Publications

Compared to other major medical imaging modalities such as X-ray, computed tomography (CT), and magnetic resonance imaging, medical ultrasound (US) has unique attributes that make it the preferred modality for many clinical applications. In particular, US is nonionizing, portable, and provides real-time imaging, with adequate spatial and depth resolution to visualize tissue dynamics. The ability to measure Doppler information is also important, particularly for measuring blood flows. The small size of US transducers is a key attribute for intravascular applications. In addition, accessibility has been increased with the use of portable US, which continues to move toward a smaller footprint and lower cost. Nowadays, some US probes can even be directly connected to a phone or tablet. On the other hand, US also has unique challenges, particularly in that image quality is highly dependent on the operator’s skill in acquiring images based on the proper position, orientation, and probe pressure. Additional challenges that further require operator skill include the presence of noise, artifacts, limited field of view, difficulty in imaging structures behind bone and air, and device variability across manufacturers. Sonographers become highly proficient through extensive training and long experience, but high intra- and interobserver variability remains. This skill dependence has limited the wider use of US by healthcare providers who are not US imaging specialists. Recent advances in machine learning (ML) have been increasingly applied to medical US (Brattain, Telfer, Dhyani, Grajo, & Samir, 2018), with a goal of reducing intra- and interobserver variability as well as interpretation time. As progress toward these goals is made, US use by nonspecialists is expected to proliferate, including nurses at the bedside or medics in the field. The acceleration in ML applications for medical US can be seen from the increasing number of publications (Fig. 8.1) and Food and Drug Administration (FDA) approvals (Table 8.1) in the past few years. Fig. 8.1 shows that cardiovascular applications (spanning the heart, brain and vessels) have received the most attention, compared to other organs. Table 8.1 shows that pace of US FDA-cleared artificial intelligence (AI) products that combine AI and ultrasound is accelerating. Of note, many of the products have been approved over the last couple of years. Companies such as Butterfly Network (Guilford, CT) have also demonstrated AI-driven applications for portable ultrasound and more FDA clearances are expected to be published. The goals of this chapter are to highlight the recent progress, as well as the current challenges and future opportunities. Specifically, this chapter addresses topics such as the following: (1) what is the current state of machine learning for medical US application, both in research and commercially; (2) what applications are receiving the most attention and have performance improvements been quantified; (3) how do ML solutions fit in an overall workflow; and (4) what open-source datasets are available for the broader community to contribute to progress in this field. The focus is on cardiovascular applications (Section Cardiovascular/echocardiography), but common themes and differences for other applications for medical US are also summarized (Section Breast, liver, and thyroid ultrasound). A discussion is offered in Discussion and outlook section.

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki Disease Shock Syndrome (KDSS). The observed symptoms for MIS-C and KD are consistent with Mast Cell Activation Syndrome (MCAS) characterized by inflammatory molecules released from activated mast cells. Based on the associations of KD with multiple viral and bacterial pathogens, we put forward the hypothesis that KD and MIS-C result from antibody activation of mast cells by Fc receptor-bound pathogen antibodies causing a hyperinflammatory response upon second pathogen exposure. Within this hypothesis, MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2. We extend the mast cell hypothesis that increased histamine levels are inducing contraction of effector cells with impeded blood flow through cardiac capillaries. In some patients, pressure from impeded blood flow, within cardiac capillaries, may result in increased coronary artery blood pressure leading to aneurysms, a well-known complication in KD.

Background: In 80% of patients, COVID-19 presents as mild disease. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immunosuppression. Methods: All major SARS-CoV-2 proteins were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non-neutralizing antibodies to variable S domains may enable an alternative infection pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV SARS-CoV-1 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) demonstrate vaccination-induced antibody-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection; pan-T depletion is present in severe COVID-19 disease and may be accelerated by APC infection. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.