The histotripsy spectrum: differences and similarities in techniques and instrumentation.

Since its inception about two decades ago, histotripsy - a non-thermal mechanical tissue ablation technique - has evolved into a spectrum of methods, each with distinct potentiating physical mechanisms: intrinsic threshold histotripsy, shock-scattering histotripsy, hybrid histotripsy, and boiling histotripsy. All methods utilize short, high-amplitude pulses of focused ultrasound delivered at a low duty cycle, and all involve excitation of violent bubble activity and acoustic streaming at the focus to fractionate tissue down to the subcellular level. The main differences are in pulse duration, which spans microseconds to milliseconds, and ultrasound waveform shape and corresponding peak acoustic pressures required to achieve the desired type of bubble activity. In addition, most types of histotripsy rely on the presence of high-amplitude shocks that develop in the pressure profile at the focus due to nonlinear propagation effects. Those requirements, in turn, dictate aspects of the instrument design, both in terms of driving electronics, transducer dimensions and intensity limitations at surface, shape (primarily, the F-number) and frequency. The combination of the optimized instrumentation and the bio-effects from bubble activity and streaming on different tissues, lead to target clinical applications for each histotripsy method. Here, the differences and similarities in the physical mechanisms and resulting bioeffects of each method are reviewed and tied to optimal instrumentation and clinical applications.

Pilot Investigation of SARS-CoV-2 Secondary Transmission in Kindergarten Through Grade 12 Schools Implementing Mitigation Strategies - St. Louis County and City of Springfield, Missouri, December 2020.

Many kindergarten through grade 12 (K-12) schools offering in-person learning have adopted strategies to limit the spread of SARS-CoV-2, the virus that causes COVID-19 (1). These measures include mandating use of face masks, physical distancing in classrooms, increasing ventilation with outdoor air, identification of close contacts,* and following CDC isolation and quarantine guidance† (2). A 2-week pilot investigation was conducted to investigate occurrences of SARS-CoV-2 secondary transmission in K-12 schools in the city of Springfield, Missouri, and in St. Louis County, Missouri, during December 7-18, 2020. Schools in both locations implemented COVID-19 mitigation strategies; however, Springfield implemented a modified quarantine policy permitting student close contacts aged ≤18 years who had school-associated contact with a person with COVID-19 and met masking requirements during their exposure to continue in-person learning.§ Participating students, teachers, and staff members with COVID-19 (37) from 22 schools and their school-based close contacts (contacts) (156) were interviewed, and contacts were offered SARS-CoV-2 testing. Among 102 school-based contacts who received testing, two (2%) had positive test results indicating probable school-based SARS-CoV-2 secondary transmission. Both contacts were in Springfield and did not meet criteria to participate in the modified quarantine. In Springfield, 42 student contacts were permitted to continue in-person learning under the modified quarantine; among the 30 who were interviewed, 21 were tested, and none received a positive test result. Despite high community transmission, SARS-CoV-2 transmission in schools implementing COVID-19 mitigation strategies was lower than that in the community. Until additional data are available, K-12 schools should continue implementing CDC-recommended mitigation measures (2) and follow CDC isolation and quarantine guidance to minimize secondary transmission in schools offering in-person learning.

Quantitative blood flow evaluation of vasodilation-stress compared with dobutamine-stress in patients with end-stage liver disease using 82Rb PET/CT.

