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In 2008, Michigan State University was selected to establish the Facility for Rare Isotope Beams (FRIB). Construction of the FRIB accelerator was completed in January 2022. Phased accelerator commissioning with heavy ion beams started in 2017 with the normal-conducting ion source and radio-frequency quadrupole. In April 2021, the full FRIB driver linear accelerator (linac) was commissioned, with heavy ion beams accelerated to energies above 200 MeV/nucleon by 324 superconducting radiofrequency (SRF) resonators operating at 2 K and 4 K with liquid-helium cooling. In preparation for high-power operation, a liquid lithium charge stripper was commissioned with heavy ion beams up to uranium-238, followed by the simultaneous acceleration of multiple-charge-state heavy ion beams to energies above 200 MeV/nucleon. In December 2021, selenium-84 was produced with the FRIB target using a krypton-86 primary beam, demonstrating FRIB’s capability for scientific discovery.

1) to compare the QIAreachQIAreach QFT measures the level of interferon-γ (IFN-γ) in plasma specimens from blood stimulated by ESAT-6 and CFP-10 peptides in one blood collection tube (equivalent to the TB2 tube of the QFT-Plus). QIAreach QFT was applied to plasma samples from 41 patients with pulmonary TB and from 42 healthy or low-TB-risk individuals.Sensitivity and specificity of QIAreach QFT vs. QFT-Plus were 100% (41/41) and 97.6% (41/42), respectively; overall concordance was 98.8% (82/83). All samples were measured within 20 min. The time to result of each sample was significantly correlated with IFN-γ level with a natural logarithmic scale (r = -0.913, p 0.001). Seven cases in the active TB group were immunocompromised (CD4200/μL) and tested positive by QIAreach QFT.QIAreach QFT provides an objective readout with a minimum blood sample volume (1 mL/subject), potentially being a useful point-of-care screening test for TB infection in high-TB-burden, low-resource countries and for immunocompromised patients.

Experimental studies of the simultaneous acceleration of three-charge-state $^{129}{\mathrm{Xe}}^{49+,50+,51+}$ beam from 17 to $180\text{ }\text{ }\mathrm{MeV}/\mathrm{nucleon}$ in a superconducting linear accelerator are presented. The beam parameters for each individual- and multiple-charge-state beam were measured and compared with the particle tracking simulations. Detailed measurements were performed to characterize the multiple-charge-state beam's recombination after a second-order achromat and isopath 180\ifmmode^\circ\else\textdegree\fi{} bending system. As a result of the recombination of three charge states in the six-dimensional phase space, the xenon beam intensity was increased by 2.5-fold compared to the single-charge-state beam. The results presented in the Letter fully validate the possibility to produce and utilize high-quality multiple-charge-state heavy-ion beams in a large-scale superconducting linac to increase the available beam power on an isotope production target.

Background The high dose (20mg/day) of apixaban is used for the initial treatment of venous thromboembolism for the first week. Although patients taking direct oral anticoagulants do not require routine coagulation monitoring, the correlations between anti-factor Xa activity (AXA) and routine coagulation markers such as prothrombin time (PT) and activated partial thromboplastin time (APTT) at peak and trough times especially when using high dose of apixaban have not been reported so far. Purpose The purpose is to assess the correlations between AXA values and PT/APTT at peak and trough times in patients with venous thromboembolism using high dose of Apixaban. Methods Twenty-six patients (10 male; 71±15 years) with proximal venous thromboembolism or pulmonary embolism using high dose (20mg/day) of apixaban were enrolled. We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT and APTT at peak and trough times. The peak time was defined as 3 hours after the intake of apixaban, and the trough time was defined as that immediately before the intake of apixaban. Results A significant and strong positive correlation was observed between AXA and PT at both peak and trough times (R=0.795, p Conclusion Our findings reveal the relationship between AXA and PT at peak and trough times has a significant strong correlation. These results suggest measuring of PT may be alternative and effective way of monitoring of AXA values when using high dose of apixaban. Figure 1 Funding Acknowledgement Type of funding source: None

