Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Providing doula support to publicly insured women in central Texas: A financial cost-benefit analysis.

BACKGROUND: Disparities in birth outcomes continue to exist in the United States, particularly for low-income, publicly insured women. Doula support has been shown to be a cost-effective intervention in predominantly middle-to-upper income White populations, and across all publicly insured women at the state level. This analysis extends previous studies by providing an estimate of benefits that incorporates variations in averted outcomes by race and ethnicity in the context of one region in Texas. The objectives of this study were to determine (1) whether the financial value of benefits provided by doula support exceeds the costs of delivering it; (2) whether the cost-benefit ratio differs by race and ethnicity; and (3) how different doula reimbursement levels affect the cost-benefit results with respect to pregnant people covered by Medicaid in central Texas. METHODS: We conducted a forward-looking cost-benefit analysis using secondary data carried out over a short-term time horizon taking a public payer perspective. We focused on a narrow set of health outcomes (preterm delivery and cesarean delivery) that was relatively straightforward to monetize. The current, usual care state was used as the comparison condition. RESULTS: Providing pregnant people covered by Texas Medicaid with access to doulas during their pregnancies was cost-beneficial (benefit-to-cost ratio: 1.15) in the base model, and 65.7% of the time in probabilistic sensitivity analyses covering a feasible range of parameters. The intervention is most cost-beneficial for Black women. Reimbursing doulas at $869 per client or more yielded costs that were greater than benefits, holding other parameters constant. CONCLUSIONS: Expanding Medicaid pregnancy-related coverage to include doula services would be cost-beneficial and improve health equity in Texas.

Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin.

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimise the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Arg(Pbf) were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser.

The gendered implications of energy gaps in health care: A comparative analysis of Haiti, Senegal, and the Democratic Republic of Congo.

Delivering quality primary health care requires reliable energy access. In rural health facilities, electricity is often unreliable or absent. Low energy access has a gendered impact, affecting the ability of mothers to experience safe childbirth, for which basic lighting and sterilization are essential. Moreover, low energy access acts as a barrier to attract and retain female medical staff, who constitute women-predominated nursing and midwifery cadres that are critical for providing care to women. Using quantitative facility-level data, we explore the intersection of energy, health care, and gender in Haiti, Senegal, and the Democratic Republic of the Congo.

Rapid Short-pulse Ultrasound Delivers Drugs Uniformly across the Murine Blood-Brain Barrier with Negligible Disruption.

Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally disruptive and efficient drug delivery method that could improve the treatment, diagnosis, and study of neurologic diseases. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Klibanov and McDannold in this issue.

Concept Mapping: Engaging Urban Men to Understand Community Influences on Partner Violence Perpetration.

Intimate partner violence (IPV) is a significant health concern rooted in community experiences and other social determinants. The purpose of this study is to understand community-based risk and protective factors of IPV perpetration through participatory research that engages men who use IPV. Secondarily, we assess the relative influence, as measured by ranking, of these factors regarding risk of IPV perpetration and stress. We conducted concept mapping with Baltimore men (n = 28), ages 18 and older, enrolled in an abuse intervention program (AIP), through partnership with a domestic violence agency. Concept mapping, a three-phase participatory process, generates ideas around an issue then visually presents impactful domains via multi-dimensional scaling and hierarchical clustering. Most participants were Black (87.5%) and 20-39 years old (75%). Seven key domains, or clusters, were established. "No hope for the future" was the greatest contributor to IPV perpetration. "Socioeconomic struggles" (i.e., lack of employment) and "life in Baltimore" (i.e., homicide) were most likely to result in stress. Emergent domains related to IPV perpetration and stress were ranked similarly, but with some nuance. Having good support systems (i.e., family, community centers) were felt to prevent IPV and reduce stress. This participant-driven process among a primarily young, Black sample of Baltimore men speaks to the influence of perceived social disempowerment and underlying trauma on intimate relationships and the potential for mitigation. Few studies have engaged men who use IPV through participatory research to understand the comprehensive dynamics of an impoverished, urban environment. Results provide direction for community-based intervention and prevention programming to increase self-efficacy, particularly among younger men, and to enact trauma-informed violence prevention policy from the perspectives of male IPV perpetrators.

