Functional ultrasound (fUS) imaging of displacement-guided focused ultrasound (FUS) neuromodulation in mice.

Focused ultrasound (FUS) stimulation is a promising neuromodulation technique with the merits of non-invasiveness, high spatial resolution, and deep penetration depth. However, simultaneous imaging of FUS-induced brain tissue displacement and the subsequent effect of FUS stimulation on brain hemodynamics has proven challenging thus far. In addition, earlier studies lack in situ confirmation of targeting except for the magnetic resonance imaging-guided FUS system-based studies. The purpose of this study is 1) to introduce a fully ultrasonic approach to in situ target, modulate neuronal activity, and monitor the resultant neuromodulation effect by respectively leveraging displacement imaging, FUS, and functional ultrasound (fUS) imaging, and 2) to investigate FUS-evoked cerebral blood volume (CBV) response and the relationship between CBV and displacement. We performed displacement imaging on craniotomized mice to confirm the in targeting for neuromodulation site. We recorded hemodynamic responses evoked by FUS and fUS revealed an ipsilateral CBV increase that peaks at 4 s post-FUS. We saw a stronger hemodynamic activation in the subcortical region than cortical, showing good agreement with the brain elasticity map that can also be obtained using a similar methodology. We observed dose-dependent CBV response with peak CBV, activated area, and correlation coefficient increasing with ultrasonic dose. Furthermore, by mapping displacement and hemodynamic activation, we found that displacement colocalizes and linearly correlates with CBV increase. The findings presented herein demonstrated that FUS evokes ipsilateral hemodynamic activation in cortical and subcortical depths and the evoked hemodynamic responses colocalized and correlate with FUS-induced displacement. We anticipate that our findings will help consolidate accurate targeting as well as an understanding of how FUS displaces brain tissue and affects cerebral hemodynamics.

Characterization of the responses of brain macrophages to focused ultrasound-mediated blood-brain barrier opening.

The opening of the blood-brain barrier (BBB) by focused ultrasound (FUS) coupled with intravenously injected microbubbles can be leveraged as a form of immunotherapy for the treatment of neurodegenerative disorders. However, how FUS BBB opening affects brain macrophages is not well understood. Here by using single-cell sequencing to characterize the distinct responses of microglia and central nervous system-associated macrophages (CAMs) to FUS-mediated BBB opening in mice, we show that the treatment remodels the immune landscape via the recruitment of CAMs and the proliferation of microglia and via population size increases in disease-associated microglia. Both microglia and CAMs showed early and late increases in population sizes, yet only the proliferation of microglia increased at both timepoints. The population of disease-associated microglia also increased, accompanied by the upregulation of genes associated with gliogenesis and phagocytosis, with the depletion of brain macrophages significantly decreasing the duration of BBB opening.

Focused ultrasound-mediated brain genome editing.

Gene editing in the brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches mainly rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.

Rationale: Bilateral sonication with focused ultrasound (FUS) in conjunction with microbubbles has been shown to separately reduce amyloid plaques and hyperphosphorylated tau protein in the hippocampal formation and the entorhinal cortex in different mouse models of Alzheimer's disease (AD) without any therapeutic agents. However, the two pathologies are expressed concurrently in human disease. Therefore, the objective of this study is to investigate the effects of repeated bilateral sonications in the presence of both pathologies. Methods: Herein, we investigate its functional and morphological outcomes on brains bearing both pathologies simultaneously. Eleven transgenic mice of the 3xTg-AD line (14 months old) expressing human amyloid beta and human tau and eleven age-matched wild-type littermates received four weekly bilateral sonications covering the hippocampus followed by working memory testing. Afterwards, immunohistochemistry and immunoassays (western blot and ELISA) were employed to assess any changes in amyloid beta and human tau. Furthermore, we present preliminary data from our clinical trial using a neuronavigation-guided FUS system for sonications in AD patients (NCT04118764). Results: Interestingly, both wild-type and transgenic animals that received FUS experienced improved working memory and spent significantly more time in the escape platform-quadrant, with wild-type animals spending 43.2% (sham: 37.7%) and transgenic animals spending 35.3% (sham: 31.0%) of the trial in the target quadrant. Furthermore, this behavioral amelioration in the transgenic animals correlated with a 58.3% decrease in the neuronal length affected by tau and a 27.2% reduction in total tau levels. Amyloid plaque population, volume and overall load were also reduced overall. Consistently, preliminary data from a clinical trial involving AD patients showed a 1.8% decrease of amyloid PET signal 3-weeks after treatment in the treated hemisphere compared to baseline. Conclusion: For the first time, it is shown that bilateral FUS-induced BBB opening significantly and simultaneously ameliorates both coexistent pathologies, which translated to improvements in spatial memory of transgenic animals with complex AD, the human mimicking phenotype. The level of cognitive improvement was significantly correlated with the volume of BBB opening. Non-transgenic animals were also shown to exhibit similar memory amelioration for the first time, indicating that BBB opening results into benefits in the neuronal function regardless of the existence of AD pathology. A potential mechanism of action for the reduction of the both pathologies investigated was the cholesterol metabolism, specifically the LRP1b receptor, which exhibited increased expression levels in transgenic mice following FUS-induced BBB opening. Initial clinical evidence supported that the beta amyloid reduction shown in rodents could be translatable to humans with significant amyloid reduction shown in the treated hemisphere.

