Distinct dynamics of social motivation drive differential social behavior in laboratory rat and mouse strains

Mice and rats are widely used to explore mechanisms of mammalian social behavior in health and disease, raising the question whether they actually differ in their social behavior. Here we address this question by directly comparing social investigation behavior between two mouse and rat strains used most frequently for behavioral studies and as models of neuropathological conditions: C57BL/6 J mice and Sprague Dawley (SD) rats. Employing novel experimental systems for behavioral analysis of both subjects and stimuli during the social preference test, we reveal marked differences in behavioral dynamics between the strains, suggesting stronger and faster induction of social motivation in SD rats. These different behavioral patterns, which correlate with distinctive c-Fos expression in social motivation-related brain areas, are modified by competition with non-social rewarding stimuli, in a strain-specific manner. Thus, these two strains differ in their social behavior, which should be taken into consideration when selecting an appropriate model organism

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizu- mab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approxi- mately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points (95% CI, –7.6 to 8.2; nominal P=0.94). CONCLUSIONS In this randomized trial involving hospitalized patients with severe Covid-19 pneu- monia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov num- ber, NCT04320615.

Fast Multispectral Optoacoustic Tomography (MSOT) for Dynamic Imaging of Pharmacokinetics and Biodistribution in Multiple Organs

The characterization of pharmacokinetic and biodistribution profiles is an essential step in the development process of new candidate drugs or imaging agents. Simultaneously, the assessment of organ function related to the uptake and clearance of drugs is of great importance. To this end, we demonstrate an imaging platform capable of high-rate characterization of the dynamics of fluorescent agents in multiple organs using multispectral optoacoustic tomography (MSOT). A spatial resolution of approximately 150 µm through mouse cross-sections allowed us to image blood vessels, the kidneys, the liver and the gall bladder. In particular, MSOT was employed to characterize the removal of indocyanine green from the systemic circulation and its time-resolved uptake in the liver and gallbladder. Furthermore, it was possible to track the uptake of a carboxylate dye in separate regions of the kidneys. The results demonstrate the acquisition of agent concentration metrics at rates of 10 samples per second at a single wavelength and 17 s per multispectral sample with 10 signal averages at each of 5 wavelengths. Overall, such imaging performance introduces previously undocumented capabilities of fast, high resolution in vivo imaging of the fate of optical agents for drug discovery and basic biological research

GPU-based ultra fast dose calculation using a finite pencil beam model

Online adaptive radiation therapy (ART) is an attractive concept that promises the ability to deliver an optimal treatment in response to the inter-fraction variability in patient anatomy. However, it has yet to be realized due to technical limitations. Fast dose deposit coefficient calculation is a critical component of the online planning process that is required for plan optimization of intensity modulated radiation therapy (IMRT). Computer graphics processing units (GPUs) are well-suited to provide the requisite fast performance for the data-parallel nature of dose calculation. In this work, we develop a dose calculation engine based on a finite-size pencil beam (FSPB) algorithm and a GPU parallel computing framework. The developed framework can accommodate any FSPB model. We test our implementation on a case of a water phantom and a case of a prostate cancer patient with varying beamlet and voxel sizes. All testing scenarios achieved speedup ranging from 200~400 times when using a NVIDIA Tesla C1060 card in comparison with a 2.27GHz Intel Xeon CPU. The computational time for calculating dose deposition coefficients for a 9-field prostate IMRT plan with this new framework is less than 1 second. This indicates that the GPU-based FSPB algorithm is well-suited for online re-planning for adaptive radiotherapy.Comment: submitted Physics in Medicine and Biolog

Photoacoustic Sentinel Lymph Node Imaging with Self-Assembled Copper Neodecanoate Nanoparticles

Photoacoustic tomography (PAT) is emerging as a novel, hybrid, and non-ionizing imaging modality because of its satisfactory spatial resolution and high soft tissue contrast. PAT combines the advantages of both optical and ultrasonic imaging methods. It opens up the possibilities for noninvasive staging of breast cancer and may replace sentinel lymph node (SLN) biopsy in clinic in the near future. In this work, we demonstrate for the first time that copper can be used as a contrast metal for near-infrared detection of SLN using PAT. A unique strategy is adopted to encapsulate multiple copies of Cu as organically soluble small molecule complexes within a phospholipid-entrapped nanoparticle. The nanoparticles assumed a size of 80–90 nm, which is the optimum hydrodynamic diameter for its distribution throughout the lymphatic systems. These particles provided at least 6-fold higher signal sensitivity in comparison to blood, which is a natural absorber of light. We also demonstrated that high SLN detection sensitivity with PAT can be achieved in a rodent model. This work clearly demonstrates for the first time the potential use of copper as an optical contrast agent

Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo

Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal, we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achieves imaging depths that are unattainable with fluorescence or multiphoton microscopy. We validated the photoacoustic results that illustrate the superior imaging depth and quality of photoacoustic imaging with optical measurements. This powerful combination of techniques will unlock the ability to measure analyte changes in deep tissue and will open up photoacoustic imaging as a diagnostic tool for continuous physiological tracking of a wide range of analytes

Multiscale photoacoustic tomography using reversibly switchable bacterial phytochrome as a near-infrared photochromic probe

Photoacoustic tomography (PAT) of genetically encoded probes allows for imaging of targeted biological processes deep in tissues with high spatial resolution; however, high background signals from blood can limit the achievable detection sensitivity. Here we describe a reversibly switchable nonfluorescent bacterial phytochrome for use in multiscale photoacoustic imaging, BphP1, with the most red-shifted absorption among genetically encoded probes. BphP1 binds a heme-derived biliverdin chromophore and is reversibly photoconvertible between red and near-infrared light-absorption states. We combined single-wavelength PAT with efficient BphP1 photoswitching, which enabled differential imaging with substantially decreased background signals, enhanced detection sensitivity, increased penetration depth and improved spatial resolution. We monitored tumor growth and metastasis with ~100-μm resolution at depths approaching 10 mm using photoacoustic computed tomography, and we imaged individual cancer cells with a suboptical-diffraction resolution of ~140 nm using photoacoustic microscopy. This technology is promising for biomedical studies at several scales

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, –7.6 to 8.2; nominal P=0.94). CONCLUSIONS In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615

Implementation and evaluation of various demons deformable image registration algorithms on GPU

Online adaptive radiation therapy (ART) promises the ability to deliver an optimal treatment in response to daily patient anatomic variation. A major technical barrier for the clinical implementation of online ART is the requirement of rapid image segmentation. Deformable image registration (DIR) has been used as an automated segmentation method to transfer tumor/organ contours from the planning image to daily images. However, the current computational time of DIR is insufficient for online ART. In this work, this issue is addressed by using computer graphics processing units (GPUs). A grey-scale based DIR algorithm called demons and five of its variants were implemented on GPUs using the Compute Unified Device Architecture (CUDA) programming environment. The spatial accuracy of these algorithms was evaluated over five sets of pulmonary 4DCT images with an average size of 256x256x100 and more than 1,100 expert-determined landmark point pairs each. For all the testing scenarios presented in this paper, the GPU-based DIR computation required around 7 to 11 seconds to yield an average 3D error ranging from 1.5 to 1.8 mm. It is interesting to find out that the original passive force demons algorithms outperform subsequently proposed variants based on the combination of accuracy, efficiency, and ease of implementation.Comment: Submitted to Physics in Medicine and Biolog

Guiding Brain Tumor Resection Using Surface-Enhanced Raman Scattering Nanoparticles and a Hand-Held Raman Scanner

The current difficulty in visualizing the true extent of malignant brain tumors during surgical resection represents one of the major reasons for the poor prognosis of brain tumor patients. Here, we evaluated the ability of a hand-held Raman scanner, guided by surface-enhanced Raman scattering (SERS) nanoparticles, to identify the microscopic tumor extent in a genetically engineered RCAS/tv-a glioblastoma mouse model. In a simulated intraoperative scenario, we tested both a static Raman imaging device and a mobile, hand-held Raman scanner. We show that SERS image-guided resection is more accurate than resection using white light visualization alone. Both methods complemented each other, and correlation with histology showed that SERS nanoparticles accurately outlined the extent of the tumors. Importantly, the hand-held Raman probe not only allowed near real-time scanning, but also detected additional microscopic foci of cancer in the resection bed that were not seen on static SERS images and would otherwise have been missed. This technology has a strong potential for clinical translation because it uses inert gold-silica SERS nanoparticles and a hand-held Raman scanner that can guide brain tumor resection in the operating room