AG5 is a potent non-steroidal anti-inflammatory and immune regulator that preserves innate immunity.

An archetypal anti-inflammatory compound against cytokine storm would inhibit it without suppressing the innate immune response. AG5, an anti-inflammatory compound, has been developed as synthetic derivative of andrographolide, which is highly absorbable and presents low toxicity. We found that the mechanism of action of AG5 is through the inhibition of caspase-1. Interestingly, we show with in vitro generated human monocyte derived dendritic cells that AG5 preserves innate immune response. AG5 minimizes inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced lung injury and exhibits in vivo anti-inflammatory efficacy in the SARS-CoV-2-infected mouse model. AG5 opens up a new class of anti-inflammatories, since contrary to NSAIDs, AG5 is able to inhibit the cytokine storm, like dexamethasone, but, unlike corticosteroids, preserves adequately the innate immunity. This is critical at the early stages of any naïve infection, but particularly in SARS-CoV-2 infections. Furthermore, AG5 showed interesting antiviral activity against SARS-CoV-2 in humanized mice.

Nuclear-medicine probes: Where we are and where we are going.

Nuclear medicine probes turned into the key for the identification and precise location of sentinel lymph nodes and other occult lesions (i.e., tumors) by using the systemic administration of radiotracers. Intraoperative nuclear probes are key in the surgical management of some malignancies as well as in the determination of positive surgical margins, thus reducing the extent and potential surgery morbidity. Depending on their application, nuclear probes are classified into two main categories, namely, counting and imaging. Although counting probes present a simple design, are handheld (to be moved rapidly), and provide only acoustic signals when detecting radiation, imaging probes, also known as cameras, are more hardware-complex and also able to provide images but at the cost of an increased intervention time as displacing the camera has to be done slowly. This review article begins with an introductory section to highlight the relevance of nuclear-based probes and their components as well as the main differences between ionization- (semiconductor) and scintillation-based probes. Then, the most significant performance parameters of the probe are reviewed (i.e., sensitivity, contrast, count rate capabilities, shielding, energy, and spatial resolution), as well as the different types of probes based on the target radiation nature, namely: gamma (γ), beta (ß) (positron and electron), and Cherenkov. Various available intraoperative nuclear probes are finally compared in terms of performance to discuss the state-of-the-art of nuclear medicine probes. The manuscript concludes by discussing the ideal probe design and the aspects to be considered when selecting nuclear-medicine probes.

Acoustic Holograms for Bilateral Blood-Brain Barrier Opening in a Mouse Model.

Transcranial focused ultrasound (FUS) in conjunction with circulating microbubbles injection is the sole non-invasive technique that temporally and locally opens the blood-brain barrier (BBB), allowing targeted drug delivery into the central nervous system (CNS). However, single-element FUS technologies do not allow the simultaneous targeting of several brain structures with high-resolution, and multi-element devices are required to compensate the aberrations introduced by the skull. In this work, we present the first preclinical application of acoustic holograms to perform a bilateral BBB opening in two mirrored regions in mice. The system consisted of a single-element focused transducer working at 1.68 MHz, coupled to a 3D-printed acoustic hologram designed to produce two symmetric foci in anesthetized mice in vivo and, simultaneously, compensate the aberrations of the wavefront caused by the skull bones. T1-weighed MR images showed gadolinium extravasation at two symmetric quasi-spherical focal spots. By encoding time-reversed fields, holograms are capable of focusing acoustic energy with a resolution near the diffraction limit at multiple spots inside the skull of small preclinical animals. This work demonstrates the feasibility of hologram-assisted BBB opening for low-cost and highly-localized targeted drug delivery in the CNS in symmetric regions of separate hemispheres.

Characterization of Viscoelastic Media Combining Ultrasound and Magnetic-Force Induced Vibrations on an Embedded Soft Magnetic Sphere.

