In Vitro Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae.

The multidrug resistance profiles of Klebsiella pneumoniae carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the in vitro activity of polymyxin B and minocycline combination therapy against six KPC-2-producing K. pneumoniae isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing K. pneumoniae is dependent on polymyxin B susceptibility. Further in vitro and animal studies must be performed to fully evaluate the efficacy of this drug combination.

Ultrasonic cerebrospinal fluid clearance improves outcomes in hemorrhagic brain injury models.

Impaired clearance of the byproducts of aging and neurologic disease from the brain exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates the removal of pathogenic substances from the cerebrospinal fluid (CSF) and the brain interstitium. This protocol clears neurofilament light chain (NfL) - an aging byproduct - in aged mice and clears red blood cells (RBCs) from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared RBCs accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treating these hemorrhagic brain injury models with this ultrasound protocol reduced neuroinflammatory and neurocytotoxic profiles, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. RBC clearance efficacy was blocked by mechanosensitive channel antagonism and was effective when applied in anesthetized subjects, indicating a mechanosensitive channel mediated mechanism that does not depend on sensory stimulation or a specific neural activity pattern. Notably, this protocol qualifies for an FDA non-significant risk designation given its low intensity, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol clears hemorrhage and other harmful substances from the brain via the meningeal lymphatic system, potentially offering a novel therapeutic tool for varied neurologic disorders.

High-throughput ultrasound neuromodulation in awake and freely behaving rats.

Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.

Acoustomechanically activatable liposomes for ultrasonic drug uncaging.

Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest.

Increasing Diversity in Radiology and Molecular Imaging: Current Challenges.

This paper summarizes the 2020 Diversity in Radiology and Molecular Imaging: What We Need to Know Conference, a three-day virtual conference held September 9-11, 2020. The World Molecular Imaging Society (WMIS) and Stanford University jointly organized this event to provide a forum for WMIS members and affiliates worldwide to openly discuss issues pertaining to diversity in science, technology, engineering, and mathematics (STEM). The participants discussed three main conference themes, "racial diversity in STEM," "women in STEM," and "global health," which were discussed through seven plenary lectures, twelve scientific presentations, and nine roundtable discussions, respectively. Breakout sessions were designed to flip the classroom and seek input from attendees on important topics such as increasing the representation of underrepresented minority (URM) members and women in STEM, generating pipeline programs in the fields of molecular imaging, supporting existing URM and women members in their career pursuits, developing mechanisms to effectively address microaggressions, providing leadership opportunities for URM and women STEM members, improving global health research, and developing strategies to advance culturally competent healthcare.

An event-related potential study of the concreteness effect between Chinese nouns and verbs.

The effect of concreteness has been heavily studied on nouns. However, there are scant reports on the effect for verbs. The present research independently manipulated concreteness and word class of Chinese disyllabic words in tasks that required different depths of semantic processing: a lexical decision task and a semantic relatedness judgment task. The results replicated the concreteness effect for nouns, indicating that concrete nouns elicited larger N400 responses than abstract nouns with a broad distribution over the scalp, irrespective of the task demands. Similar to the findings from English unambiguous verbs, the concreteness effect for Chinese verbs was also robustly observed from fontal to posterior electrodes in both tasks. These results suggest that when Chinese nouns and verbs are typical and unambiguous in both meanings and word classes, the similar topographic distributions of the N400 components reflect the same underlying cause(s) of the concreteness effect for these two word classes.