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.

A megastudy of text-based nudges encouraging patients to get vaccinated at an upcoming doctor's appointment.

Many Americans fail to get life-saving vaccines each year, and the availability of a vaccine for COVID-19 makes the challenge of encouraging vaccination more urgent than ever. We present a large field experiment (N = 47,306) testing 19 nudges delivered to patients via text message and designed to boost adoption of the influenza vaccine. Our findings suggest that text messages sent prior to a primary care visit can boost vaccination rates by an average of 5%. Overall, interventions performed better when they were 1) framed as reminders to get flu shots that were already reserved for the patient and 2) congruent with the sort of communications patients expected to receive from their healthcare provider (i.e., not surprising, casual, or interactive). The best-performing intervention in our study reminded patients twice to get their flu shot at their upcoming doctor's appointment and indicated it was reserved for them. This successful script could be used as a template for campaigns to encourage the adoption of life-saving vaccines, including against COVID-19.

Capillary-Scale Hydrogel Microchannel Networks by Wire Templating.

Microvascular networks are essential for the efficient transport of nutrients, waste products, and drugs throughout the body. Wire-templating is an accessible method for generating laboratory models of these blood vessel networks, but it has difficulty fabricating microchannels with diameters of ten microns and narrower, a requirement for modeling human capillaries. This study describes a suite of surface modification techniques to  selectively control the interactions amongst wires, hydrogels, and world-to-chip interfaces. This wire templating method enables the fabrication of perfusable hydrogel-based rounded cross-section capillary-scale networks whose diameters controllably narrow at bifurcations down to 6.1 ± 0.3 microns in diameter. Due to its low cost, accessibility, and compatibility with a wide range of common hydrogels of tunable stiffnesses such as collagen, this technique may increase the fidelity of experimental models of capillary networks for the study of human health and disease.

Angular dependence of the acoustic signal of a microbubble cloud.

Microbubble-mediated ultrasound therapies have a common need for methods that can noninvasively monitor the treatment. One approach is to use the bubbles' acoustic emissions as feedback to the operator or a control unit. Current methods interpret the emissions' frequency content to infer the microbubble activities and predict therapeutic outcomes. However, different studies placed their sensors at different angles relative to the emitter and bubble cloud. Here, it is evaluated whether such angles influence the captured emissions such as the frequency content. In computer simulations, 128 coupled bubbles were sonicated with a 0.5-MHz, 0.35-MPa pulse, and the acoustic emissions generated by the bubbles were captured with two sensors placed at different angles. The simulation was replicated in experiments using a microbubble-filled gel channel (0.5-MHz, 0.19-0.75-MPa pulses). A hydrophone captured the emissions at two different angles. In both the simulation and the experiments, one angle captured periodic time-domain signals, which had high contributions from the first three harmonics. In contrast, the other angle captured visually aperiodic time-domain features, which had much higher harmonic and broadband content. Thus, by placing acoustic sensors at different positions, substantially different acoustic emissions were captured, potentially leading to very different conclusions about the treatment outcome.

Which Early Withdrawal Penalty Attracts the Most Deposits to a Commitment Savings Account?

Previous research has shown that some people voluntarily use commitment contracts that restrict their own choice sets. We study how people divide money between two accounts: a liquid account that permits unrestricted withdrawals and a commitment account that is randomly assigned in a between-subject design to have either a 10% early withdrawal penalty, or a 20% early withdrawal penalty, or not to allow early withdrawals at all (i.e., an infinite penalty). When the liquid account and the commitment account pay the same interest rate, higher early-withdrawal penalties attract more commitment account deposits. This pattern is predicted by the hypothesis that some participants are partially- or fully-sophisticated present-biased agents. Such agents perceive that higher penalties generate greater scope for commitment by disincentivizing (penalized) early withdrawals. The experiment also shows that when the commitment account pays a higher interest rate than the liquid account, the positive empirical slope relating penalties and commitment deposits is flattened, suggesting that naïve present-biased agents or agents with standard exponential discounting are also in our sample. Across all of our experimental treatments, higher early withdrawal penalties on the commitment account sometimes increase and never reduce allocations to the commitment account.

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.

Comparison of outcome and cost between the open, laparoscopic, and robotic surgical treatments for colon cancer: a propensity score-matched analysis using nationwide hospital record database.