We report a method to locally assess the complex shear modulus of a viscoelastic medium. The proposed approach is based on the application of a magnetic force to a millimeter-sized steel sphere embedded in the medium and the subsequent monitoring of its dynamical response. A coil is used to create a magnetic field inducing the displacement of the sphere located inside a gelatin phantom. Then, a phased-array system using 3 MHz ultrasound probe operating in pulse-echo mode is used to track the displacement of the sphere. Experiments were conducted on several samples and repeated as a function of phantom temperature. The dynamic response of the sphere measured experimentally is in good agreement with Kelvin-Voigt theory. Since the magnetic force is not affected by weak diamagnetic media, our proposal results in an accurate estimation of the force acting on the inclusion. Consequently, the estimated viscoelastic parameters show excellent robustness and the elastic modulus agrees with the measurements using a quasi-static indentation method, obtaining errors below 10% in the whole temperature range. The use of the macroscopic inclusion limits the direct application of this method in a biomedical context, but it provides a robust estimation of the elastic modulus that can be used for material characterization in industrial applications.

Gamma Camera Imaging with Rotating Multi-Pinhole Collimator. A Monte Carlo Feasibility Study.

In this work, we propose and analyze a new concept of gamma ray imaging that corresponds to a gamma camera with a mobile collimator, which can be used in vivo, during surgical interventions for oncological patients for localizing regions of interest such as tumors or ganglia. The benefits are a much higher sensitivity, better image quality and, consequently, a dose reduction for the patient and medical staff. This novel approach is a practical solution to the overlapping problem which is inherent to multi-pinhole gamma camera imaging and single photon emission computed tomography and which translates into artifacts and/or image truncation in the final reconstructed image. The key concept consists in introducing a relative motion between the collimator and the detector. Moreover, this design could also be incorporated into most commercially available gamma camera devices, without any excessive additional requirements. We use Monte Carlo simulations to assess the feasibility of such a device, analyze three possible designs and compare their sensitivity, resolution and uniformity. We propose a final design of a gamma camera with a high sensitivity ranging from 0.001 to 0.006 cps/Bq, and a high resolution of 0.5-1.0 cm (FWHM), for source-to-detector distances of 4-10 cm. Additionally, this planar gamma camera provides information about the depth of source (with approximate resolution of 1.5 cm) and excellent image uniformity.

Macrolides May Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Entry into Cells: A Quantitative Structure Activity Relationship Study and Experimental Validation.

The global pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening the health and economic systems worldwide. Despite the enormous efforts of scientists and clinicians around the world, there is still no drug or vaccine available worldwide for the treatment and prevention of the infection. A rapid strategy for the identification of new treatments is based on repurposing existing clinically approved drugs that show antiviral activity against SARS-CoV-2 infection. In this study, after developing a quantitative structure activity relationship analysis based on molecular topology, several macrolide antibiotics are identified as promising SARS-CoV-2 spike protein inhibitors. To confirm the in silico results, the best candidates were tested against two human coronaviruses (i.e., 229E-GFP and SARS-CoV-2) in cell culture. Time-of-addition experiments and a surrogate model of viral cell entry were used to identify the steps in the virus life cycle inhibited by the compounds. Infection experiments demonstrated that azithromycin, clarithromycin, and lexithromycin reduce the intracellular accumulation of viral RNA and virus spread as well as prevent virus-induced cell death, by inhibiting the SARS-CoV-2 entry into cells. Even though the three macrolide antibiotics display a narrow antiviral activity window against SARS-CoV-2, it may be of interest to further investigate their effect on the viral spike protein and their potential in combination therapies for the coronavirus disease 19 early stage of infection.

Effect of the early use of antivirals on the COVID-19 pandemic. A computational network modeling approach.

It seems that we are far from controlling COVID-19 pandemics, and, consequently, returning to a fully normal life. Until an effective vaccine is found, safety measures as the use of face masks, social distancing, washing hands regularly, etc., have to be taken. Also, the use of appropriate antivirals in order to alleviate the symptoms, to control the severity of the illness and to prevent the transmission, could be a good option that we study in this work. In this paper, we propose a computational random network model to study the transmission dynamics of COVID-19 in Spain. Once the model has been calibrated and validated, we use it to simulate several scenarios where effective antivirals are available. The results show how the early use of antivirals may significantly reduce the incidence of COVID-19 and may avoid a new collapse of the health system.

