Contrast-enhanced ultrasound in pediatric echocardiography.

The safety and benefits of cardiac contrast-enhanced ultrasound (CEUS) have been demonstrated in children and adolescents for a variety of clinical indications, including congenital heart disease. Cardiac CEUS is performed with US and the intravenous administration of ultrasound contrast agents (UCAs). It improves transthoracic echocardiography, which can be challenging in children and adults with acoustic window limitations (e.g., from obesity) and alterations in chest wall and cardiac geometry (e.g., from prior surgical procedures). Cardiac CEUS is also used to evaluate ischemia in the follow-up of congenital and acquired heart disease. In 2019, the United States Food and Drug Administration (FDA) approved a UCA for pediatric echocardiography. This article focuses on the clinical applications of UCAs in pediatric and adult echocardiography, outlining its diagnostic value, safety and potential for future applications.

Expecting the unexpected: Echo laboratory preparedness in the time of COVID-19.

COVID-19 poses a unique set of challenges to the healthcare system due to its rapid spread, intensive resource utilization, and relatively high morbidity and mortality. Healthcare workers are at especially high risk of exposure given the viruses spread through close contact. Reported cardiac complications of COVID-19 include myocarditis, acute coronary syndrome, cardiomyopathy, pericardial effusion, arrhythmia, and shock. Thus, echocardiography is integral in the timely diagnosis and clinical management of COVID-19 patients. Rush University Medical Center has been at the forefront of the COVID-19 response in Illinois with high numbers of cases reported in Chicago and surrounding areas. The echocardiography laboratory at Rush University Medical Center (RUMC) proactively took numerous steps to balance the imaging needs of a busy, nearly 700-bed academic medical center while maintaining safety.

Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes.

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.

60 Years of the 3Rs symposium: Lessons learned and the road ahead.

When The Principles of Humane Experimental Technique was published in 1959, authors William Russell and Rex Burch had a modest goal: to make researchers think about what they were doing in the laboratory - and to do it more humanely. Sixty years later, their groundbreaking book was celebrated for inspiring a revolution in science and launching a new field: The 3Rs of alternatives to animal experimentation. On November 22, 2019, some pioneering and leading scientists and researchers in the field gathered at the Johns Hopkins Bloomberg School of Public Health in Bal-timore for the 60 Years of the 3Rs Symposium: Lessons Learned and the Road Ahead. The event was sponsored by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the Foundation for Chemistry Research and Initiatives, the Alternative Research & Development Foundation (ARDF), the American Cleaning Institute (ACI), the International Fragrance Association (IFRA), the Institute for In Vitro Sciences (IIVS), John "Jack" R. Fowle III, and the Society of Toxicology (SoT). Fourteen pres-entations shared the history behind the groundbreaking publication, international efforts to achieve its aims, stumbling blocks to progress, as well as remarkable achievements. The day was a tribute to Russell and Burch, and a testament to what is possible when people from many walks of life - science, government, and industry - work toward a common goal.

William Russell and Rex Burch published their book The Principles of Humane Experimental Technique in 1959. The book encouraged researchers to replace animal experiments where it was possible, to refine experiments with animals in order to reduce their suffering, and to reduce the number of animals that had to be used for experiments to the minimum. Sixty years later, a group of pioneering and leading scientists and researchers in the field gathered to share how the publi­cation came about and how the vision inspired international collaborations and successes on many different levels including new laws. The paper includes an overview of important milestones in the history of alternatives to animal experimentation.

The 35th annual advances in contrast ultrasound international bubble conference, Chicago 2021: synopsis and take-home messages.

The 35th Annual Advances in Contrast Ultrasound International Bubble Conference convened in Chicago, IL, USA, on September 30th to October 1st, 2021. It featured a range of novel research from animal studies to clinical applications in multiple organ systems, demonstrating the utility of contrast enhanced ultrasound (CEUS). A multidisciplinary group of experts on the use of CEUS, including physicians, basic scientists, engineers, and industry partners, convened to discuss cutting edge research and new applications for CEUS. The conference demonstrated the wide range of CEUS uses and potential uses, including cardiac risk stratification, sonothrombolysis, peripheral vascular reperfusion, liver and renal mass evaluation, lymphatic evaluation, sentinel node identification, and CEUS use in pediatrics. The International Contrast Ultrasound Society uses this information to continue advocating for the safe and appropriate use of CEUS.

Echocardiographic predictors of mortality and morbidity in COVID-19 disease using focused cardiovascular ultrasound.