BACKGROUND: There are limited studies that compare the cost and outcome of robotic-assisted surgery to open and laparoscopic surgery for colon cancer treatment. We aimed to compare the three surgical modalities for colon cancer treatment. METHODS: We performed a cohort study using the population-based Nationwide Inpatient Sample database. Patients with a primary diagnosis of colon cancer who underwent robotic, laparoscopic, or open surgeries between 2008 and 2014 were eligible for enrollment. We compared in-hospital mortality, complications, length of hospital stay, and cost for patients undergoing one of these three procedures using a multivariate adjusted logistic regression analysis and propensity score matching. RESULTS: Of the 531,536 patients undergoing surgical treatment for colon cancer during the study period, 348,645 (65.6%) patients underwent open surgeries, 174,748 (32.9%) underwent laparoscopic surgeries, and 8143 (1.5%) underwent robotic surgeries. In-hospital mortality, length of hospital stay, wound complications, general medical complications, general surgical complications, and costs of the three surgical treatment modalities. Compared to those undergoing laparoscopic surgery, patients undergoing open surgery had a higher mortality rate (OR 2.98, 95% CI 2.61-3.40), more general medical complications (OR 1.77, 95% CI 1.67-1.87), a longer length of hospital stay (6.60 vs. 4.36 days), and higher total cost ($18,541 vs. $14,487) in the propensity score matched cohort. Mortality rate and general medical complications were equivalent in the laparoscopic and robotic surgery groups, but the median cost was lower in the laparoscopic group ($14641 vs. $16,628 USD). CONCLUSIONS: Laparoscopic colon cancer surgery was associated with a favourable short-term outcome and lower cost compared with open surgery. Robot-assisted surgery had comparable outcomes but higher cost as compared to laparoscopic surgery.

Displacement of a bubble located at a fluid-viscoelastic medium interface.

A model for estimating the displacement of a bubble located at a fluid-viscoelastic medium interface in response to acoustic radiation force is presented by extending the model for a spherical object embedded in a bulk material. The effects of the stiffness and viscosity of the viscoelastic medium and the amplitude and duration of the excitation force on bubble displacement were investigated using the proposed model. The results show that bubble displacement has a nonlinear relationship with excitation duration and viscosity. The time at which the steady state is reached increases with increasing medium viscosity and decreasing medium stiffness.

Displacement of a bubble by acoustic radiation force into a fluid-tissue interface.

Microbubbles in an ultrasound beam experience a primary Bjerknes force, which pushes the microbubbles against a fluid-tissue interface and deforms the tissue. This interaction has been used to measure tissue elasticity and is a common interaction in many therapeutic and diagnostic applications, but the mechanisms of deformation, and how the deformation dynamic depends on the bubble and ultrasound parameters, remain unknown. In this study, a mathematical model is proposed for the displacement of a bubble onto a fluid-tissue interface and the tissue deformation in response to the primary Bjerknes force. First, a model was derived for static loading and the model's prediction of bubble-mediated tissue displacement and stresses in tissue were explored. Second, the model was updated for dynamic loading. The results showed that the bubble is both displaced by the applied force and changes its shape. The bubble displacement changes nonlinearly with the applied force. The stress values in tissue are quite high for a distance within one radius of the bubble from the bubble surface. The model proposed here is permissible in human tissue and can be used for biomedical ultrasound applications, including material characterization.

The effects of ultrasound parameters and microbubble concentration on acoustic particle palpation.

The elasticity of tissue-an indicator of disease progression-can be imaged by ultrasound elasticity imaging technologies. An acoustic particle palpation (APP) has recently been developed-the use of ultrasonically driven acoustic particles (e.g., microbubbles)-as an alternative method of tissue deformation. APP has the potential to improve the resolution, contrast, and depth of ultrasound elasticity imaging; but the tissue displacement dynamics and its dependence on acoustic pressure, center frequency, and microbubble concentration remains unknown. Here, displacements of at least 1 µm were produced by applying ultrasound onto a microbubble solution (concentration: 10 × 106 microbubbles ml-1) placed within a tunnel surrounded by a 5% gelatin phantom. Displacements of more than 10 µm were produced using a 1, 3.5, or 5 MHz center frequency pulse with peak-rarefactional pressures of 470, 785, and 1210 kPa, respectively. The deformation of the distal wall varied spatially and temporally according to the different parameters investigated. At low pressures, the deformation increased over several milliseconds until it was held at a nearly constant value. At high pressures, a large deformation occurred within a millisecond followed by a sharp decrease and long stabilization. Ultrasound exposure in the presence of microbubbles produced tissue deformation (p < 0.05) while without microbubbles, no deformation was observed.

Clustering dynamics of microbubbles exposed to low-pressure 1-MHz ultrasound.

