A Clinically Validated, Broadly Active, Oral Viral Superinfection Therapy Could Mitigate Symptoms in Early-stage COVID-19 Patients.

More than 200 viruses infect humans, but treatments are available for less than ten of them. To narrow the gap between 'bugs and drugs,' a paradigm shift is required. The "one drug, one bug" approach can be expanded to a "one drug, multiple bugs" strategy such that the host's defense system is targeted rather than the virus. Viral superinfection therapy (SIT) activates interferon genes' natural, antiviral defense system of host cells following exposure to viral infection, e.g., superinfection with an attenuated infectious bursal disease virus (IBDV) with the release of its double-stranded RNA (dsRNA) cargo inside host cells. An attenuated IBDV therapeutic vaccine has successfully treated hepatitis A virus infection (HAV) in marmoset monkeys as well as acute hepatitis B and hepatitis C virus infections (HBV/HCV) in 42 patients. SIT has also been shown to be safe and effective in four patients with chronic HBV or HCV infection with hepatic decompensation. The proof-of-principle of SIT has also been demonstrated in a 43-year-old male patient with COVID-19. Three doses of orally administered IBDV (3x106 IU) alleviated most of his COVID-19 symptoms; even his sense of smell returned within a week. Two additional COVID-19 patients responded similarly to oral treatment with IBDV. Furthermore, a severe herpes zoster ophthalmicus outbreak with orbital edema responded to a combination of acyclovir and 7 doses of IBDV (7x106 IU) within a few days. IBDV is simple to manufacture and affordable, even in resource-limited settings. Acid-resistant IBDV can be orally administered in an outpatient setting, providing simple dosing and high medication adherence. Under an Emergency Use Authorization, the broad-spectrum IBDV drug candidate could be tested immediately in clinical trials and rapidly distributed to millions of early-stage patients with COVID-19. The German Paul Ehrlich Institute is currently supporting a phase I safety study for persons acutely infected with SARS­CoV-2. An expert team of the US National Institutes of Health-sponsored ACTIV public-private partnership came to the conclusion that the IBDV drug candidate shows merit as a potential treatment for COVID19, and an FDA-approved clinical trial is in the pipelines in Los Angeles.

Skin sodium measured with ²³Na MRI at 7.0 T.

Skin sodium (Na(+) ) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na(+) storage in humans ((23) Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution (23) Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean ± standard deviation, 46 ± 18 years; range, 20-79 years) were investigated. Transverse slices of the calf were imaged with (23) Na MRI using a high in-plane resolution of 0.9 × 0.9 mm(2) . Skin Na(+) content was determined using external agarose standards covering a physiological range of Na(+) concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na(+) content was investigated. The (23) Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na(+) content in the volunteer population was <10.3%. An age-dependent increase in skin Na(+) content was observed (r = 0.78). The assignment of Na(+) stores with (23) Na MRI techniques could be improved at 7.0 T compared with current 3.0 T technology. The benefits of such improvements may have the potential to aid basic research and clinical applications designed to unlock questions regarding the Na(+) balance and Na(+) storage function of skin.

Modular 32-channel transceiver coil array for cardiac MRI at 7.0T.

PURPOSE: To design and evaluate a modular transceiver coil array with 32 independent channels for cardiac MRI at 7.0T. METHODS: The modular coil array comprises eight independent building blocks, each containing four transceiver loop elements. Numerical simulations were used for B1 (+) field homogenization and radiofrequency (RF) safety validation. RF characteristics were examined in a phantom study. The array's suitability for accelerated high spatial resolution two-dimensional (2D) FLASH CINE imaging of the heart was examined in a volunteer study. RESULTS: Transmission field adjustments and RF characteristics were found to be suitable for the volunteer study. The signal-to-noise intrinsic to 7.0T together with the coil performance afforded a spatial resolution of 1.1 × 1.1 × 2.5 mm(3) for 2D CINE FLASH MRI, which is by a factor of 6 superior to standardized CINE protocols used in clinical practice at 1.5T. The 32-channel transceiver array supports one-dimensional acceleration factors of up to R = 4 without impairing image quality significantly. CONCLUSION: The modular 32-channel transceiver cardiac array supports accelerated and high spatial resolution cardiac MRI. The array is compatible with multichannel transmission and provides a technological basis for future clinical assessment of parallel transmission techniques at 7.0T.