Wound Care Follow-Up From the Emergency Department Using a Mobile Application: A Pilot Study.

BACKGROUND: Many patients presenting to emergency departments (EDs) do not have primary care and risk being lost to follow-up. Technology has been used successfully in surgical populations for wound care follow-up yet this is not well studied in ED populations. OBJECTIVE: We aimed to conduct a pilot study demonstrating "smartphone" application-based follow-up after wound care in the ED. METHODS: We enrolled participants in 2 urban EDs using a smartphone application called Mobile Post-Operative Wound Evaluator (mPOWEr) and defined participation as photographic submission at any time during the study period. We collected demographic data, frequency of use of mPOWEr, number of photographs uploaded, and timing of uploads. RESULTS: We approached patients for study enrollment, and 67 patients (28%) were not enrolled because they had no access to a smartphone. Seventy-one patients (30%) declined to enroll, leaving 100 (42%) successfully enrolled. Smartphone ownership was more common among patients <40 years of age (81% vs. 64%, p = 0.004), more common among white patients than nonwhite patients (75% vs. 15%, p = 0.046), more common among patients approached at the university medical center than the trauma center (84% vs. 66%, p = 0.003), and among patients with commercial or other insurance than those with Medicare or Medicaid (92% vs. 54%, p < 0.001). Of those enrolled, 58% submitted a photograph. CONCLUSIONS: Patients presenting for wound care to the ED will participate in smartphone-based app communication for wound care follow-up and are satisfied with this option. Disparities in smartphone access must be considered when using this follow-up method.

Response to sexual assault in Bogotá, Colombia: A qualitative evaluation of health providers' readiness and role in policy implementation.

Colombia has an extensive policy framework to address violence against women. In this qualitative study the authors address the health system and policy response to sexual violence in Bogotá. Interviews were conducted with doctors, nurses, and social workers (n = 46) in emergency departments at public hospitals in Bogotá in 2015, and were analyzed for thematic content. Key findings were compared with district and national policies and 2013 WHO clinical and policy guidelines. Most providers exhibited sensitivity towards victims, but reported inadequate capacity building, undermining policy implementation. Our participants' eagerness to provide quality care suggests that health system strengthening may be timely and effective.

The legacy of gender-based violence and HIV/AIDS in the postgenocide era: Stories from women in Rwanda.

Drawing on qualitative interviews with 22 Rwandan women, we describe the lived experiences of women survivors of gender-based violence (GBV) more than a decade and a half after the 1994 Genocide. We argue that the intersection between GBV and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) has long-term implications: the majority of women interviewed continue to endure trauma, stigma, social isolation, and economic hardship in the postgenocide era and are in need of expanded economic and mental health support. Our findings have implications for the importance of providing integrated psychosocial support to survivors of GBV postconflict contexts.

Randomized feasibility trial of remote ischemic conditioning to enhance resuscitation (RICE).

RATIONALE: Restoration of blood flow after out-of-hospital cardiac arrest (OHCA) is associated with inflammation that causes cellular injury. The extent of this reperfusion injury (RI) is associated with the duration of ischemia and adequacy of resuscitation. Remote ischemic conditioning (RIC) consists of repeated application of non-lethal ischemia then reperfusion to a limb distal to the heart by inflating a blood pressure (BP) cuff. Trials in animal models in cardiac arrest and in humans with acute infarction show RIC reduces RI. OBJECTIVE: We sought to demonstrate the feasibility and safety of RIC in patients resuscitated from OHCA and transported to hospital. METHODS: This study was conducted under exception from informed consent (EFIC) for emergency research. Eligible subjects were randomized with masked allocation to control (standard care) versus intervention (standard care and RIC). Included were adults with non-traumatic OHCA. The primary outcome was attrition, the proportion of patients enrolled and not on allocated therapy for the study duration. Key secondary outcomes were survival to discharge, neurologic status at discharge, hospital-free survival, and adverse events. Results were summarized descriptively as recommended for pilot studies. RESULTS: N = 30 patients were enrolled (n = 14 control, n = 16 intervention). Mean age of enrolled patients was 52.5 ± 16.2 years. Eight (27%) were female gender and 7 (23%) had a shockable first recorded rhythm. 100% of enrolled patients completed their allocated study intervention (i.e., 0% attrition). The RIC group had 7 (44%) survival to discharge and median Rankin score of 6 (IQR 1, 6) at discharge as compared to the standard care group which had 6 (43%) survival to discharge and median Rankin score of 6 (IQR 1.5, 6) at discharge. A single patient (6%) in the intervention group had transient occlusion of their upper extremity intravenous line, which immediately resolved on repositioning of the blood pressure cuff. CONCLUSION: Application of RIC to patients resuscitated from CA and transported to an ED is feasible and safe. An adequately powered trial is required to assess whether RIC is effective at decreasing morbidity and mortality after CA.