Ultrasound-driven microbubbles have been used in therapeutic applications to deliver drugs across capillaries and into cells or to dissolve blood clots. Yet the performance and safety of these applications have been difficult to control. Microbubbles exposed to ultrasound not only volumetrically oscillate, but also move due to acoustic radiation, or Bjerknes, forces. The purpose of this work was to understand the extent to which microbubbles moved and clustered due to secondary Bjerknes forces. A microbubble population was exposed to a 1-MHz ultrasound pulse with a peak-rarefactional pressure of 50-100 kPa and a pulse length of 20 ms. Microbubbles exposed to low-pressure therapeutic ultrasound were observed to cluster at clustering rates of 0.01-0.02 microbubbles per duration (in ms) per initial average inter-bubble distance (in µm), resulting in 1 to 3 clustered microbubbles per initial average inter-bubble distance (in µm). Higher pressures caused faster clustering rates and a larger number of clustered microbubbles. Experimental data revealed clustering time scales, cluster localizations, and cluster sizes that were in reasonable agreement with simulations using a time-averaged model at low pressures. This study demonstrates that clustering of microbubbles occurs within a few milliseconds and is likely to influence the distribution of stimuli produced in therapeutic applications.

Does front-loading taxation increase savings? Evidence from Roth 401(k) introductions.

Can governments increase private savings by taxing savings up front instead of in retirement? Roth 401(k) contributions are not tax-deductible in the contribution year, but withdrawals in retirement are untaxed. The more common before-tax 401(k) contribution is tax-deductible in the contribution year, but both principal and investment earnings are taxed upon withdrawal. Using administrative data from eleven companies that added a Roth contribution option to their existing 401(k) plan between 2006 and 2010, we find no evidence that total 401(k) contribution rates differ between employees hired before versus after Roth introduction, which implies that take-home pay declines and the amount of retirement consumption being purchased by 401(k) contributions increases after Roth introduction. We reject several neoclassical explanations for our null finding. Results from a survey experiment suggest two behavioral explanations: (1) employee confusion about and neglect of the tax properties of Roth balances and (2) partition dependence.

Small Cues Change Savings Choices.

We present evidence from randomized field experiments that 401(k) savings choices are significantly affected by one- to two-sentence anchoring, goal-setting, or savings threshold cues embedded in emails sent to employees about their 401(k) plan. Even though these cues contain little to no marginal information, cues that make high savings rates salient increased 401(k) contribution rates by up to 2.9% of income in a pay period, and cues that make low savings rates salient decreased 401(k) contribution rates by up to 1.4% of income in a pay period. Cue effects persist between two months and a year after the email.

Vaccination Rates are Associated With Functional Proximity But Not Base Proximity of Vaccination Clinics.

BACKGROUND: Routine annual influenza vaccinations are recommended for persons 6 months of age and older, but less than half of US adults get vaccinated. Many employers offer employees free influenza vaccinations at workplace clinics, but even then take-up is low. OBJECTIVE: To determine whether employees are significantly more likely to get vaccinated if they have a higher probability of walking by the clinic for reasons other than vaccination. METHOD: We obtained data from an employer with a free workplace influenza vaccination clinic. Using each employee's building entry/exit swipe card data, we test whether functional proximity-the likelihood that the employee walks by the clinic for reasons other than vaccination-predicts whether the employee gets vaccinated at the clinic. We also test whether base proximity-the inverse of walking distance from the employee's desk to the clinic-predicts vaccination probability. PARTICIPANTS: A total of 1801 employees of a health benefits administrator that held a free workplace influenza vaccination clinic. RESULTS: A 2 SD increase in functional proximity is associated with a 6.4 percentage point increase in the probability of vaccination (total vaccination rate at company=40%), even though the average employee's desk is only 166 meters from the clinic. Base proximity does not predict vaccination probability. CONCLUSIONS AND RELEVANCE: Minor changes in the environment can have substantial effects on the probability of vaccination. If these results generalize, health systems should emphasize functional proximity over base proximity when locating preventive health services.

Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions.