BACKGROUND: Our aim was to determine if end-stage liver disease (ESLD) is associated with an attenuated response to vasodilator-stress or dobutamine-stress using 82Rb-PET MPI with blood flow quantification. METHODS AND RESULTS: Pre-liver transplant patients who had a normal dipyridamole-stress (n = 27) or dobutamine-stress (n = 26) 82Rb PET/CT MPI study with no identifiable coronary artery calcium were identified retrospectively and compared to a prospectively identified low-risk of liver disease dipyridamole-stress control group (n = 20). The dipyridamole-stress liver disease group had a lower myocardial flow reserve (MFR) (1.89 ± 0.79) than the control group (2.79 ± 0.96, P < .05). The dobutamine-stress group had a higher MFR than both other groups (3.69 ± 1.49, P < .05). A moderate negative correlation between MELD score and MFR was demonstrated for the dipyridamole-stress liver disease group (r = - 0.473, P < .05). This correlation was not observed for the dobutamine-stress liver disease group (r = - 0.253, P = .21). The liver failure group as a whole (n = 53) had a higher resting myocardial blood flow (0.97 ± 0.33 mL/min/g) than the control group (0.82 ± 0.26, P < .05). CONCLUSION: Dipyridamole demonstrates an attenuated vasodilatory response in ESLD patients compared to a non-ESLD control group related to higher resting blood flow and comparatively reduced stress blood flow. Dobutamine does not demonstrate this effect implying it may be the preferred pharmacologic MPI stress agent for ESLD patients.

Towards acoustic particle velocity sensors in air using entrained balloons: Measurements and modeling.

In this article, the feasibility of using balloons for the measurement of acoustic particle velocity in air is investigated by exploring the behavior of an elastic balloon in air as it vibrates in response to an incident acoustic wave. This is motivated by the frequent use of neutrally buoyant spheres as underwater inertial particle velocity sensors. The results of experiments performed in an anechoic chamber are presented, in which a pair of laser Doppler vibrometers simultaneously captured the velocities of the front and back surfaces of a Mylar balloon in an acoustic field. From phase measurements, the motion is described in terms of contributions from odd-order vibration modes (including bulk translation) and even-order vibration modes. The measured entrainment factors for the balloon are seen to be in good agreement with a physical model based on the scattering from an entrained rigid sphere. This demonstrates the feasibility of using entrained balloons for direct measurement of acoustic particle velocity in air.

The Opioid Crisis in Missouri: A Call to Action for Physicians, Legislators, and Society.

Opioid overdose deaths in the United States increased sharply over the last decade leading the President to declare a national emergency. The neurobiology of opioid addiction is explored in conjunction with the historical events preceding the current epidemic. A patient-centric perspective is provided along with rationale for contemporary Medical Assisted Therapy (MAT) options to safely reduce overdose deaths and other preventable consequences of prescription misuse and heroin abuse. A multidisciplinary medical provider approach is essential, in addition to legislative efforts to reduce current regulatory burdens that reduce access to MAT in many settings. This review introduces a new Missouri Medicine series intended to explore key concepts to simultaneously reduce opioid prescribing, while effectively managing acute and chronic pain across complex healthcare settings.

Thévenin acoustics.

Thévenin's theorem is commonly used in the analysis of acoustic transducers to provide a simplified representation of a transducer or its environment. The method may be extended to the analyses of other acoustic systems, without limitation to systems that have been reduced to analogous circuit models, and is particularly convenient in the analysis of acoustic scattering when the scattering object is mobile. In this paper, the method is illustrated through an alternative derivation of the well-known "mass law" for transmission through a partition, and is also applied to the case of acoustic scattering from a rigid, mobile cylinder of arbitrary size in an ideal plane progressive wave. Differences between the conventional solution approach for such problems and the Thévenin-inspired method are discussed, along with the potential benefits of taking such an approach for the simplification of other problems in physical acoustics.

A shirt containing multistage phase change material and active cooling components was associated with increased exercise capacity in a hot, humid environment.