Design, evaluation and application of an eight channel transmit/receive coil array for cardiac MRI at 7.0 T.

The objective of this work is to design, examine and apply an eight channel transmit/receive coil array tailored for cardiac magnetic resonance imaging at 7.0 T that provides image quality suitable for clinical use, patient comfort, and ease of use. The cardiac coil array was designed to consist of a planar posterior section and a modestly curved anterior section. For radio frequency (RF) safety validation, numerical computations of the electromagnetic field (EMF) and the specific absorption rate (SAR) distribution were conducted. In vivo cardiac imaging was performed using a 2D CINE FLASH technique. For signal-to-noise ratio (SNR) assessment reconstructed images were scaled in SNR units. The parallel imaging capabilities of the coil were examined using GRAPPA and SENSE reconstruction with reduction factors of up to R=4. The assessment of the RF characteristics yielded a maximum noise correlation of 0.33. The baseline SNR advantage at 7.0 T was put to use to acquire 2D CINE images of the heart with a spatial resolution of 1 mm × 1 mm × 4 mm. The coil array supports 1D acceleration factors of up to R=3 without impairing image quality significantly. For un-accelerated 2D CINE FLASH acquisitions the results revealed an SNR of approximately 140 for the left ventricular blood pool. Blood/myocardium contrast was found to be approximately 90 for un-accelerated 2D CINE FLASH acquisitions. The proposed 8 channel cardiac transceiver surface coil has the capability to acquire high contrast, high spatial and temporal resolution in vivo images of the heart at 7.0 T.

Detailing radio frequency heating induced by coronary stents: a 7.0 Tesla magnetic resonance study.

The sensitivity gain of ultrahigh field Magnetic Resonance (UHF-MR) holds the promise to enhance spatial and temporal resolution. Such improvements could be beneficial for cardiovascular MR. However, intracoronary stents used for treatment of coronary artery disease are currently considered to be contra-indications for UHF-MR. The antenna effect induced by a stent together with RF wavelength shortening could increase local radiofrequency (RF) power deposition at 7.0 T and bears the potential to induce local heating, which might cause tissue damage. Realizing these constraints, this work examines RF heating effects of stents using electro-magnetic field (EMF) simulations and phantoms with properties that mimic myocardium. For this purpose, RF power deposition that exceeds the clinical limits was induced by a dedicated birdcage coil. Fiber optic probes and MR thermometry were applied for temperature monitoring using agarose phantoms containing copper tubes or coronary stents. The results demonstrate an agreement between RF heating induced temperature changes derived from EMF simulations versus MR thermometry. The birdcage coil tailored for RF heating was capable of irradiating power exceeding the specific-absorption rate (SAR) limits defined by the IEC guidelines by a factor of three. This setup afforded RF induced temperature changes up to +27 K in a reference phantom. The maximum extra temperature increase, induced by a copper tube or a coronary stent was less than 3 K. The coronary stents examined showed an RF heating behavior similar to a copper tube. Our results suggest that, if IEC guidelines for local/global SAR are followed, the extra RF heating induced in myocardial tissue by stents may not be significant versus the baseline heating induced by the energy deposited by a tailored cardiac transmit RF coil at 7.0 T, and may be smaller if not insignificant than the extra RF heating observed under the circumstances used in this study.

Comparison of three multichannel transmit/receive radiofrequency coil configurations for anatomic and functional cardiac MRI at 7.0T: implications for clinical imaging.

OBJECTIVES: To implement, examine, and compare three multichannel transmit/receive coil configurations for cardiovascular MR (CMR) at 7T. METHODS: Three radiofrequency transmit-receive (TX/RX) coils with 4-, 8-, and 16-coil elements were used. Ten healthy volunteers (seven males, age 28 ± 4 years) underwent CMR at 7T. For all three RX/TX coils, 2D CINE FLASH images of the heart were acquired. Cardiac chamber quantification, signal-to-noise ratio (SNR) analysis, parallel imaging performance assessment, and image quality scoring were performed. RESULTS: Mean total examination time was 29 ± 5 min. All images obtained with the 8- and 16-channel coils were diagnostic. No significant difference in ejection fraction (EF) (P > 0.09) or left ventricular mass (LVM) (P > 0.31) was observed between the coils. The 8- and 16-channel arrays yielded a higher mean SNR in the septum versus the 4-channel coil. The lowest geometry factors were found for the 16-channel coil (mean ± SD 2.3 ± 0.5 for R = 4). Image quality was rated significantly higher (P < 0.04) for the 16-channel coil versus the 8- and 4-channel coils. CONCLUSIONS: All three coil configurations are suitable for CMR at 7.0T under routine circumstances. A larger number of coil elements enhances image quality and parallel imaging performance but does not impact the accuracy of cardiac chamber quantification. KEY POINTS : • Cardiac chamber quantification using 7.0T magnetic resonance imaging is feasible. • Examination times for cardiac chamber quantification at 7.0T match current clinical practice. • Multichannel transceiver RF technology facilitates improved image quality and parallel imaging performance. • Increasing the number of RF channels does not influence cardiac chamber quantification.