Design and implementation of an intensive panel survey with refugees and other migrants in need of protection in Costa Rica.

Over the last decade, the global population of refugees and other migrants in need of international protection (MNP) has more than doubled. Despite their rapid growth, panel data collection among MNP remains rare, leaving scholars with few data sources to draw on to understand dynamic changes in their social, economic, legal, or health circumstances. With that paucity in mind, we developed and piloted the Encuesta de Refugiados: Experiencias Sociales y Salud (ERESS), a weekly panel survey conducted with MNP living in Costa Rica. To our knowledge, this panel constitutes one of the first weekly surveys with MNP anywhere in the world. Here, we describe the overall study design, sample recruitment and retention, and key descriptive findings. We show that retaining demographically and socioeconomically diverse MNP in intensive panel surveys is possible and that doing so reveals valuable insights into dynamic changes in their incorporation, family dynamics, and health and wellbeing. By offering a summary of our field experiences and central methodological findings, we highlight the potential benefits and challenges of collecting intensive panel data with MNP, as scholars increasingly seek to understand their pre- and post-migration trajectories and relationships between the two.

3D Acoustic Wave Sparsely Activated Localization Microscopy With Phase Change Contrast Agents.

OBJECTIVE: The aim of this study is to demonstrate 3-dimensional (3D) acoustic wave sparsely activated localization microscopy (AWSALM) of microvascular flow in vivo using phase change contrast agents (PCCAs). MATERIALS AND METHODS: Three-dimensional AWSALM using acoustically activable PCCAs was evaluated on a crossed tube microflow phantom, the kidney of New Zealand White rabbits, and the brain of C57BL/6J mice through intact skull. A mixture of C 3 F 8 and C 4 F 10 low-boiling-point fluorocarbon gas was used to generate PCCAs with an appropriate activation pressure. A multiplexed 8-MHz matrix array connected to a 256-channel ultrasound research platform was used for transmitting activation and imaging ultrasound pulses and recording echoes. The in vitro and in vivo echo data were subsequently beamformed and processed using a set of customized algorithms for generating 3D super-resolution ultrasound images through localizing and tracking activated contrast agents. RESULTS: With 3D AWSALM, the acoustic activation of PCCAs can be controlled both spatially and temporally, enabling contrast on demand and capable of revealing 3D microvascular connectivity. The spatial resolution of the 3D AWSALM images measured using Fourier shell correlation is 64 µm, presenting a 9-time improvement compared with the point spread function and 1.5 times compared with half the wavelength. Compared with the microbubble-based approach, more signals were localized in the microvasculature at similar concentrations while retaining sparsity and longer tracks in larger vessels. Transcranial imaging was demonstrated as a proof of principle of PCCA activation in the mouse brain with 3D AWSALM. CONCLUSIONS: Three-dimensional AWSALM generates volumetric ultrasound super-resolution microvascular images in vivo with spatiotemporal selectivity and enhanced microvascular penetration.

A qualitative study of people who use methamphetamine during the early COVID-19 pandemic to inform future ED harm reduction strategies.