Despite the promise of microbubble-mediated focused ultrasound therapies, in vivo findings have revealed over-treated and under-treated regions distributed throughout the focal volume. This poor distribution cannot be improved by conventional pulse shapes and sequences, due to their limited ability to control acoustic cavitation dynamics within the ultrasonic focus. This paper describes the design of a rapid short-pulse (RaSP) sequence which is comprised of short pulses separated by µs off-time intervals. Improved acoustic cavitation distribution was based on the hypothesis that microbubbles can freely move during the pulse off-times. Flowing SonoVue® microbubbles (flow velocity: 10 mm/s) were sonicated with a 0.5 MHz focused ultrasound transducer using RaSP sequences (peak-rarefactional pressures: 146-900 kPa, pulse repetition frequency: 1.25 kHz, and pulse lengths: 5-50 cycles). The distribution of cavitation activity was evaluated using passive acoustic mapping. RaSP sequences generated uniform distributions within the focus in contrast to long pulses (50 000 cycles) that produced non-uniform distributions. Fast microbubble destruction occurred for long pulses, whereas microbubble activity was sustained for longer durations for shorter pulses. High-speed microscopy revealed increased mobility in the direction of flow during RaSP sonication. In conclusion, RaSP sequences produced spatiotemporally uniform cavitation distributions and could result in efficient therapies by spreading cavitation throughout the treatment area.

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles.

Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 µs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.

Using implementation intentions prompts to enhance influenza vaccination rates.

We evaluate the results of a field experiment designed to measure the effect of prompts to form implementation intentions on realized behavioral outcomes. The outcome of interest is influenza vaccination receipt at free on-site clinics offered by a large firm to its employees. All employees eligible for study participation received reminder mailings that listed the times and locations of the relevant vaccination clinics. Mailings to employees randomly assigned to the treatment conditions additionally included a prompt to write down either (i) the date the employee planned to be vaccinated or (ii) the date and time the employee planned to be vaccinated. Vaccination rates increased when these implementation intentions prompts were included in the mailing. The vaccination rate among control condition employees was 33.1%. Employees who received the prompt to write down just a date had a vaccination rate 1.5 percentage points higher than the control group, a difference that is not statistically significant. Employees who received the more specific prompt to write down both a date and a time had a 4.2 percentage point higher vaccination rate, a difference that is both statistically significant and of meaningful magnitude.

What Makes Annuitization More Appealing?

We conduct and analyze two large surveys of hypothetical annuitization choices. We find that allowing individuals to annuitize a fraction of their wealth increases annuitization relative to a situation where annuitization is an "all or nothing" decision. Very few respondents choose declining real payout streams over flat or increasing real payout streams of equivalent expected present value. Highlighting the effects of inflation increases demand for cost of living adjustments. Frames that highlight flexibility, control, and investment significantly reduce annuitization. A majority of respondents prefer to receive an extra "bonus" payment during one month of the year that is funded by slightly lower payments in the remaining months. Concerns about later-life income, spending flexibility, and counterparty risk are the most important self-reported motives that influence the annuitization decision.

An Ultrasound Array of Emitter-Receiver Stacks for Microbubble-Based Therapy.

Most therapeutic ultrasound devices place emitters and receivers in separate locations, so that the long therapeutic pulses (>1 ms) can be emitted while receivers monitor the procedure. However, with such placement, emitters and receivers are competing for the same space, producing a trade-off between emission efficiency and reception sensitivity. Taking advantage of recent studies demonstrating that short-pulse ultrasound can be used therapeutically, we aimed to develop a device that overcomes such trade-offs. The array was composed of emitter-receiver stacks, which enabled both emission and reception from the same location. Each element was made of a lead zirconate titanate (PZT)-polyvinylidene fluoride (PVDF) stack. The PZT (frequency: 500 kHz, diameter: 16 mm) was used for emission and the PVDF (thickness: 28 µm, diameter: 16 mm) for broadband reception. 32 elements were assembled in a 3D-printed dome-shaped frame (focal length: 150 mm; [Formula: see text]-number: 1) and was tested in free-field and through an ex-vivo human skull. In free-field, the array had a 4.5 × 4.5 × 32 mm focus and produced a peak-negative pressure (PNP) of 2.12 MPa at its geometric center. The electronic steering range was ±15 mm laterally and larger than ±15 mm axially. Through the skull, the array produced a PNP of 0.63 MPa. The PVDF elements were able to localize broadband microbubble emissions across the skull. We built the first multi-element array for short-pulse and microbubble-based therapeutic applications. Stacked arrays overcome traditional trade-offs between the transmission and reception quality and have the potential to create a step change in treatment safety and efficacy.

What Goes Up Must Come Down? Experimental Evidence on Intuitive Forecasting.

Do laboratory subjects correctly perceive the dynamics of a mean-reverting time series? In our experiment, subjects receive historical data and make forecasts at different horizons. The time series process that we use features short-run momentum and long-run partial mean reversion. Half of the subjects see a version of this process in which the momentum and partial mean reversion unfold over 10 periods ('fast'), while the other subjects see a version with dynamics that unfold over 50 periods ('slow'). Typical subjects recognize most of the mean reversion of the fast process and none of the mean reversion of the slow process.