Two-dimensional sixteen channel transmit/receive coil array for cardiac MRI at 7.0 T: design, evaluation, and application.

PURPOSE: To design, evaluate, and apply a 2D 16-channel transmit/receive (TX/RX) coil array tailored for cardiac magnetic resonance imaging (MRI) at 7.0 T. MATERIALS AND METHODS: The cardiac coil array consists of two sections each using eight elements arranged in a 2 × 4 array. Radiofrequency (RF) safety was validated by specific absorption rate (SAR) simulations. Cardiac imaging was performed using 2D CINE FLASH imaging, T 2 mapping, and fat-water separation imaging. The characteristics of the coil array were analyzed including parallel imaging performance, left ventricular chamber quantification, and overall image quality. RESULTS: RF characteristics were found to be appropriate for all subjects included in the study. The SAR values derived from the simulations fall well within the limits of legal guidelines. The baseline signal-to-noise ratio (SNR) advantage at 7.0 T was put to use to acquire 2D CINE images of the heart with a very high spatial resolution of (1 × 1 × 4) mm(3) . The proposed coil array supports 1D acceleration factors of up to R = 4 without significantly impairing image quality. CONCLUSION: The 16-channel TX/RX coil has the capability to acquire high contrast and high spatial resolution images of the heart at 7.0 T.

Detailing the use of magnetohydrodynamic effects for synchronization of MRI with the cardiac cycle: a feasibility study.

PURPOSE: To investigate the feasibility of using magnetohydrodynamic (MHD) effects for synchronization of magnetic resonance imaging (MRI) with the cardiac cycle. MATERIALS AND METHODS: The MHD effect was scrutinized using a pulsatile flow phantom at B(0) = 7.0 T. MHD effects were examined in vivo in healthy volunteers (n = 10) for B(0) ranging from 0.05-7.0 T. Noncontrast-enhanced MR angiography (MRA) of the carotids was performed using a gated steady-state free-precession (SSFP) imaging technique in conjunction with electrocardiogram (ECG) and MHD synchronization. RESULTS: The MHD potential correlates with flow velocities derived from phase contrast MRI. MHD voltages depend on the orientation between B(0) and the flow of a conductive fluid. An increase in the interelectrode spacing along the flow increases the MHD potential. In vivo measurement of the MHD effect provides peak voltages of 1.5 mV for surface areas close to the common carotid artery at B(0) = 7.0 T. Synchronization of MRI with the cardiac cycle using MHD triggering is feasible. MHD triggered MRA of the carotids at 3.0 T showed an overall image quality and richness of anatomic detail, which is comparable to ECG-triggered MRAs. CONCLUSION: This feasibility study demonstrates the use of MHD effects for synchronization of MR acquisitions with the cardiac cycle.

(23)Na magnetic resonance imaging of tissue sodium.

Hypertension is linked to disturbed total-body sodium (Na(+)) regulation; however, measuring Na(+) disposition in the body is difficult. We implemented (23)Na magnetic resonance spectroscopy ((23)Na-MR) and imaging technique ((23)Na-MRI) at 9.4T for animals and 3T for humans to quantify Na(+) content in skeletal muscle and skin. We compared (23)Na-MRI data with actual tissue Na(+) content measured by chemical analysis in animal and human tissue. We then quantified tissue Na(+) content in normal humans and in patients with primary aldosteronism. We found a 29% increase in muscle Na(+) content in patients with aldosteronism compared with normal women and men. This tissue Na(+) was mobilized after successful treatment without accompanying weight loss. We suggest that, after further refinements, this tool could facilitate understanding the relationships between Na(+) accumulation and hypertension. Furthermore, with additional technical advances, a future clinical use may be possible.