Author Correction: High resolution and sensitivity gamma camera with active septa. A first Monte Carlo study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Roadmap toward the 10 ps time-of-flight PET challenge.

Since the seventies, positron emission tomography (PET) has become an invaluable medical molecular imaging modality with an unprecedented sensitivity at the picomolar level, especially for cancer diagnosis and the monitoring of its response to therapy. More recently, its combination with x-ray computed tomography (CT) or magnetic resonance (MR) has added high precision anatomic information in fused PET/CT and PET/MR images, thus compensating for the modest intrinsic spatial resolution of PET. Nevertheless, a number of medical challenges call for further improvements in PET sensitivity. These concern in particular new treatment opportunities in the context personalized (also called precision) medicine, such as the need to dynamically track a small number of cells in cancer immunotherapy or stem cells for tissue repair procedures. A better signal-to-noise ratio (SNR) in the image would allow detecting smaller size tumours together with a better staging of the patients, thus increasing the chances of putting cancer in complete remission. Moreover, there is an increasing demand for reducing the radioactive doses injected to the patients without impairing image quality. There are three ways to improve PET scanner sensitivity: improving detector efficiency, increasing geometrical acceptance of the imaging device and pushing the timing performance of the detectors. Currently, some pre-localization of the electron-positron annihilation along a line-of-response (LOR) given by the detection of a pair of annihilation photons is provided by the detection of the time difference between the two photons, also known as the time-of-flight (TOF) difference of the photons, whose accuracy is given by the coincidence time resolution (CTR). A CTR of about 10 picoseconds FWHM will ultimately allow to obtain a direct 3D volume representation of the activity distribution of a positron emitting radiopharmaceutical, at the millimetre level, thus introducing a quantum leap in PET imaging and quantification and fostering more frequent use of 11C radiopharmaceuticals. The present roadmap article toward the advent of 10 ps TOF-PET addresses the status and current/future challenges along the development of TOF-PET with the objective to reach this mythic 10 ps frontier that will open the door to real-time volume imaging virtually without tomographic inversion. The medical impact and prospects to achieve this technological revolution from the detection and image reconstruction point-of-views, together with a few perspectives beyond the TOF-PET application are discussed.

High resolution and sensitivity gamma camera with active septa. A first Monte Carlo study.

Gamma cameras are of great interest due to their high potential in the field of Nuclear Medicine Imaging. They allow for an early diagnosis of reduced size tumors, and also for a wide variety of preclinical studies with the aim of designing more effective treatments against cancer. In this work we propose a significantly improved multi-pinhole collimator gamma camera and perform a first Monte Carlo analysis of its characteristics. Maintaining the configuration of a multi-pinhole collimator with a high degree of overlapping (thus with a high sensitivity), we add a new element, an active septa, that besides acting as a collimator, is able to measure the impact coordinates of the incident photon. This way one is able to unambiguously identify through which pinhole any gamma ray passes before being detected. The result is a high sensitivity and resolution multi-pinhole gamma camera with an arbitrarily large field of view. As a consequence, the final reconstructed image does not suffer from the undesired artifacts or truncation associated to the multiplexing phenomenon. In this study we focus on the development of a system able to visualize in 3D tumors, nodes and metastasis in real time in the operating room with very low dose. We also briefly analyse and propose a novel design for a Single Photon Emission Computed Tomography system.

Simulations of the gain profile and performance of a diode side-pumped QCW Nd:YAG laser.

A design of a diode side-pumped Nd:YAG laser module and simulations of the gain distribution inside the active medium are presented in this paper. The code is based on a nonsequential ray-tracing Monte Carlo method for the light generated by the laser diodes. The fluorescence image of the active medium was analyzed in order to compare it with the simulations, which were found to be in good agreement with experimental data. The laser was tested in QCW mode and provided a maximum average power of 220 W while maintaining constant energy per pulse in the 100-1000 Hz range.