Characteristics of Suspected COVID-19 Discharged Emergency Department Patients Who Returned During the First Wave.

INTRODUCTION: Limited information exists on patients with suspected coronavirus disease 2019 (COVID-19) who return to the emergency department (ED) during the first wave. In this study we aimed to identify predictors of ED return within 72 hours for patients with suspected COVID-19. METHODS: Incorporating data from 14 EDs within an integrated healthcare network in the New York metropolitan region from March 2-April 27, 2020, we analyzed this data on predictors for a return ED visit-including demographics, comorbidities, vital signs, and laboratory results. RESULTS: In total, 18,599 patients were included in the study. The median age was 46 years old [interquartile range 34-58]), 50.74% were female, and 49.26% were male. Overall, 532 (2.86%) returned to the ED within 72 hours, and 95.49% were admitted at the return visit. Of those tested for COVID-19, 59.24% (4704/7941) tested positive. Patients with chief complaints of "fever" or "flu" or a history of diabetes or renal disease were more likely to return at 72 hours. Risk of return increased with persistently abnormal temperature (odds ratio [OR] 2.43, 95% CI 1.8-3.2), respiratory rate (2.17, 95% CI 1.6-3.0), and chest radiograph (OR 2.54, 95% CI 2.0-3.2). Abnormally high neutrophil counts, low platelet counts, high bicarbonate values, and high aspartate aminotransferase levels were associated with a higher rate of return. Risk of return decreased when discharged on antibiotics (OR 0.12, 95% CI 0.0-0.3) or corticosteroids (OR 0.12, 95% CI 0.0-0.9). CONCLUSION: The low overall return rate of patients during the first COVID-19 wave indicates that physicians' clinical decision-making successfully identified those acceptable for discharge.

Pulse wave and vector flow Imaging for atherosclerotic disease progression in hypercholesterolemic swine.

Non-invasive monitoring of atherosclerosis remains challenging. Pulse Wave Imaging (PWI) is a non-invasive technique to measure the local stiffness at diastolic and end-systolic pressures and quantify the hemodynamics. The objective of this study is twofold, namely (1) to investigate the capability of (adaptive) PWI to assess progressive change in local stiffness and homogeneity of the carotid in a high-cholesterol swine model and (2) to assess the ability of PWI to monitor the change in hemodynamics and a corresponding change in stiffness. Nine (n=9) hypercholesterolemic swine were included in this study and followed for up to 9 months. A ligation in the left carotid was used to cause a hemodynamic disturbance. The carotids with detectable hemodynamic disturbance showed a reduction in wall shear stress immediately after ligation (2.12 ± 0.49 to 0.98 ± 0.47 Pa for 40-90% ligation (Group B) and 1.82 ± 0.25 to 0.49 ± 0.46 Pa for >90% ligation (Group C)). Histology revealed subsequent lesion formation after 8-9 months, and the type of lesion formation was dependent on the type of the induced ligation, with more complex plaques observed in the carotids with a more significant ligation (C: >90%). The compliance progression appears differed for groups B and C, with an increase in compliance to 2.09 ± 2.90×10-10 m2 Pa-1 for group C whereas the compliance of group B remained low at 8 months (0.95 ± 0.94×10-10 m2 Pa-1). In summary, PWI appeared capable of monitoring a change in wall shear stress and separating two distinct progression pathways resulting in distinct compliances.