Comparison of peritoneal adhesion formation in bowel retraction by cotton towels versus the silicone lap pak device in a rabbit model.

OBJECTIVE: Manipulation of cotton operating room towels within the abdominal cavity in open abdominal surgery has been associated with the formation of peritoneal adhesions. In a rabbit model, the use of standard cotton operating room towels is compared to the Lap Pak, a silicone bowel-packing device, to determine the potential for reducing the risk of adhesions. METHODS: Thirty rabbits were randomly assigned to 3 groups. The rabbits underwent a sham surgery with incision only (n = 10), placement of operating room towels (n = 10), or placement of a Lap Pak (n = 10). After 14 days, the rabbits were sacrificed and the peritoneal cavity explored for adhesions. The number, tenacity, ease of dissection, and density of adhesions were recorded, and the adhesions quantitatively graded using a Modified Hopkins Adhesion scoring system. RESULTS: The operating room towel group had an average adhesion score of 2.5, and 8 (80%) rabbits developed adhesions. The sham group had an average adhesion score of 0.3 and one rabbit (10%) developed adhesions. The Lap Pak group had an average adhesion score of 0.2 and 1 rabbit (10%) developed adhesions. The frequency and severity of adhesions in the operating room towel group were significantly greater from that of the baseline sham group. There was no significant difference between the Lap Pak and sham groups. CONCLUSIONS: In this rabbit laparotomy model, the use of the Lap Pak to retract the bowels resulted in significantly fewer adhesions compared to cotton operating room towels. Lap Pak may be beneficial for bowel packing in general abdominal surgeries.

Development and evaluation of a small and mobile Magneto Alert Sensor (MALSE) to support safety requirements for magnetic resonance imaging.

OBJECTIVE: The purpose of this study is to (i) design a small and mobile Magnetic field ALert SEnsor (MALSE), (ii) to carefully evaluate its sensors to their consistency of activation/deactivation and sensitivity to magnetic fields, and (iii) to demonstrate the applicability of MALSE in 1.5 T, 3.0 T and 7.0 T MR fringe field environments. METHODS: MALSE comprises a set of reed sensors, which activate in response to their exposure to a magnetic field. The activation/deactivation of reed sensors was examined by moving them in/out of the fringe field generated by 7TMR. RESULTS: The consistency with which individual reed sensors would activate at the same field strength was found to be 100% for the setup used. All of the reed switches investigated required a substantial drop in ambient magnetic field strength before they deactivated. CONCLUSIONS: MALSE is a simple concept for alerting MRI staff to a ferromagnetic object being brought into fringe magnetic fields which exceeds MALSEs activation magnetic field. MALSE can easily be attached to ferromagnetic objects within the vicinity of a scanner, thus creating a barrier for hazardous situations induced by ferromagnetic parts which should not enter the vicinity of an MR-system to occur.

Design and application of a four-channel transmit/receive surface coil for functional cardiac imaging at 7T.

PURPOSE: To design and evaluate a four-channel cardiac transceiver coil array for functional cardiac imaging at 7T. MATERIALS AND METHODS: A four-element cardiac transceiver surface coil array was developed with two rectangular loops mounted on an anterior former and two rectangular loops on a posterior former. specific absorption rate (SAR) simulations were performed and a B 1+ calibration method was applied prior to obtain 2D FLASH CINE (mSENSE, R = 2) images from nine healthy volunteers with a spatial resolution of up to 1 × 1 × 2.5 mm(3). RESULTS: Tuning and matching was found to be better than 10 dB for all subjects. The decoupling (S(21)) was measured to be >18 dB between neighboring loops, >20 dB for opposite loops, and >30 dB for other loop combinations. SAR values were well within the limits provided by the IEC. Imaging provided clinically acceptable signal homogeneity with an excellent blood-myocardium contrast applying the B 1+ calibration approach. CONCLUSION: A four-channel cardiac transceiver coil array for 7T was built, allowing for cardiac imaging with clinically acceptable signal homogeneity and an excellent blood-myocardium contrast. Minor anatomic structures, such as pericardium, mitral, and tricuspid valves and their apparatus, as well as trabeculae, were accurately delineated.

Acoustic cardiac triggering: a practical solution for synchronization and gating of cardiovascular magnetic resonance at 7 Tesla.