Background Although patients taking direct oral anticoagulants (DOACs) do not require routine coagulation monitoring, the distribution of anti-factor Xa activity (AXA) values, prothrombin time (PT), PT-international normalized ratio (INR) and activated partial thromboplastin time (APTT) in patients on apixaban, edoxaban and rivaroxaban therapy is still not clear. Purpose The aim is to set the standard values of AXA values, PT, PT-INR and APTT in patients using DOACs. Methods We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT, PT-INR and APTT at trough and peak times in 224 patients with non-valvular atrial fibrillation and venous thromboembolism, of whom 90 received apixaban, 100 received edoxaban and 34 received rivaroxaban. The peak time was defined as 3 hours after the intake of apixaban or rivaroxaban, and 2 hours after the intake of edoxaban. The trough time was defined as that immediately before the intake. The AXA values, PT, PT-INR and APTT were measured at least 72 hours after the start of treatment. The dosage of DOACs is defined according to the prescribing information in Japan. Results (The order of results below is apixaban, edoxaban and rivaroxaban, respectively.) The average AXA values were 2.29, 0.23 and 0.39 (IU/mL) at trough time, and 3.04, 1.01 and 1.70 (IU/mL) at peak time. The average PT values were 17.9, 12.9 and 13.1 (s) at trough time, and 19.7, 15.5 and 17.5 (s) at peak time. The average PT-INR values were 1.49, 1.07 and 1.08 at trough time, and 1.65, 1.29 and 1.45 at peak time. The average APPT values were 34.5, 31.3 and 32.0 (s) at trough time, and 39.5, 35.9 and 39.8 (s) at peak time. Conclusion Our findings reveal the standard values of AXA, PT, PT-INR and APTT in patients using apixaban, edoxaban and rivaroxaban in each dosage. The DOACs should be changed if the measured value is out of those standard values in 90% confidence interval. Funding Acknowledgement Type of funding source: None

Setting QuantiFERON®-TB Gold Plus (QFT-Plus), recently approved for use in the United States, is a new-generation QuantiFERON assay that differs from its predecessors in that it uses an additional antigen tube containing peptides to elicit both CD8+ and CD4+ T-lymphocyte responses. Objective To assess the sensitivity of QFT-Plus compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) in participants with active TB. Design Adult patients with active TB at three US and two Japanese sites were eligible for this study if they had culture-confirmed TB and were either untreated or had received 14 days of anti-tuberculosis treatment. Results We enrolled 164 participants, nine of whom had indeterminate results. Excluding indeterminate values, there were 150 QFT-GIT-positive results among 159 tests and 146 QFT-Plus-positive results among 157 tests, with sensitivities of respectively 94.3% (95%CI 89.5-97.4) and 93.02% (95%CI 87.8-96.5%). The estimated sensitivities for the two tests were not significantly different (P = 0.16). Overall test agreement was 98.7%, with a κ statistic of 0.89 (95%CI 0.75-1.00). Conclusion In this multisite study, we found that QFT-Plus had similar sensitivity to QFT-GIT in adult patients with active TB.

Purpose Papillary muscle ischemia (PMI) is caused by micro-vessels' occlusion in the broad endocardium because papillary muscle perfusion is supply from micro-vessels of peripheral coronary arteries and is easy to fail by the increase in peripheral vascular resistance. However, the clinical significant is not understood because PMI could not be detected by existing perfusion imaging such as SPECT and MRI. We propose the detection method of PMI using 13N-ammonia PET (NH3-PET), and investigate the association with the global myocardial flow reserve (Global-MFR) reflecting coronary microvascular dysfunction. Methods Data of adenosine-stress NH3-PET for consecutive 260 patients with coronary artery disease (CAD) or suspected CAD was retrospectively analyzed. Using high-resolution cine imaging derived from NH3-PET, PMI was defined as the absence of the PM accumulation at stress conditions. Myocardial flow was generated from the time activity curve of left ventricle input and myocardial uptake using 3-compartment model and the first 2 minutes' dataset of list mode images. Global-MFR was calculated by stress to rest flow ratio. Summed stress score (SSS) was used as an estimate of the extent of myocardial ischemia. 150 out of 260 patients (58%) with SSS ≥4 or with the past history of coronary artery diseases were classified as ischemic group, and 110 patients (42%) with SSS Results PMI was seen in 68 of 260 patients (26.6%). The frequency of PMI was higher in the ischemic group than the non-ischemic group (37.8% vs. 10.1%, p Typical case of PMI Conclusion High-resolution cine imaging derived from NH3-PET makes it possible to detect PMI in about a quarter of patients with CAD or suspected CAD. PMI associates with reduced Global-MFR regardless of the presence of myocardial ischemia, suggesting that PMI is an important sign of early ischemia confined to the papillary muscle or the broad microvascular injury.

Severity assessment in biomedical research is required by the European authorities. Therefore, a variety of score sheets are available. The first score sheets were designed and introduced by Morton and Griffith (M&G) in 1985, to assess pain and distress in animals. Score sheets are an important part of the 3R principles to evaluate the degree of severity in different studies. Here, we used a modified score sheet from M&G for severity assessment of 12 Aachen minipigs after partial liver resection for safety testing of a novel synthetic sealant (VIVO-107). The control group was treated with the clinical standard fibrin. Estimation of recovery status of both groups was performed from the day of surgery to postoperative day 7 using a score sheet. Included parameters were blood loss during the surgical procedure, general state, spontaneous behaviour and clinical results. Values from 0 to 20 were graded for each category and resulted in the degree of strain (DS) from DS0 to DS4. An increasing DS indicated higher severity. Suitability of the implemented score sheet was evaluated. Higher score points were documented almost exclusively as an outcome of the clinical results, influenced mainly by increased temperature in the fibrin treated control group, whereas, spontaneous behaviour had only slight influence and general state had no influence. The average score seven days after surgery was