Recent advances in clothing design include the incorporation of phase change materials (PCM) and other active cooling components (ACC) to provide better body heat dissipation. The purpose of this study was to determine the effect of wearing a shirt containing multistage PCM/ACC on exercise capacity at low (5.0), moderate-high (7.5) and extreme (9.0) levels of the physiological strain index (PSI). Fourteen individuals tested two shirts (control vs. cooling) during 45-min of interval running in a hot, humid (35 ± 1 °C; 55 ± 6% RH) environment. The cooling shirt resulted in an 8% improvement in exercise capacity at a PSI of 7.5 (p < 0.05). The observed increase in exercise capacity would likely translate to a significant improvement in exercise performance. More research is needed to determine a best practice approach for the use of cooling clothing as a counter to exercise-induced heat exposure. Practitioner Summary: In this report, we demonstrate that when forced to exercise in a hot, humid environment, an individual's exercise capacity may increase by as much as 8% when wearing a shirt composed of multistage phase change material and active cooling components.

Image-based cytometry reveals three distinct subsets of activated granulocytes based on phagocytosis and oxidative burst.

Granulocytes play a key role in innate immunity and the most common functional assays are phagocytosis and oxidative burst. The purpose of this technical note is to use image-based flow cytometry to divide activated granulocytes into unique subsets based on their degree of phagocytosis and oxidative burst in response to different experimental incubations. Prior to the experiments, all reagents were titered to determine the lowest dose that resulted in an acceptable signal to noise ratio. Heparinized, whole blood (100 µl) was mixed with one of two bioparticles (E. coli and S. aureus) and DHE (10 µg/ml) and incubated for 5, 10, 20, 40, 60, 80, 100, 120, and 140 min in a 37°C water bath. An additional tube kept on ice was used as a negative control. All subsequent processing steps were completed on ice in the dark to minimize additional activation of cells. After the 37°C incubation, N-ethylmaleimide (15 mM) was added to halt phagocytosis, preventing the uptake of additional microparticles. Suspensions were labeled with CD66b-APC and CD45-APCeFluor780 for 60 min and a fix/lyse solution was added. Prior to acquisition, 7AAD was added to stain nuclear DNA. A minimum of 5,000 granulocyte (CD66b+) events were acquired using a Millipore-Amnis FlowSight equipped with blue (488 nm, 60 mW), red (642 nm, 100 mW), and side scatter (785 nm, 12 mW) lasers. Samples were compensated and analyzed using Amnis IDEAS software (v.5.0.983.0). Image-based analysis allowed us to divide activated granulocytes into three distinct subsets, whose relative abundance changed as a function of both bioparticle type and incubation length. The method described in this technical note represents a potential novel adaptation to common methods of assessing granulocyte function. More research is needed to test and validate our image-based method in clinical conditions that impair granulocyte function.

Dual-Mode 1-D Linear Ultrasound Array for Image-Guided Drug Delivery Enhancement Without Ultrasound Contrast Agents.

Pulsed high-intensity focused ultrasound (pHIFU) uses nonlinearly distorted millisecond-long ultrasound pulses of moderate intensity to induce inertial cavitation in tissue without administration of contrast agents. The resulting mechanical disruption permeabilizes the tissue and enhances the diffusion of systemically administered drugs. This is especially beneficial for tissues with poor perfusion such as pancreatic tumors. Here, we characterize the performance of a dual-mode ultrasound array designed for image-guided pHIFU therapies in producing inertial cavitation and ultrasound imaging. The 64-element linear array (1.071 MHz, an aperture of 14.8×51.2 mm, and a pitch of 0.8 mm) with an elevational focal length of 50 mm was driven by the Verasonics V-1 ultrasound system with extended burst option. The attainable focal pressures and electronic steering range in linear and nonlinear operating regimes (relevant to pHIFU treatments) were characterized through hydrophone measurements, acoustic holography, and numerical simulations. The steering range at ±10% from the nominal focal pressure was found to be ±6 mm axially and ±11 mm azimuthally. Focal waveforms with shock fronts of up to 45 MPa and peak negative pressures up to 9 MPa were achieved at focusing distances of 38-75 mm from the array. Cavitation behaviors induced by isolated 1-ms pHIFU pulses in optically transparent agarose gel phantoms were observed by high-speed photography across a range of excitation amplitudes and focal distances. For all focusing configurations, the appearance of sparse, stationary cavitation bubbles occurred at the same P- threshold of 2 MPa. As the output level increased, a qualitative change in cavitation behavior occurred, to pairs and sets of proliferating bubbles. The pressure P- at which this transition was observed corresponded to substantial nonlinear distortion and shock formation in the focal region and was thus dependent on the focal distance of the beam ranging within 3-4 MPa for azimuthal F -numbers of 0.74-1.5. The array was capable of B-mode imaging at 1.5 MHz of centimeter-sized targets in phantoms and in vivo pig tissues at depths of 3-7 cm, relevant to pHIFU applications in abdominal targets.