BACKGROUND: Morbidity and mortality rates related to methamphetamine are on the rise. Simultaneously, social-distancing guidelines were issued in March 2020 to decrease transmission of COVID-19. The aim of this study was to explore concerns regarding methamphetamine use during the COVID-19 pandemic and subsequent harm reduction strategies with patients who use methamphetamine to inform emergency department (ED)-based harm reduction approaches. METHODS: A mixed-methods study of adults residing in Washington with high-risk methamphetamine use and a recent ED visit from April-September 2020 was performed. Participants completed a survey and a semi-structured interview on perceptions and experiences of COVID-19. Descriptive statistics were used for survey responses. Interview transcripts were analyzed and guided by modified grounded theory using an iterative approach to refine the guide and codebook. Interviews were independently coded by 2 investigators and discussed until consensus. RESULTS: Twenty-five participants completed the survey; 20 participants were interviewed (45% recently used heroin, 40% unstably housed). Thirty-five percent was worried about COVID-19 infection. Three themes emerged from the interviews: (1) increase in meth use, (2) interplay of meth obtention and COVID-19, and (3) interactions with healthcare and social services. CONCLUSIONS: People who use methamphetamine noted an increase in use along with the social distancing guidelines put in place for COVID-19 and employed a variety of harm reduction profiles when obtaining methamphetamine. Also, the pandemic brought difficulties in accessing care and amplified mistrust in healthcare instructions and public health messages. Based on these qualitative interviews, further work should consider aligning methamphetamine and COVID-19 harm reduction messages and working with trusted community resources to improve harm reduction strategies for methamphetamine use and COVID-19. IRB: Informed Consent by the University of Washington Human Subjects Division (approval number, STUDY00009277).

Health Care Use, Coverage, and Experiences During the Year Prior to Pregnancy in a Primarily Hispanic Population with Low Income: A Descriptive Qualitative Study.

INTRODUCTION: A qualitative picture of the health care experiences prior to pregnancy can inform patient-centered strategies to optimize preconception health. This study describes health care utilization and experiences and how health care costs were covered in the year prior to pregnancy in a population of primarily Hispanic women with low income. METHODS: Pregnant participants were recruited from 5 Federally Qualified Health Center clinics. Semistructured interviews included questions about health care in the year prior to pregnancy. Transcripts were analyzed using a thematic approach that integrated deductive and inductive analysis. RESULTS: Most participants self-identified as Hispanic. Just under half were US citizens. All but one were Medicaid or Children's Health Insurance Program Perinatal coverage insurance during pregnancy and relied on a variety of strategies to cover prepregnancy health care costs. Almost all received health care during the year prior to pregnancy. Fewer than half reported an annual preventive visit. Health care needs that led to care-seeking included a prior pregnancy, chronic depression, contraception, workplace injury, a persistent rash, screening and treatment for sexually transmitted infection, breast pain, stomach pain (leading to gallbladder removal), and kidney infection. The ways in which study participants covered the costs of health care ranged in terms of sources and complexity. Although some participants described stable health care coverage, most reported changes throughout the year as they pieced together various health care coverage programs and out-of-pocket payments. When participants did seek health care prior to their current pregnancy, most described the experience in positive terms and focused on health care provider communication quality. Respect of patient autonomy was highly valued. DISCUSSION: Women with pregnancy-related health care coverage accessed care for a wide range of health care needs prior to pregnancy. Health care providers may consider strategies to respectfully introduce preconception care into any visit by an individual who could become pregnant.

Rapid short-pulses of focused ultrasound and microbubbles deliver a range of agent sizes to the brain.