Linac segment 1 (LS1) of the FRIB driver linac is composed of 15 cryomodules, consisting of 104 superconducting (SC) resonators and 39 SC solenoids. Four ion beam species (Ne, Ar, Kr, and Xe) were successfully accelerated up to 20.3 MeV/u in LS1 and transported to the designated beam dumps located in folding segment 1 (FS1). 100% beam transmission was measured through all cryomodules and the warm section of LS1. High-power equivalent beams were delivered to the beam dump in two modes: pulsed and continuous wave (cw). In the pulsed mode, the peak intensity of the argon beam was 14.8 pμA at 3% duty factor, which constitutes 30% of the FRIB design intensity for this particular ion beam. A cw argon beam was accelerated, demonstrating that the FRIB linac in its current configuration is the highest-energy cw superconducting hadron linac in the world. This paper presents a detailed study of beam dynamics in LS1 prior to and after charge stripping with a carbon foil.

The Facility for Rare Isotope Beams (FRIB) being constructed at Michigan State University [J. Wei et al., The FRIB superconducting linac---status and plans, LINAC'16, Lansing, MI, p. 1, http://accelconf.web.cern.ch/AccelConf/linac2016/papers/mo1a01.pdf] is based on a cw superconducting linear accelerator which is designed to deliver unprecedented 400 kW heavy ion beam power to the fragmentation target. The installation of the accelerator equipment is approaching completion and multistage beam commissioning activities started in the summer of 2017 with expected completion in 2021. A room-temperature test electron cyclotron resonance ion source, ARTEMIS, provided argon and krypton beams for the commissioning of the low energy beam transport, a radio frequency quadrupole (RFQ), the medium energy beam transport (MEBT) and the first three accelerating cryomodules. The commissioning of the first linac segment (LS1), composed of 15 cryomodules, is planned in the spring of 2019. This paper describes the first results of experimental beam dynamics studies in the LEBT, RFQ, MEBT and the first three cryomodules with comparison to the numerical simulations.

Background SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. Aim The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. Materials and methods The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining. Results Bosu induced the massive caspase-independent cell death, and blocked autophagy flux, which resulted from lysosomal dysfunction. Lysosomal dysfunction caused by Bosu was due to lysosomal membrane permeabilization (LMP), which resulted in the release of lysosomal hydrolases including cathepsin B. Conclusion Our data suggest that Bosu induces the cell death through induction of LMP in melanoma cells and is a promising therapeutic agent for treatment of melanoma in both dogs and humans.

Score sheets were first introduced 30 years ago to assess pain, distress and suffering in animals. To date, however, there is still no general agreement on their use in research practice, and only a few publications can be found on this topic. In the present work, we demonstrate the use of a special score sheet for severity assessment in the first three postoperative days in two showcased studies performed on Wistar and Lewis rats undergoing liver resection or orthotopic liver transplantation, respectively. Scoring of different criteria and the total score were evaluated within each intervention. Additionally, both procedures were compared regarding their degree of severity. Suitability of these score sheets was evaluated for assessing severity of the procedures and these showed a minor severity within each investigated study. A comparison of both studies showed slightly higher scores involving liver transplantation. In contradiction to the common classification of these procedures as a moderate severity grade the score sheets applied here indicates a minor severity grade within each investigated study. Also, limitations and possible improvements in the design of our score sheets for defined interventions are reconsidered.

Although the recognition of pain, distress and discomfort has already been described in 1985 by Morton and Griffiths there is still very little known about the establishment of score sheets especially, regarding post-surgical pain and severity assessment for laboratory animals such as rabbits. In this paper we describe the estimation of severity and recovery status of 36 female New Zealand White rabbits (NZW) in a standardized liver resection model using two different adhesive treatments and one control group. Welfare was assessed at 3–4 consecutive days after surgery using a scoring system which included the following criteria: body weight, general state, clinical results, spontaneous behavior and clinical examination. Values could range from 0 to 20 where increasing values indicated increasing severity with a predefined humane endpoint for a score ≥20 points. Documented score points were almost exclusively a result of body weight loss, whereas clinical signs and general health status had no influence on the overall sum of points scored. Behavioral variation was solely observed postoperatively, within the first 24 h, with an average score ≤1. In contrast to the classification of a laparotomy as a moderate procedure in the EU Directive 2010/63 (annex VIII) the assessment herein presented showed a mild burden in all groups according to the scoring system used. The partial hepatectomy itself, as well as the adhesive treatment using either synthetic glue VIVO-107 or fibrin glue, were well tolerated.