Multidisciplinary Team Approach to Addressing Child Sexual Abuse at Nemours Children's Health, Delaware.

In 2019, 4.4 million referrals of maltreatment were made that affected approximately 7.9 million children. It was estimated that 9.3% of the referrals were related to child sexual abuse (CSA). To prevent negative psychosocial and health-related outcomes associated with CSA, CSA survivors often participate in a forensic interview, medical and behavioral health assessments, and behavioral health treatment while navigating other life disruptions or changing family dynamics precipitated by the CSA (e.g., change in custody or household, lack of contact with preparator, etc.). The assessment and treatment of pediatric survivors of CSA by multidisciplinary teams (MDT) can enhance families' engagement and participation with the legal process, medical evaluation, and behavioral health services. This paper explores the Nemours Children's Health, Delaware MDT's approach to assessing and treating CSA, explores benefits and barriers associated with the current model, and discusses public health implications of a MDT approach to addressing CSA.

Drug-induced acute pancreatitis in a cohort of 328 patients. A single-centre experience from Australia.

CONTEXT: Acute pancreatitis is associated with risk of morbidity and even mortality. Routine prescription drugs have been linked to the causation of acute pancreatitis. OBJECTIVE: To determine the incidence, presentation, course and outcome of drug-induced acute pancreatitis amongst patients admitted to a public hospital. DESIGN/SETTING: A retrospective analysis of patients presenting with acute pancreatitis to the Modbury Hospital, South Australia from January 2006 to April 2011. MAIN OUTCOME MEASURE: Each admission was reviewed within the electronic database for patient details as well as to determine the aetiological factor. In patients with drug-induced acute pancreatitis, the WHO Probability Scale was used to evaluate causality relationship. RESULTS: Three-hundreds and 28 patients were treated for acute pancreatitis during the study period. Biliary and alcohol-induced acute pancreatitis accounted for 80.8% of cases. Eleven patients (2 male and 9 female patients; median age: 59 years) were diagnosed with drug-induced acute pancreatitis. These included 5 cases of codeine-, 2 cases of azathioprine-, and 1 case each of chlorothiazide-, valproic acid-, oestradiol- and simvastatin-induced acute pancreatitis. Nine patients had a mild disease while 2 patients had severe acute pancreatitis with a median hospital stay of 4 days. Withdrawal of the drug resulted in cessation of the attacks in all patients over a median follow-up of 24 months. CONCLUSIONS: Routine prescription drugs, as an aetiological factor, accounted for 3.4% of cases of acute pancreatitis. The disease appeared to be more common in middle-aged women. It is likely that the overall incidence of this entity is under-reported owing to the stringent criteria needed to conclusively determine a causal relationship.

Marked improvement of heart failure upon adequate titration of continuous positive airway pressure in a patient with obstructive sleep apnea.

Sleep disordered breathing (SDB) is frequently present in heart failure (HF), and it may take the form of obstructive (OSA) and central (CSA) sleep apnea. The use of continuous positive airway pressure (CPAP) in patients with OSA and HF is associated with an improved neuroendocrine profile and cardiac function. The degree of upper airway obstruction and the airway closing pressure (and the PAP pressure used to relieve it) may all be highly variable in a setting of uncontrolled HF, mostly due to variable airway oedema. We present a case of a man with HF whose cardiac symptoms radically improved after adequate treatment of his OSA with an auto-adjusting PAP device.