Focused ultrasound and microbubbles can non-invasively and locally deliver therapeutics and imaging agents across the blood-brain barrier. Uniform treatment and minimal adverse bioeffects are critical to achieve reliable doses and enable safe routine use of this technique. Towards these aims, we have previously designed a rapid short-pulse ultrasound sequence and used it to deliver a 3 kDa model agent to mouse brains. We observed a homogeneous distribution in delivery and blood-brain barrier closing within 10 min. However, many therapeutics and imaging agents are larger than 3 kDa, such as antibody fragments and antisense oligonucleotides. Here, we evaluate the feasibility of using rapid short-pulses to deliver higher-molecular-weight model agents. 3, 10 and 70 kDa dextrans were successfully delivered to mouse brains, with decreasing doses and more heterogeneous distributions with increasing agent size. Minimal extravasation of endogenous albumin (66.5 kDa) was observed, while immunoglobulin (~ 150 kDa) and PEGylated liposomes (97.9 nm) were not detected. This study indicates that rapid short-pulses are versatile and, at an acoustic pressure of 0.35 MPa, can deliver therapeutics and imaging agents of sizes up to a hydrodynamic diameter between 8 nm (70 kDa dextran) and 11 nm (immunoglobulin). Increasing the acoustic pressure can extend the use of rapid short-pulses to deliver agents beyond this threshold, with little compromise on safety. This study demonstrates the potential for deliveries of higher-molecular-weight therapeutics and imaging agents using rapid short-pulses.

"That Line Just Kept Moving": Motivations and Experiences of People Who Use Methamphetamine.

INTRODUCTION: Methamphetamine use is on the rise with increasing emergency department (ED) visits, behavioral health crises, and deaths associated with use and overdose. Emergency clinicians describe methamphetamine use as a significant problem with high resource utilization and violence against staff, but little is known about the patient's perspective. In this study our objective was to identify the motivations for initiation and continued methamphetamine use among people who use methamphetamine and their experiences in the ED to guide future ED-based approaches. METHODS: This was a qualitative study of adults residing in the state of Washington in 2020, who used methamphetamine in the prior 30 days, met criteria for moderate- to high-risk use, reported recently receiving care in the ED, and had phone access. Twenty individuals were recruited to complete a brief survey and semi-structured interview, which was recorded and transcribed prior to being coded. Modified grounded theory guided the analysis, and the interview guide and codebook were iteratively refined. Three investigators coded the interviews until consensus was reached. Data was collected until thematic saturation. RESULTS: Participants described a shifting line that separates the positive attributes from the negative consequences of using methamphetamine. Many initially used methamphetamine to enhance social interactions, combat boredom, and escape difficult circumstances by numbing the senses. However, continued use regularly led to isolation, ED visits for the medical and psychological sequelae of methamphetamine use, and engagement in increasingly risky behaviors. Because of their overwhelmingly frustrating experiences in the past, interviewees anticipated difficult interactions with healthcare clinicians, leading to combativeness in the ED, avoidance of the ED at all costs, and downstream medical complications. Participants desired a non-judgmental conversation and linkage to outpatient social resources and addiction treatment. CONCLUSION: Methamphetamine use can lead patients to seek care in the ED, where they often feel stigmatized and are provided little assistance. Emergency clinicians should acknowledge addiction as a chronic condition, address acute medical and psychiatric symptoms adequately, and provide positive connections to addiction and medical resources. Future work should incorporate the perspectives of people who use methamphetamine into ED-based programs and interventions.

Using focused ultrasound to modulate microglial structure and function.

Transcranial focused ultrasound (FUS) has the unique ability to target regions of the brain with high spatial precision, in a minimally invasive manner. Neuromodulation studies have shown that FUS can excite or inhibit neuronal activity, demonstrating its tremendous potential to improve the outcome of neurological diseases. Recent evidence has also shed light on the emerging promise that FUS has, with and without the use of intravenously injected microbubbles, in modulating the blood-brain barrier and the immune cells of the brain. As the resident immune cells of the central nervous system, microglia are at the forefront of the brain's maintenance and immune defense. Notably, microglia are highly dynamic and continuously survey the brain parenchyma by extending and retracting their processes. This surveillance activity aids microglia in performing key physiological functions required for brain activity and plasticity. In response to stressors, microglia rapidly alter their cellular and molecular profile to help facilitate a return to homeostasis. While the underlying mechanisms by which both FUS and FUS + microbubbles modify microglial structure and function remain largely unknown, several studies in adult mice have reported changes in the expression of the microglia/macrophage marker ionized calcium binding adaptor molecule 1, and in their phagocytosis, notably of protein aggregates, such as amyloid beta. In this review, we discuss the demonstrated and putative biological effects of FUS and FUS + microbubbles in modulating microglial activities, with an emphasis on the key cellular and molecular changes observed in vitro and in vivo across models of brain health and disease. Understanding how this innovative technology can modulate microglia paves the way for future therapeutic strategies aimed to promote beneficial physiological microglial roles, and prevent or treat maladaptive responses.

