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.

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.

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.

The GAP-ED Project: Improving Care for Elderly Patients Presenting to the Emergency Department.

BACKGROUND: Older adults presenting to the emergency department (ED) represent a highly vulnerable patient population with complex conditions and multiple comorbidities. The introduction of a Geriatric and Palliative (GAP)-ED partnership may be an effective strategy to avoid unneeded admissions and improve outcomes for this population. OBJECTIVES: The primary objective was to decrease 30-day revisit and hospitalization rates in this population through identifying patients that could be safely sent home with connection to community resources. Secondary outcomes included achieving high patient and family satisfaction scores assessed through follow-up interviews. METHODS: The GAP-ED intervention included the placement of a Specialist in the ED to coordinate care for older adults presenting to the ED who were likely to be discharged home. Independent t-tests and chi-squared tests were used to assess for changes in outcomes between the intervention group and a blocked matched historical usual-care group. RESULTS: There was no significant difference in 30-day ED revisits between the two groups, but there was a statistically significant reduction in hospital admissions from these 30-day revisits. Patient and family satisfaction with the presence of the GAP-ED Specialist was high. CONCLUSION: The implementation of a GAP-ED partnership and use of a GAP-ED Specialist is an effective means of reducing hospitalization in older adults revisiting the ED.

Cold therapy to prevent paclitaxel-induced peripheral neuropathy.

PURPOSE: This case-control study was designed to assess the efficacy of cryotherapy to prevent paclitaxel-induced painful peripheral neuropathy in women with breast cancer. METHODS: Participants served as their own paired control, with randomization of the cooled glove/sock to either the dominant or the non-dominant hand/foot, worn for 15 min prior to, during, and 15 min after completion of the paclitaxel infusion. Outcome measures included the Neuropathic Pain Symptom Inventory, the Brief Pain Inventory, and quantitative sensory testing. Data were measured at each of six time points-baseline, post-treatment (approximately 2 weeks after the last paclitaxel infusion), and at the first, fifth, ninth, and final weekly paclitaxel treatments. RESULTS: Of 29 randomized participants, 20 (69%) received at least one cryotherapy treatment, and 11 (38%) received all four cryotherapy treatments. Ten (34%) participants could not tolerate the cryotherapy, and six (21%) declined further participation at some point during the trial. Only seven participants (24%) were available for the final post-chemotherapy QST and questionnaires. There were no significant differences in measures of neuropathy or pain between treated and untreated hands or feet. CONCLUSIONS: Strategies to prevent painful peripheral neuropathy are urgently needed. In this current trial, dropout due to discomfort precluded adequate power to fully understand the potential benefits of cryotherapy. Much more research is needed to discover safe and effective preventive strategies that can be easily implemented within busy infusion centers.

Identifying Advanced Illness Patients in the Emergency Department and Having Goals-of-Care Discussions to Assist with Early Hospice Referral.

BACKGROUND: The emergency department (ED) is often where patients with advanced illness (AI) present when faced with an acute deterioration in their disease. OBJECTIVES: To investigate the effectiveness of our AI Management program in the ED on key outcomes. METHODS: We conducted a pre-post study with a retrospective chart review with ED patients at an academic, tertiary care hospital in the New York metropolitan area. We assessed changes from baseline to intervention period on percent of patients identified in the ED with AI, percent who received an ED-led goals-of-care (GOC) discussion, and percent referred to hospice from the ED. We used the Fisher's exact test or the Mann-Whitney test to compare groups, as appropriate. RESULTS: Our sample consisted of 82 patients (21 baseline and 61 intervention). Patients in the baseline period had a median age of 75 years, with 61.9% being female, whereas those in the intervention period had a median age of 83 years, with 67.2% being female. Patients in the intervention, compared with baseline, were significantly more likely to be identified as having AI in the ED (90.2% vs. 0.0%; p < 0.0001), to receive an ED-led GOC conversation (83.6% vs. 0.0%; p < 0.0001), and to be discharged to home hospice (39.3% vs. 0.0%; p < 0.0001). CONCLUSIONS: The ED provides a critical opportunity to identify AI patients, have ED-led GOC discussions, and refer appropriate patients to hospice.

Prevalence of undiagnosed dysglycemia in an emergency department observation unit.

BACKGROUND: The proposed 2015 US Preventive Services Task Force guidelines recommend diabetes screening for individuals ≥45 years or demonstrating other risk factors for dysglycemia. Still, many patients with dysglycemia remain undiagnosed, and opportunities for early intervention are lost. METHODS: To test novel approaches for diagnosis using the haemoglobin A1c (HbA1c ) test, we screened adult patients who were admitted to an observation unit from the emergency department with no known history of pre-diabetes or diabetes. RESULTS: Of 256 subjects, 9% were newly diagnosed with diabetes and 52% were newly diagnosed with pre-diabetes. Of those aged 18-29 years, 33% were newly diagnosed with dysglycemia, while 55% of those aged 30-44 years and 70% of those aged ≥45 years were newly diagnosed with dysglycemia. CONCLUSIONS: Our results suggest that regardless of age, a large proportion of patients in the emergency department observation unit have undiagnosed dysglycemia, an important finding given the large number of observation admissions. Copyright © 2015 John Wiley & Sons, Ltd.