Novel Discharge Center for Transition of Care in Vulnerable Emergency Department Treat and Release Patients.

Introduction The majority of emergency department (ED) patients are discharged following evaluation and treatment. Most patients are recommended to follow up with a primary care provider (PCP) or specialist. However, there is considerable variation between providers and EDs in discharge process practices that might facilitate such follow-up (e.g., simply discharging patients with follow-up physician names/contact information vs. making appointments for patients). Patients who do not follow up with their PCPs or specialists are more likely to be readmitted within 30 days than those who do. Furthermore, vulnerable patients have difficulty arranging transitional care appointments due to poor health literacy, inadequate insurance, appointment availability, and self-efficacy. Our innovative ED discharge process utilizes an Emergency Department Discharge Center (EDDC) staffed by ED Care Coordinators and assists patients with scheduling post-discharge appointments to improve rates of follow-up with outpatient providers. This study describes the structure and activities of the EDDC, characterizes the EDDC patient population, and demonstrates the volume and specialties of appointments scheduled by EDDC Care Coordinators. The impact of the EDDC on operational metrics (72-hour returns, 30-day admissions, and length-of-stay [LOS]) and the impact of the EDDC on patient satisfaction are evaluated. Methods The Long Island Jewish Medical Center (LIJMC) EDDC is an intervention developed in July 2020 within a 583-bed urban hospital serving a racially, ethnically, and socio-economically diverse population, with many patients having limited access to healthcare. Data from the Emergency Medicine Service Line (EMSL), an ED Care Coordinator database, and manual chart review were collected from July 2020 to July 2021 to examine the impact of the EDDC on 72-hour returns, 30-day admissions, and Press Ganey's® "likelihood to recommend ED" score (a widely used patient satisfaction survey question). The EDDC pilot cohort was compared to non-EDDC discharged patients during the same period. Results In unadjusted analysis, EDDC patients were moderately less likely to return to the ED within 72 hours (5.3% vs. 6.5%; p = 0.0044) or be admitted within 30 days (3.4% vs. 4.2%). The program was particularly beneficial for uninsured and elderly patients. For both EDDC and non-EDDC patients, most revisits and 30-day admissions were for the same chief complaint as the index visit. The length-of-stay increased by ~10 minutes with no impact on satisfaction with ED visits. Musculoskeletal conditions (~20%) and specialties (~15%) were the most commonly represented. Approximately 10% of referrals were to obtain a PCP. Nearly 90% were to new providers or specialties. Most scheduled appointments occurred within a week.  Conclusion This novel EDDC program, developed to facilitate outpatient follow-up for discharged ED patients, produced a modest but statistically significant difference in 72-hour returns and 30-day admissions for patients with EDDC-scheduled appointments vs. those referred to outpatient providers using the standard discharge process. ED LOS increased by ~10 minutes for EDDC vs. non-EDDC patients, with no difference in satisfaction. Future analyses will investigate impacts on 72-hour returns, 30-day admissions, LOS, and satisfaction after adjusting for characteristics such as age, insurance, having a PCP, and whether the scheduled appointment was attended.

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.

Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.

Focused ultrasound-mediated brain genome editing.

Gene editing in the mammalian brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

Adaptive Wall Shear Stress Imaging in Phantoms, Simulations and In Vivo.

WSS measurement is challenging since it requires sensitive flow measurements at a distance close to the wall. The aim of this study is to develop an ultrasound imaging technique which combines vector flow imaging with an unsupervised data clustering approach that automatically detects the region close to the wall with optimally linear flow profile, to provide direct and robust WSS estimation. The proposed technique was evaluated in phantoms, mimicking normal and atherosclerotic vessels, and spatially registered Fluid Structure Interaction (FSI) simulations. A relative error of 6.7% and 19.8% was obtained for peak systolic (WSSPS) and end diastolic (WSSED) WSS in the straight phantom, while in the stenotic phantom, a good similarity was found between measured and simulated WSS distribution, with a correlation coefficient, R, of 0.89 and 0.85 for WSSPS and WSSED, respectively. Moreover, the feasibility of the technique to detect pre-clinical atherosclerosis was tested in an atherosclerotic swine model. Six swines were fed atherogenic diet, while their left carotid artery was ligated in order to disturb flow patterns. Ligated arterial segments that were exposed to low WSSPS and WSS characterized by high frequency oscillations at baseline, developed either moderately or highly stenotic plaques (p < 0.05). Finally, feasibility of the technique was demonstrated in normal and atherosclerotic human subjects. Atherosclerotic carotid arteries with low stenosis had lower WSSPS as compared to control subjects (p < 0.01), while in one subject with high stenosis, elevated WSS was found on an arterial segment, which coincided with plaque rupture site, as determined through histological examination.