Feasibility of Very Early Identification of Cardiogenic Shock by Semi-automated Ultrasound Exam in the Emergency Department.

Background Cardiogenic shock (CS) is critical end-organ hypoperfusion due to reduced cardiac output. Early therapy, such as vasoactive agents or the initiation of mechanical circulatory support (MCS), requires early diagnosis and is associated with better outcomes. A novel ultrasound platform (GE Healthcare, Milwaukee, WI) has semi-automated imaging software (SAIS), which could simplify the point-of-care ultrasound (POCUS) diagnosis of CS. We assessed the feasibility of using POCUS with SAIS in patients in shock, determined the ability of SAIS to identify the subset of patients with CS, and described the process and outcome of care of patients with vs. without CS after presenting to Emergency Department (ED) with hypotension. Methods This prospective case-control study was conducted at an urban ED. Physicians with prior POCUS education received one hour of training with the study device. The qualitative ejection fraction was determined by visual assessment. SAIS measurements of hemodynamics were made with the study device and included left ventricle outflow tract velocity time integral (LVOT VTI), inferior vena cava collapsibility or distensibility indices, and pulmonary B-line assessment. ED patients with a systolic blood pressure ≤ 90 mmHg or need for a vasopressor initiation in the ED were enrolled. The diagnosis of CS was determined by a medical record review. All data were summarized descriptively. Results Twenty-nine cases underwent POCUS, and 87 controls did not. Baseline characteristics, process, and outcome of care were similar between groups. Seventy-nine percent (79%) of cases had a complete POCUS with SAIS. Of these, 55% had reduced LVOT VTI, 38% had IVC collapsibility <50%, and 48% of cases had a B-line pattern consistent with pulmonary edema. The mean LVOT VTI for cases with CS was 9.4± 5.4 cm; the mean LVOT VTI for cases without CS was 15.2 ± 6.0 cm. Among patients who did not undergo POCUS, 31 (36%) had a formal echocardiogram, and eight (9%) had a final diagnosis of cardiogenic shock during hospitalization. Conclusion Physicians with one hour of platform-specific training were able to implement POCUS with SAIS among patients who present with shock. POCUS with SAIS may aid in the early recognition of CS.

Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles.

Liposomes are clinically used drug carriers designed to improve the delivery of drugs to specific tissues while minimising systemic distribution. However, liposomes are unable to cross the blood-brain barrier (BBB) and enter the brain, mostly due to their large size (ca. 100 nm). A noninvasive and localised method of delivering liposomes across the BBB is to intravenously inject microbubbles and apply long pulses of ultrasound (pulse length: >1 ms) to a targeted brain region. Recently, we have shown that applying rapid short pulses (RaSP) (pulse length: 5 µs) can deliver drugs with an improved efficacy and safety profile. However, this was tested with a relatively smaller 3-kDa molecule (dextran). In this study, we examine whether RaSP can deliver liposomes to the murine brain in vivo. Fluorescent DiD-PEGylated liposomes were synthesized and injected intravenously alongside microbubbles. The left hippocampus of mice was then sonicated with either a RaSP sequence (5 µs at 1.25 kHz in groups of 10 ms at 0.5 Hz) or a long pulse sequence (10 ms at 0.5 Hz), with each pulse having a 1-MHz centre frequency (0.35 and 0.53 MPa). The delivery and distribution of the fluorescently-labelled liposomes were assessed by fluorescence imaging of the brain sections. The safety profile of the sonicated brains was assessed by histological staining. RaSP was shown to locally deliver liposomes across the BBB at 0.53 MPa with a more diffused and safer profile compared to the long pulse ultrasound sequence. Cellular uptake of liposomes was observed in neurons and microglia, while no uptake within astrocytes was observed in both RaSP and long pulse-treated brains. This study shows that RaSP allows a targeted and safe delivery of liposomal drugs into the murine brain with potential to deliver drugs into neuronal and glial targets.