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.

Preliminary validation of the Defense and Veterans Pain Rating Scale (DVPRS) in a military population.

BACKGROUND: The Army Surgeon General released the Pain Management Task Force final report in May 2010. Among military providers, concerns were raised that the standard numeric rating scale (NRS) for pain was inconsistently administered and of questionable clinical value. In response, the Defense and Veterans Pain Rating Scale (DVPRS) was developed. METHODS: The instrument design integrates pain rating scale features to improve interpretability of incremental pain intensity levels, and to improve communication and documentation across all transitions of care. A convenience sample of 350 inpatient and outpatient active duty or retired military service members participated in the study at Walter Reed Army Medical Center. Participants completed the five-item DVPRS-one pain intensity NRS with and without word descriptors presented in random order and four supplemental items measuring general activity, sleep, mood, and level of stress and the Brief Pain Inventory seven interference items. Using systematic sampling, a random sample was selected for a word descriptor validation procedure matching word phases to corresponding pain intensity on the NRS. RESULTS: Parallel forms reliability and concurrent validity testing demonstrated a robust correlation. When the DVPRS was presented with the word descriptors first, the correlation between the two ratings was slightly higher, r = 0.929 (N = 171; P < 0.001), than ordering first without the descriptors, r = 0.882 (N = 177; P < 0.001). Intraclass correlation coefficient was 0.943 showing excellent alignment of word descriptors by respondents (N = 42), matching them correctly with pain level. CONCLUSIONS: The DVPRS tool demonstrated acceptable psychometric properties in a military population.

A survey of the prevalence of cell phones capable of receiving health information among patients presenting to an Urban Emergency Department.

BACKGROUND: Mobile devices have been shown to assist patients with comprehension of health information, yet sparse data exist on what mobile devices patients own and preferences for receiving health information. OBJECTIVES: To determine the prevalence of mobile devices capable of receiving health information among patients/visitors presenting to an urban Emergency Department (ED). METHODS: A random sample of patients/visitors ≥18 years was surveyed. The primary outcome was prevalence of mobile devices capable of receiving health information among patient/visitor units presenting to the ED. Means and 95% confidence intervals were derived for continuous data; proportions with Fisher's exact 95% confidence intervals were derived for categorical data. Institutional review board approval was received before study initiation. RESULTS: Surveyors approached 1307 subjects: 68% (885) were eligible; 70% (620) agreed to participate; 4 participants were excluded, leaving 70% (616) in the final sample. Of the 616 participants, 82% stated cell phone ownership (95% confidence interval [CI] 0.79-0.85). Among cell phone owners (n = 507), 90% had the device with them (95% CI 0.87-0.92) in the ED. Of these participants (n = 456), 77% had text messaging (95% CI 0.73-0.81), 51% had Internet (95% CI 0.47-0.56), 51% had e-mail (95% CI 0.46-0.56), 39% could download audio content (95% CI 0.34-0.43), and 35% could download videos (95% CI 0.31-0.40). Even among those having an annual income ≤$20,000, nearly 80% of persons owned cell phones. CONCLUSIONS: Cell phones capable of receiving health information are prevalent among patients/visitors presenting to an urban ED.

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.

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.

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.

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.

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.

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.

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.

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 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.

Impact of an acute pain service on pain outcomes with combat-injured soldiers at Camp Bastion, Afghanistan.

BACKGROUND: Few studies demonstrate the impact of early aggressive analgesia with acute pain service (APS) involvement at combat support hospitals (CSHs) using real-time data. Collaboration between the British and the United States (US) Army led to a 3-month deployment of a US Army APS to Camp Bastion, the main British military base in southern Afghanistan, from April to July 2009. METHODS: Pain outcomes data were collected at Camp Bastion from 71 soldiers sustaining major combat injuries followed by an APS. RESULTS: The sample was predominantly male (98.6%) and Caucasian (98.8%) with a mean age 25.4 years ± 5.4 (range 18-45). Regional nerve blocks were performed in 51 (71.8%) and epidurals placed in 11 (15.5%) of the cases. Repeated measures analysis of variance showed a statistically significant decreases in pain intensity (numeric rating scale from 0 for "none" to 10 for "as bad as you can imagine") over the three data collection points; first 3, 4-6, and 7-10 hours (F = 133.35; degrees of freedom [df; 1,68]; P < 0.001). Mean percent pain relief (0% "no relief" to 100% "complete relief") increased significantly over time (F = 193.12; df[1,69]; P < 0.001) with scores 31.29% ± 20.3 (initial 3 hours), 74.86% ± 27.5 (4-6 hours), and 83.14% ± 19.3 (7-24 hours). Overall, the perceived quality of pain control by soldiers was high. CONCLUSIONS: Findings from this quality of pain care study show that aggressive multimodal analgesia interventions by an APS in a CSH is associated with decreased pain intensity and increased pain relief.