BACKGROUND: Focused transthoracic echocardiography (fTTE) has emerged as a critical diagnostic tool during the COVID-19 pandemic, allowing for efficient cardiac imaging while minimizing staff exposure. The utility of fTTE in predicting clinical outcomes in COVID-19 remains under investigation. METHODS: We conducted a retrospective study of 2,266 hospitalized patients at Rush University Medical Center with COVID-19 infection between March and November 2020 who received a fTTE. fTTE data were analyzed for association with primary adverse outcomes (60-day mortality) and with secondary adverse outcomes (need for renal replacement therapy, need for invasive ventilation, shock, and venous thromboembolism). RESULTS: Of the 427 hospitalized patients who had a fTTE performed (mean 62 years, 43% female), 109 (26%) had died by 60 days. Among patients with an available fTTE measurement, right ventricular (RV) dilation was noted in 34% (106/309), 43% (166/386) had RV dysfunction, and 17% (72/421) had left ventricular (LV) dysfunction. In multivariable models accounting for fTTE data, RV dilation was significantly associated with 60-day mortality (OR 1.93 [CI 1.13-3.3], p = 0.016). LV dysfunction was not significantly associated with 60-day mortality (OR 0.95 [CI: 0.51-1.78], p = 0.87). CONCLUSIONS: Abnormalities in RV echocardiographic parameters are adverse prognosticators in COVID-19 disease. Patients with RV dilation experienced double the risk for 60-day mortality due to COVID-19. To our knowledge, this is the largest study to date that highlights the adverse prognostic implications of RV dilation as determined through fTTE in hospitalized COVID-19 patients.

Benzocaine-related methaemoglobinemia after transoesophageal echocardiography: a rare, life-threatening complication.

Methaemoglobinemia is an uncommon but potentially life-threatening complication of topical benzocaine use that requires prompt identification in patients who undergo transoesophageal echocardiography (TEE). In this case, a 21-year-old patient who had sustained a stroke with residual right-sided weakness a few days prior to presentation underwent TEE to evaluate for intracardiac shunt. She required intubation as part of her poststroke care with some instrumentation to the posterior oropharynx. Shortly after TEE, the patient experienced sudden onset respiratory distress and hypoxia that did not improve with supplemental oxygen. Chest X-ray did not reveal any acute cardiopulmonary process. Arterial blood gas co-oximetry panel with methaemoglobin level confirmed the diagnosis of methaemoglobinemia. The patient promptly received methylene blue, recovered quickly and did not have any additional episodes of hypoxia.

The 34th Annual Advances in Contrast Ultrasound International Bubble Conference, Chicago 2019: synopsis and take-home messages.

The 34th annual Advances in Contrast Ultrasound (ACU) International Bubble Conference convened in Chicago, IL, USA, on September 5-6, 2019 to feature new directions of research, preclinical and first-in-man clinical trials, and novel clinical applications highlighting the diversity and utility of contrast enhanced ultrasound (CEUS). An expert group comprising clinicians, engineers, basic scientists, government officials, attorneys, and industry partners convened to collaborate on cutting-edge ultrasound enhancement technology. Utilizing this information, the International Contrast Ultrasound Society (ICUS) continues to have cause to advocate for the safe and appropriate use of CEUS with expanding indications and applications.

Hypertension in older adults: Assessment, management, and challenges.

Hypertension in older adults is related to adverse cardiovascular outcomes, such as heart failure, stroke, myocardial infarction, and death. The global burden of hypertension is increasing due to an aging population and increasing prevalence of obesity, and is estimated to affect one third of the world's population by 2025. Adverse outcomes in older adults are compounded by mechanical hemodynamic changes, arterial stiffness, neurohormonal and autonomic dysregulation, and declining renal function. This review highlights the current evidence and summarizes recent guidelines on hypertension, pertaining to older adults. Management strategies for hypertension in older adults must consider the degree of frailty, increasingly complex medical comorbidities, and psycho-social factors, and must therefore be individualized. Non-pharmacological lifestyle interventions should be encouraged to mitigate the risk of developing hypertension, and as an adjunctive therapy to reduce the need for medications. Pharmacological therapy with diuretics, renin-angiotensin system blockers, and calcium channel blockers have all shown benefit on cardiovascular outcomes in older patients. Given the economic and public health burden of hypertension in the United States and globally, it is critical to address lifestyle modifications in younger generations to prevent hypertension with age.

