkolb, F., … Zietara, K. (2017). Performance verification of the FlashCam prototype camera for the Cherenkov Telescope Array. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 876, 31-34. doi:10.1016/j.nima.2016.12.05

Improvement of renal function after transcatheter aortic valve replacement and its impact on survival

Background Chronic kidney disease as well as acute kidney injury are associated with adverse outcomes after transcatheter aortic valve replacement (TAVR). However, little is known about the prognostic implications of an improvement in renal function after TAVR. Methods Renal improvement (RI) was defined as a decrease in postprocedural creatinine in μmol/l of ≥1% compared to its preprocedural baseline value. A propensity score representing the likelihood of RI was calculated to define patient groups which were comparable regarding potential confounders (age, sex, BMI, NYHA classification, STS score, log. EuroSCORE, history of atrial fibrillation/atrial flutter, pulmonary disease, previous stroke, CRP, creatinine, hsTNT and NT-proBNP). The cohort was stratified into 5 quintiles according to this propensity score and the survival time after TAVR was compared within each subgroup. Results Patients in quintile 5 (n = 93) had the highest likelihood for RI. They were characterized by higher creatinine, lower eGFR, higher NYHA class, higher NT-proBNP, being mostly female and having shorter overall survival time. Within quintile 5, patients without RI had significantly shorter survival compared to patients with RI (p = 0.002, HR = 0.32, 95% CI = [0.15-0.69]). There was no survival time difference between patients with and without RI in the whole cohort (p = 0.12) and in quintiles 1 to 4 (all p > 0.16). Analyses of specific subgroups showed that among patients with NYHA class IV, those with RI also had a significant survival time benefit (p < 0.001, HR = 0.15; 95%-CI = [0.05-0.44]) compared to patients without RI. Conclusions We here describe a propensity score-derived specific subgroup of patients in which RI after TAVR correlated with a significant survival benefit

Red blood cell lingering modulates hematocrit distribution in the microcirculation

The distribution of red blood cells (RBCs) in the microcirculation determines the oxygen delivery and solute transport to tissues. This process relies on the partitioning of RBCs at successive bifurcations throughout the microvascular network, and it has been known since the last century that RBCs partition disproportionately to the fractional blood flow rate, therefore leading to heterogeneity of the hematocrit (i.e., volume fraction of RBCs in blood) in microvessels. Usually, downstream of a microvascular bifurcation, the vessel branch with a higher fraction of blood flow receives an even higher fraction of RBC flux. However, both temporal and time-average deviations from this phase-separation law have been observed in recent studies. Here, we quantify how the microscopic behavior of RBC lingering (i.e., RBCs temporarily residing near the bifurcation apex with diminished velocity) influences their partitioning, through combined in vivo experiments and in silico simulations. We developed an approach to quantify the cell lingering at highly confined capillary-level bifurcations and demonstrate that it correlates with deviations of the phase-separation process from established empirical predictions by Pries et al. Furthermore, we shed light on how the bifurcation geometry and cell membrane rigidity can affect the lingering behavior of RBCs; e.g., rigid cells tend to linger less than softer ones. Taken together, RBC lingering is an important mechanism that should be considered when studying how abnormal RBC rigidity in diseases such as malaria and sickle-cell disease could hinder the microcirculatory blood flow or how the vascular networks are altered under pathological conditions (e.g., thrombosis, tumors, aneurysm)

EASIX for Prediction of Outcome in Hospitalized SARS-CoV-2 Infected Patients

BackgroundThe coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has evoked a pandemic that challenges public health-care systems worldwide. Endothelial cell dysfunction plays a key role in pathophysiology, and simple prognosticators may help to optimize allocation of limited resources. Endothelial activation and stress index (EASIX) is a validated predictor of endothelial complications and outcome after allogeneic stem cell transplantation. Aim of this study was to test if EASIX could predict life-threatening complications in patients with COVID-19.MethodsSARS-CoV-2-positive, hospitalized patients were enrolled onto a prospective non-interventional register study (n=100). Biomarkers were assessed at hospital admission. Primary endpoint was severe course of disease (mechanical ventilation and/or death, V/D). Results were validated in 126 patients treated in two independent institutions.ResultsEASIX at admission was a strong predictor of severe course of the disease (odds ratio for a two-fold change 3.4, 95%CI 1.8-6.3, p&lt;0.001), time to V/D (hazard ratio (HR) for a two-fold change 2.0, 95%CI 1.5-2.6, p&lt;0.001) as well as survival (HR for a two-fold change 1.7, 95%CI 1.2-2.5, p=0.006). The effect was retained in multivariable analysis adjusting for age, gender, and comorbidities and could be validated in the independent cohort. At hospital admission EASIX correlated with increased suppressor of tumorigenicity-2, soluble thrombomodulin, angiopoietin-2, CXCL8, CXCL9 and interleukin-18, but not interferon-alpha.ConclusionEASIX is a validated predictor of COVID19 outcome and an easy-to-access tool to segregate patients in need for intensive surveillance