BACKGROUND: To demonstrate the applicability of acoustic cardiac triggering (ACT) for imaging of the heart at ultrahigh magnetic fields (7.0 T) by comparing phonocardiogram, conventional vector electrocardiogram (ECG) and traditional pulse oximetry (POX) triggered 2D CINE acquisitions together with (i) a qualitative image quality analysis, (ii) an assessment of the left ventricular function parameter and (iii) an examination of trigger reliability and trigger detection variance derived from the signal waveforms. RESULTS: ECG was susceptible to severe distortions at 7.0 T. POX and ACT provided waveforms free of interferences from electromagnetic fields or from magneto-hydrodynamic effects. Frequent R-wave mis-registration occurred in ECG-triggered acquisitions with a failure rate of up to 30% resulting in cardiac motion induced artifacts. ACT and POX triggering produced images free of cardiac motion artefacts. ECG showed a severe jitter in the R-wave detection. POX also showed a trigger jitter of approximately Δt = 72 ms which is equivalent to two cardiac phases. ACT showed a jitter of approximately Δt = 5 ms only. ECG waveforms revealed a standard deviation for the cardiac trigger offset larger than that observed for ACT or POX waveforms.Image quality assessment showed that ACT substantially improved image quality as compared to ECG (image quality score at end-diastole: ECG = 1.7 ± 0.5, ACT = 2.4 ± 0.5, p = 0.04) while the comparison between ECG vs. POX gated acquisitions showed no significant differences in image quality (image quality score: ECG = 1.7 ± 0.5, POX = 2.0 ± 0.5, p = 0.34). CONCLUSIONS: The applicability of acoustic triggering for cardiac CINE imaging at 7.0 T was demonstrated. ACT's trigger reliability and fidelity are superior to that of ECG and POX. ACT promises to be beneficial for cardiovascular magnetic resonance at ultra-high field strengths including 7.0 T.

Cardiac chamber quantification using magnetic resonance imaging at 7 Tesla--a pilot study.

OBJECTIVES: Interest in cardiovascular magnetic resonance (CMR) at 7 T is motivated by the expected increase in spatial and temporal resolution, but the method is technically challenging. We examined the feasibility of cardiac chamber quantification at 7 T. METHODS: A stack of short axes covering the left ventricle was obtained in nine healthy male volunteers. At 1.5 T, steady-state free precession (SSFP) and fast gradient echo (FGRE) cine imaging with 7 mm slice thickness (STH) were used. At 7 T, FGRE with 7 mm and 4 mm STH were applied. End-diastolic volume, end-systolic volume, ejection fraction and mass were calculated. RESULTS: All 7 T examinations provided excellent blood/myocardium contrast for all slice directions. No significant difference was found regarding ejection fraction and cardiac volumes between SSFP at 1.5 T and FGRE at 7 T, while volumes obtained from FGRE at 1.5 T were underestimated. Cardiac mass derived from FGRE at 1.5 and 7 T was larger than obtained from SSFP at 1.5 T. Agreement of volumes and mass between SSFP at 1.5 T and FGRE improved for FGRE at 7 T when combined with an STH reduction to 4 mm. CONCLUSIONS: This pilot study demonstrates that cardiac chamber quantification at 7 T using FGRE is feasible and agrees closely with SSFP at 1.5 T.

Degenerate mode band-pass birdcage coil for accelerated parallel excitation.

An eight-rung, 3T degenerate birdcage coil (DBC) was constructed and evaluated for accelerated parallel excitation of the head with eight independent excitation channels. Two mode configurations were tested. In the first, each of the eight loops formed by the birdcage was individually excited, producing an excitation pattern similar to a loop coil array. In the second configuration a Butler matrix transformed this "loop coil" basis set into a basis set representing the orthogonal modes of the birdcage coil. In this case the rung currents vary sinusoidally around the coil and only four of the eight modes have significant excitation capability (the other four produce anticircularly polarized (ACP) fields). The lowest useful mode produces the familiar uniform B(1) field pattern, and the higher-order modes produce center magnitude nulls and azimuthal phase variations. The measured magnitude and phase excitation profiles of the individual modes were used to generate one-, four-, six-, and eightfold-accelerated spatially tailored RF excitations with 2D and 3D k-space excitation trajectories. Transmit accelerations of up to six-fold were possible with acceptable levels of spatial artifact. The orthogonal basis set provided by the Butler matrix was found to be advantageous when an orthogonal subset of these modes was used to mitigate B(1) transmit inhomogeneities using parallel excitation.