Seroprevalence of Antibodies to SARS-CoV-2 in 10 Sites in the United States, March 23-May 12, 2020.

IMPORTANCE: Reported cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely underestimate the prevalence of infection in affected communities. Large-scale seroprevalence studies provide better estimates of the proportion of the population previously infected. OBJECTIVE: To estimate prevalence of SARS-CoV-2 antibodies in convenience samples from several geographic sites in the US. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study performed serologic testing on a convenience sample of residual sera obtained from persons of all ages. The serum was collected from March 23 through May 12, 2020, for routine clinical testing by 2 commercial laboratory companies. Sites of collection were San Francisco Bay area, California; Connecticut; south Florida; Louisiana; Minneapolis-St Paul-St Cloud metro area, Minnesota; Missouri; New York City metro area, New York; Philadelphia metro area, Pennsylvania; Utah; and western Washington State. EXPOSURES: Infection with SARS-CoV-2. MAIN OUTCOMES AND MEASURES: The presence of antibodies to SARS-CoV-2 spike protein was estimated using an enzyme-linked immunosorbent assay, and estimates were standardized to the site populations by age and sex. Estimates were adjusted for test performance characteristics (96.0% sensitivity and 99.3% specificity). The number of infections in each site was estimated by extrapolating seroprevalence to site populations; estimated infections were compared with the number of reported coronavirus disease 2019 (COVID-19) cases as of last specimen collection date. RESULTS: Serum samples were tested from 16 025 persons, 8853 (55.2%) of whom were women; 1205 (7.5%) were 18 years or younger and 5845 (36.2%) were 65 years or older. Most specimens from each site had no evidence of antibodies to SARS-CoV-2. Adjusted estimates of the proportion of persons seroreactive to the SARS-CoV-2 spike protein antibodies ranged from 1.0% in the San Francisco Bay area (collected April 23-27) to 6.9% of persons in New York City (collected March 23-April 1). The estimated number of infections ranged from 6 to 24 times the number of reported cases; for 7 sites (Connecticut, Florida, Louisiana, Missouri, New York City metro area, Utah, and western Washington State), an estimated greater than 10 times more SARS-CoV-2 infections occurred than the number of reported cases. CONCLUSIONS AND RELEVANCE: During March to early May 2020, most persons in 10 diverse geographic sites in the US had not been infected with SARS-CoV-2 virus. The estimated number of infections, however, was much greater than the number of reported cases in all sites. The findings may reflect the number of persons who had mild or no illness or who did not seek medical care or undergo testing but who still may have contributed to ongoing virus transmission in the population.

The Enhancing Secondary Prevention in Coronary Artery Disease trial.

BACKGROUND: Proven efficacious therapies are sometimes underused in patients with chronic cardiac conditions, resulting in suboptimal outcomes. We evaluated whether evidence summaries, which were either unsigned or signed by local opinion leaders, improved the quality of secondary prevention care delivered by primary care physicians of patients with coronary artery disease. METHODS: We performed a randomized trial, clustered at the level of the primary care physician, with 3 study arms: control, unsigned statements or opinion leader statements. The statements were faxed to primary care physicians of adults with coronary artery disease at the time of elective cardiac catheterization. The primary outcome was improvement in statin management (initiation or dose increase) 6 months after catheterization. RESULTS: We enrolled 480 adults from 252 practices. Although statin use was high at baseline (n=316 [66%]), most patients were taking a low dose (mean 32% of the guideline-recommended dose), and their low-density lipoprotein (LDL) cholesterol levels were elevated (mean 3.09 mmol/L). Six months after catheterization, statin management had improved in 79 of 157 patients (50%) in the control arm, 85 of 158 (54%) patients in the unsigned statement group (adjusted odds ratio [OR] 1.18, 95% CI 0.71-1.94, p=0.52) and 99 of 165 (60%) patients in the opinion leader statement group (adjusted OR 1.51, 95% CI 0.94-2.42, p=0.09). The mean fasting LDL cholesterol levels after 6 months were similar in all 3 study arms: 2.35 (standard deviation [SD] 0.86) mmol/L in the control arm compared with 2.24 (SD 0.73) among those in the opinion leader group (p=0.48) and 2.19 (SD 0.68) in the unsigned statement group (p=0.32). INTERPRETATION: Faxed evidence reminders for primary care physicians, even when endorsed by local opinion leaders, were insufficient to optimize the quality of care for adults with coronary artery disease. ClinicalTrials.gov trial register no. NCT00175240.