Performance of the New FlashCam-based Camera in the 28\,m Telescope of H.E.S.S

In October 2019, the central 28 m telescope of the H.E.S.S. experiment has been upgraded with a new camera. The camera is based on the FlashCam design which has been developed in view of a possible future implementation in the Medium-Sized Telescopes of the Cherenkov Telescope Array (CTA), with emphasis on cost and performance optimization and on reliability. The fully digital design of the trigger and readout system makes it possible to operate the camera at high event rates and to precisely adjust and understand the trigger system. The novel design of the front-end electronics achieves a dynamic range of over 3,000 photoelectrons with only one electronics readout circuit per pixel. Here we report on the performance parameters of the camera obtained during the first year of operation in the field, including operational stability and optimization of calibration algorithms.Comment: Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021

Modeling of GERDA Phase II data

The GERmanium Detector Array (GERDA) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double-beta ($0\nu\beta\beta$) decay of $^{76}$Ge. The technological challenge of GERDA is to operate in a "background-free" regime in the region of interest (ROI) after analysis cuts for the full 100$\,$kg$\cdot$yr target exposure of the experiment. A careful modeling and decomposition of the full-range energy spectrum is essential to predict the shape and composition of events in the ROI around $Q_{\beta\beta}$ for the $0\nu\beta\beta$ search, to extract a precise measurement of the half-life of the double-beta decay mode with neutrinos ($2\nu\beta\beta$) and in order to identify the location of residual impurities. The latter will permit future experiments to build strategies in order to further lower the background and achieve even better sensitivities. In this article the background decomposition prior to analysis cuts is presented for GERDA Phase II. The background model fit yields a flat spectrum in the ROI with a background index (BI) of $16.04^{+0.78}_{-0.85} \cdot 10^{-3}\,$cts/(kg$\cdot$keV$\cdot$yr) for the enriched BEGe data set and $14.68^{+0.47}_{-0.52} \cdot 10^{-3}\,$cts/(kg$\cdot$keV$\cdot$yr) for the enriched coaxial data set. These values are similar to the one of Gerda Phase I despite a much larger number of detectors and hence radioactive hardware components

Modeling of GERDA Phase II data

The GERmanium Detector Array (Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double-beta (0νββ) decay of 76Ge. The technological challenge of Gerda is to operate in a “background-free” regime in the region of interest (ROI) after analysis cuts for the full 100 kg·yr target exposure of the experiment. A careful modeling and decomposition of the full-range energy spectrum is essential to predict the shape and composition of events in the ROI around Qββ for the 0νββ search, to extract a precise measurement of the half-life of the double-beta decay mode with neutrinos (2νββ) and in order to identify the location of residual impurities. The latter will permit future experiments to build strategies in order to further lower the background and achieve even better sensitivities. In this article the background decomposition prior to analysis cuts is presented for Gerda Phase II. The background model fit yields a flat spectrum in the ROI with a background index (BI) of 16.04+0.78−0.85⋅10−3 cts/(keV·kg·yr) for the enriched BEGe data set and 14.68+0.47−0.52⋅10−3 cts/(keV·kg·yr) for the enriched coaxial data set. These values are similar to the one of Phase I despite a much larger number of detectors and hence radioactive hardware components

The Youngest Victims: Children and Youth Affected by War

In 1989, the United Nation Convention on the Rights of the Child declared, “[state parties] shall take all feasible measures to ensure protection and care of children who are affected by an armed conflict.” In addition to attempting to secure the welfare of children in armed conflict, the Convention went on to ban the recruitment and deployment of children during armed conflict. Despite the vast majority of sovereign nations signing and ratifying this agreement, this treaty, unfortunately, has not prevented children and youth from witnessing, becoming victims of, or participating in political, ethnic, religious, and cultural violence across the past three decades. This chapter offers an “ecological perspective” on the psychosocial consequences of exposure to the trauma of war-related violence and social disruption