Evaluation of Non-invasive Optogenetic Stimulation with Transcranial Functional Ultrasound Imaging.

Optogenetics employs engineered viruses to genetically modify cells to express specific light-sensitive ion channels. The standard method for gene delivery in the brain involves invasive craniotomies that expose the brain and direct injections of viruses that invariably damage neural tissue along the syringe tract. A recently proposed alternative in which non-invasive optogenetics is performed with focused ultrasound (FUS)-mediated blood-brain barrier (BBB) openings has been found to non-invasively facilitate gene delivery for optogenetics in mice. Although gene delivery can be performed non-invasively, validating successful viral transduction and expression of encoded ion channels in target tissue typically involves similar invasive techniques, such as craniotomies in longitudinal studies and/or postmortem histology. Functional ultrasound imaging (fUSi) is an emerging neuroimaging technique that can be used to transcranially detect changes in cerebral blood volume following introduction of a stimulus. In this study, we implemented a fully non-invasive combined FUS-fUSi technique for performing optogenetics in mice. FUS successfully delivered viruses encoding the red-shifted channelrhodopsin variant ChrimsonR in all treated subjects. fUSi successfully identified stimulus-evoked cerebral blood volume changes preferentially in brain regions expressing the light-sensitive ion channels. Improvements in cell-specific targeting of viral vectors and transcranial ultrasound imaging will make the combined technique a useful tool for neuroscience research in small animals.

Implementing a text-messaging intervention for unhealthy alcohol use in emergency departments: protocol for implementation strategy development and a pilot cluster randomized implementation trial.

BACKGROUND: Unhealthy alcohol use (UAU) is a leading cause of premature mortality among adults in the USA. Emergency departments (EDs) are key intervention settings for UAU but often have limited time and resources. One low-burden, scalable approach to address UAU is text-messaging interventions. Despite strong research support and promise for scalability, there is little research on how to implement such interventions in healthcare settings. The process of providers making them available to patients in an efficient way within already busy and overburdened ED workflows and patients adopting them remains a new area of research. The purpose of this three-phase study is to develop and test an implementation strategy for UAU text-messaging interventions in EDs. METHOD: Our first aim is to examine barriers and facilitators to staff offering and patients accepting a text-messaging intervention in the ED using an explanatory, sequential mixed methods approach. We will examine alcohol screening data in the electronic health records of 17 EDs within a large integrated health system in the Northeast and conduct surveys among chairpersons in each. This data will be used to purposively sample 4 EDs for semi-structured interviews among 20 clinical staff, 20 patients, and 4 chairpersons. Our second aim is to conduct a stakeholder-engaged intervention mapping process to develop a multi-component implementation strategy for EDs. Our third aim is to conduct a mixed method 2-arm cluster randomized pilot study in 4 EDs that serve ~11,000 UAU patients per year to assess the feasibility, acceptability, and preliminary effectiveness of the implementation strategy. The Integrated Promoting Action on Research Implementation in Health Services framework will guide study activities. DISCUSSION: Low-burden technology, like text messaging, along with targeted implementation support and strategies driven by identified barriers and facilitators could sustain large-scale ED-based alcohol screening programs and provide much needed support to patients who screen positive while reducing burden on EDs. The proposed study would be the first to develop and test this targeted implementation strategy and will prepare for a larger, fully powered hybrid effectiveness-implementation trial. Findings may also be broadly applicable to implementation of patient-facing mobile health technologies. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (NCT05350878) on 4/28/2022.

Non-invasive optogenetics with ultrasound-mediated gene delivery and red-light excitation.