The role of an academic centre.

On FRAME's 40th anniversary, I had the opportunity to examine FRAME and CAAT's missions as closely linked to those of their universities. The roles of education, research and service are key, both to the universities and to our two centres. By examining the current programmes, and identifying the needs of the future, the research activities, policy studies and training, it becomes clear that the Three Rs of alternatives contribute significantly to our respective universities' missions.

Small Cell Lung Cancer Invading the Left Atrium With Subsequent Malignant Embolic Stroke: A Case Report and Review of Literature.

Cardiac tumors are uncommon, and the vast majority of them are metastases from extracardiac sources. Metastatic spread to the heart causes symptoms by mechanical obstruction of circulation, direct myocardial invasion, or distal embolization. We herein report a case of a 58-year-old male who presented to the hospital with multilobar intracranial embolic infarcts who was found to have small cell lung cancer (SCLC) with invasion of the left atrium and pulmonary artery resulting in malignant embolic stroke. Cerebral tumor thromboembolism from SCLC is extremely rare. This case demonstrates the thromboembolic risk associated with metastatic endoluminal cardiac tumors.

Meeting report: alternatives for developmental neurotoxicity testing.

Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13-15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children's health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders.

Workgroup report: incorporating in vitro alternative methods for developmental neurotoxicity into international hazard and risk assessment strategies.

This is the report of the first workshop on Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity (DNT) Testing into International Hazard and Risk Assessment Strategies, held in Ispra, Italy, on 19-21 April 2005. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and jointly organized by ECVAM, the European Chemical Industry Council, and the Johns Hopkins University Center for Alternatives to Animal Testing. The primary aim of the workshop was to identify and catalog potential methods that could be used to assess how data from in vitro alternative methods could help to predict and identify DNT hazards. Working groups focused on two different aspects: a) details on the science available in the field of DNT, including discussions on the models available to capture the critical DNT mechanisms and processes, and b) policy and strategy aspects to assess the integration of alternative methods in a regulatory framework. This report summarizes these discussions and details the recommendations and priorities for future work.

Meeting report: hazard assessment for nanoparticles--report from an interdisciplinary workshop.

In this report we present the findings from a nanotoxicology workshop held 6-7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders.

Pulmonary hypertension: diagnosis, imaging techniques, and novel therapies.

Pulmonary hypertension (PH), defined as the elevation of mean pulmonary arterial pressure (mPAP) above 25 mmHg, has numerous causes, which the World Health Organization (WHO) has divided into five distinct categories based upon the underlying mechanism of action. This review will explore the pathophysiology, diagnostic testing, and treatment of PH. Identification of PH depends on a strong clinical suspicion, a detailed history, and a thorough physical exam. We review the evidence supporting experimental and clinical laboratory parameters for diagnosis and monitoring of PH. Transthoracic echocardiogram (TTE) is the initial screening test of choice. This review will detail specific echocardiographic techniques for the assessment and classification of PH. Furthermore, the importance of advanced imaging, including computed tomography (CT) and magnetic resonance imagining (MRI) is explored. New developments in pharmacology, percutaneous intervention, and surgical approaches are summarized. Finally, we will address the tools available to predict morbidity and mortality.

From in vivo to in vitro: The medical device testing paradigm shift.

Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals in research, there is a growing recognition that in vitro testing of medical devices can be more effective, both in terms of cost and time, and also more reliable than in vivo testing. Although the technological landscape has evolved rapidly in support of these concepts, regulatory acceptance of alternative testing methods has not kept pace. Despite the acceptance by regulators of some in vitro tests (cytotoxicity, gene toxicity, and some hemocompatibility assays), many toxicity tests still rely on animals (irritation, sensitization, acute toxicity, reproductive/developmental toxicity), even where other industrial sectors have already abandoned them. Bringing about change will require a paradigm shift in current approaches to testing - and a concerted effort to generate better data on risks to human health from exposure to leachable chemicals from medical devices, and to boost confidence in the use of alternative methods to test devices. To help advance these ideas, stir debate about best practices, and coalesce around a roadmap forward, the JHU-Center for Alternatives to Animal Testing (CAAT) hosted a symposium believed to be the first gathering dedicated to the topic of in vitro testing of medical devices. Industry representatives, academics, and regulators in attendance presented evidence to support the unique strengths and challenges associated with the approaches currently in use as well as new methods under development, and drew next steps to push the field forward from their presentations and discussion.