A Population-Based Study of Adherence to Guideline Recommendations and Appropriate-Use Criteria for Implantable Cardioverter Defibrillators.

Studies evaluating physician adherence to guideline recommendations for implantable cardioverter defibrillator (ICD) therapy are sparse, and none exist for the application of appropriate-use criteria (AUC) in clinical practice. As part of a quality improvement initiative, a review of all ICD procedures was performed from January 1, 2015 to December 31, 2016 in Alberta, Canada, to evaluate the proportion of patients receiving appropriate ICD therapy and to identify reasons for nonadherence. Our device-implant process involves an electrophysiologist or implanting cardiologist evaluation, reminders of ICD eligibility criteria on the device requisition, and peer-review consensus. Implants were classified according to the 2008 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) ICD guidelines, 2013 Canadian Cardiovascular Society (CCS) Cardiac Resynchronization Therapy (CRT) guidelines, and 2013 AUC. There were 1,300 ICD procedures performed, and the mean age was 63.8 ± 12.9 years; 79% were male; the mean ejection fraction was 0.32 ± 0.13, and 69% were for primary prevention. Among all implants, < 1% were discordant with American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) recommendations. Among CRT implants, 10% were inconsistent with Canadian Cardiovascular Society (CCS) recommendations. According to AUC, 92% of implants were appropriate. Reasons for nonadherence to ACC/AHA/HRS recommendations included QRS width < 120 msec (n = 3), LVEF > 0.35 (n = 2) and recent myocardial infarction (MI) (n = 1). The most common reason for nonadherence to AUC was the absence of criteria for classification (n = 57, 4%). In this population-based study, we found that a process of specialist evaluation, eligibility reminders on device forms, and peer-review consensus may improve adherence to guideline recommendations and AUC for ICD therapy.

Efficacy of N-acetylcysteine and hydration versus placebo and hydration in decreasing contrast-induced renal dysfunction in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention.

OBJECTIVE: Contrast-induced renal dysfunction is an iatrogenic complication that occurs more frequently in patients with preexisting renal dysfunction. A prospective, double-blind, randomized, placebo, controlled trial was completed to assess the efficacy of N-acetylcysteine in decreasing the incidence of contrast-induced renal dysfunction in patients with an acute coronary syndrome and renal insufficiency who underwent coronary angiography with or without percutaneous coronary intervention. METHODS: With similar intravenous hydration protocols, 20 patients received N-acetylcysteine (treatment group) and 20 patients received placebo (control group) in a twice per day dosing regimen with one dose before and three doses after contrast media exposure. RESULTS: The two groups were similar at baseline on demographic and clinical characteristics, and preexisting renal insufficiency. Contrast-induced renal dysfunction, defined as an increase in serum creatinine greater than 44 micromol/L (.5 mg/dL) and/or 25% above baseline within 48 hours, occurred in 7.5% of the cohort, with 2.5% in the treatment group, and 5% in the control group, for an absolute difference of 2.5%. There was no difference in serum creatinine or creatinine clearance at 24 hours or at 48 hours between the treatment and control groups. CONCLUSION: These results suggest that this cohort gained no added protection to renal function with the use of N-acetylcysteine.