Optogenetics has revolutionized the capability of controlling genetically modified neurons in vitro and in vivo and has become an indispensable neuroscience tool. Using light as a probe for selective neuronal activation or inhibition and as a means to read out neural activity has dramatically enhanced our understanding of complex neural circuits. However, a common limitation of optogenetic studies to date is their invasiveness and spatiotemporal range. Direct viral injections into the brain tissue along with implantation of optical fibers and recording electrodes can disrupt the neuronal circuitry and cause significant damage. Conventional approaches are spatially limited around the site of the direct injection and insufficient in examining large networks throughout the brain. Lastly, optogenetics is currently not easily scalable to large animals or humans. Here, we demonstrate that optogenetic excitation can be achieved entirely non-invasively through the intact skull in mice. Using a needle-free combination of focused ultrasound-mediated viral delivery and extracorporeal illumination with red light, we achieved selective neuronal activation at depths up to 4 mm in the murine brain, confirmed through cFos expression and electrophysiology measurements within the treated areas. Ultrasound treatment significantly reduced freezing time during recall in fear conditioning experiments, but remote light exposure had a moderate effect on the freezing behavior of mice treated with viral vectors. The proposed method has the potential to open new avenues of studying, but also stimulating, neuronal networks, in an effort to elucidate normal or dysfunctional brain activity and treat neurological diseases. Finally, the same non-invasive methodology could be combined with gene therapy and applied to other organs, such as the eye and the heart.

Examining the Gender Gap in Emergency Medicine Research Publications.

STUDY OBJECTIVE: The objective of this study was to describe the proportion of female authors on original research articles and editorials across 4 emergency medicine journals from 2013 to 2019. A secondary objective was to examine the gender composition of middle authors in relation to the genders of their respective first and last authors. METHODS: In this observational study, we selected 4 journals in emergency medicine using the Journal of Citation Reports and prior literature to analyze genders of all authors from research articles and editorials published from January 2013 to September 2019. Reviewers identified author genders through web searches with matching academic qualifications or used a gender identification application programming interface to identify likelihood of male or female identity. The primary outcome was the proportion of female authors in each position. RESULTS: Selected publications included 2,980 original research articles with 18,224 authors (median 6, interquartile range [IQR] 4 to 8) and 433 editorials with 986 authors (median 2, IQR 1 to 2). Women occupied 34.9%, 24.3%, and 36.5% of first, last, and middle author positions on original research articles and 23.8%, 20.5%, and 34.2% of first, last, and middle author positions among editorials, respectively. Publications with female first and last authors (n=340 articles) had a larger proportion of female middle authors (49%, 634/1,290) compared to publications with male first and last authors (n=1667 articles, female middle authors 33% [2,215/6,771]). CONCLUSION: Over the 7 years examined, female authorship in these emergency medicine journals increased. A more pronounced gender gap exists in editorial authorship compared to research articles. On publications where the first and last author were women, a higher proportion of middle authors were women.

Feasibility of longitudinal monitoring of atherosclerosis with pulse wave imaging in a swine model.

Objective.Atherosclerosis is a vascular disease characterized by compositional and mechanical changes in the arterial walls that lead to a plaque buildup. Depending on its geometry and composition, a plaque can ruptured and cause stroke, ischemia or infarction. Pulse wave imaging (PWI) is an ultrasound-based technique developed to locally quantify the stiffness of arteries. This technique has shown promising results when applied to patients. The objective of this study is to assess the capability of PWI to monitor the disease progression in a swine model that mimics human pathology.Approach.The left common carotid of three hypercholesterolemic Wisconsin miniature swines, fed an atherogenic diet, was ligated. Ligated and contralateral carotids were imaged once a month over 9 months, at a high-frame-rate, with a 5-plane wave compounding sequence and a 5 MHz linear array. Each acquisition was repeated after probe repositioning to evaluate the reproducibility. Wall displacements were estimated from the beamformed RF-data and were arranged as spatiotemporal maps depicting the wave propagation. The pulse wave velocity (PWV) estimated by tracking the 50% upstroke of the wave was converted in compliance using the Bramwell-Hill model. At the termination of the experiment, the carotids were extracted for histology analysis.Main results.PWI was able to monitor the evolution of compliance in both carotids of the animals. Reproducibility was demonstrated as the difference of PWV between cardiac cycles was similar to the difference between acquisitions (9.04% versus 9.91%). The plaque components were similar to the ones usually observed in patients. Each animal presented a unique pattern of compliance progression, which was confirmed by the plaque composition observed histologically.Significance.This study provides important insights on the vascular wall stiffness progression in an atherosclerotic swine model. It therefore paves the way for a thorough longitudinal study that examines the role of stiffness in both the plaque formation and plaque progression.

Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates.

An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood-brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

BACKGROUND: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy. METHODS: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs. RESULTS: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038). CONCLUSIONS: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment. LAY SUMMARY: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.

A Case Report of Coronavirus Disease 2019 Presenting with Tremors and Gait Disturbance.

INTRODUCTION: Neurologic symptoms present as significant complications of coronavirus disease 2019 (COVID-19) infection. This report describes a novel manifestation of tremors triggered by severe acute respiratory syndrome coronavirus 2 infection. CASE PRESENTATION: We describe a case of a 46-year-old man with COVID-19 infection complicated by a bilateral intention tremor and wide-based gait. Although neurological manifestations have been reported related to COVID-19, tremulousness has not yet been described. CONCLUSION: Considering the evolving diversity of neurologic manifestations in this infection, emergency physicians should be vigilant of possible COVID-19 infection in patients presenting with unexplained neurologic symptoms.

Evaluating the Diversity of Emergency Medicine Foundation (EMF) Grant Recipients in the Last Decade.

INTRODUCTION: To study diversity of researchers and barriers to success among Emergency Medicine Foundation (EMF) grant recipients in the last 10 years. METHODS: EMF grant awardees were approached to complete a brief survey, which included demographics, queries related to contributions to the literature, success in obtaining grants, and any perceived barriers they encountered. RESULTS: Of the 342 researchers contacted by email, a total of 147 completed the survey for a response rate of 43%. The respondents were predominately mid to late career white-male-heterosexual-Christian with an average age of 44 years (range 25-69 years of age). With regards to training and education, the majority of respondents (50%) were either Associate or Professor clinical rank (8% instructor/resident/fellow and 31% Assistant). Sixty-two percent of the respondents reported perceived barriers to career advancement since completion of residency. The largest perceived barrier to success was medical specialty (26%), followed by gender (21%) and age (16%). CONCLUSION: Our survey of EMF grant recipients in the last 10 years shows a considerable lack of diversity. The most commonly perceived barriers to career advancement by this cohort were medical specialty, gender, and age. An opportunity exists for further definition of barriers and development of mechanisms to overcome them, with a goal of increased success for those that are underrepresented.

Image-guided focused ultrasound modulates electrically evoked motor neuronal activity in the mouse peripheral nervous system in vivo.

OBJECTIVE: Focused ultrasound (FUS) has recently been demonstrated capable of exciting motor neuronal activity. However, comprehensive understanding of elucidated excitatory and inhibitory effects is required to better assess FUS-mediated modulation. In this study, we demonstrate that image-guided FUS can selectively modulate motor neuron activity in the mouse sciatic nerve in vivo and attribute motor responses to thermal effects. APPROACH: FUS was applied on the sciatic nerve of anesthetized mice in vivo through the intact skin and muscle using ultrasound imaging for targeting. Both excitatory and inhibitory effects were recorded using electromyography (EMG) along with muscle response of the hind limb. The effects of FUS modulation versus heating by invasive alternative heating source (AHS) on electrically evoked EMG responses in the sciatic nerve in vivo were also investigated. The safety and reversibility of the technique were validated using histology and EMG recovery. MAIN RESULTS: The FUS was capable of eliciting motor neuronal activity comparable to electrical stimulation ES, and facilitating motor neuronal response on electrically evoked potentials with temperature elevation up to 11.5 °C ± 0.3 °C (PRF ⩽ 40 Hz). On the other hand, FUS-induced temperature elevations above 15.1 °C ± 1.6 °C (PRF ⩾ 100 Hz) resulted in the suppression of electrically-evoked motor neuronal activity along with a decrease in EMG latency and area under the curve (AUC), which was validated against the invasive AHS with temperature elevation of 18.1 °C ± 8.5 °C. Histological findings along with EMG responses after FUS modulation demonstrated a reversible or irreversible modulation. SIGNIFICANCE: The findings reported herein indicate that image-guided FUS (PRF ⩽ 100 Hz) induces safe and controllable modulation of involuntarily evoked motor neuron activity in vivo.