SWIFT: A deep learning approach to prediction of hypoxemic events in critically-Ill patients using SpO2 waveform prediction.

Hypoxemia is a significant driver of mortality and poor clinical outcomes in conditions such as brain injury and cardiac arrest in critically ill patients, including COVID-19 patients. Given the host of negative clinical outcomes attributed to hypoxemia, identifying patients likely to experience hypoxemia would offer valuable opportunities for early and thus more effective intervention. We present SWIFT (SpO2 Waveform ICU Forecasting Technique), a deep learning model that predicts blood oxygen saturation (SpO2) waveforms 5 and 30 minutes in the future using only prior SpO2 values as inputs. When tested on novel data, SWIFT predicts more than 80% and 60% of hypoxemic events in critically ill and COVID-19 patients, respectively. SWIFT also predicts SpO2 waveforms with average MSE below .0007. SWIFT predicts both occurrence and magnitude of potential hypoxemic events 30 minutes in the future, allowing it to be used to inform clinical interventions, patient triaging, and optimal resource allocation. SWIFT may be used in clinical decision support systems to inform the management of critically ill patients during the COVID-19 pandemic and beyond.

Factors Driving Rapid Adoption of Telemedicine in an Academic Orthopedic Surgery Department.

Introduction: With the COVID-19 epidemic ever-expanding, nonemergent access to health care resources has been reduced to decrease the exposure for patients and health care providers. Alternatives to in-office outpatient medical evaluations are necessary. We aimed to analyze how quickly orthopedic surgery providers at a large academic institution adopted telemedicine, and identify any factors that were associated with earlier or "faster" telemedicine adoption. Methods: We analyzed the telemedicine activity of 39 providers within the Department of Orthopedic Surgery between March 16, 2020, and May 30, 2020, and constructed logistic regression models to identify characteristics with significant association to earlier or faster telemedicine adoption. Results: No significant predictors of percentage of visits conducted via telemedicine were found. However, increased experience and practice at multiple locations was associated with slower telemedicine adoption time, while Professor level academic rank was associated with a faster time to achieving 10% of pre-COVID visit volumes via telemedicine. Higher pre-COVID visit volumes were also significantly associated with faster telemedicine adoption. Demographic factors, including, age, gender, practice locations, academic degrees, pediatric specialty, and use of physician assistants/nurse practitioners, were not found to have significant associations with telemedicine use. Conclusions: These results indicate that telemedicine has an important role to play within academic orthopedic surgery practices, with a wide and diverse range of orthopedic surgery providers choosing to utilize it during the COVID-19 pandemic. Given the rapid expansion and urgency driving the adoption of telemedicine, these results illustrate the importance of considering provider-side characteristics in ensuring that providers are well equipped to utilize telemedicine.

Age and Racial Disparities in Telemedicine Utilization in an Academic Orthopedic Surgery Department.

Introduction: The COVID-19 pandemic has highlighted significant racial and age-related health disparities. In response to pandemic-related restrictions, orthopedic surgery departments have expanded telemedicine use. We analyzed data from a tertiary care institute during the pandemic to understand potential racial and age-based disparities in access to care and telemedicine utilization. Materials and Methods: Data on patient race and age, and numbers of telemedicine visits, in-person office visits, and types of telemedicine were extracted for time periods during and preceding the pandemic. We calculated odds ratios for visit occurrence and type across race and age groups. Results: Patients ages 27-54 were 1.3 (95% confidence interval [CI] 1.1-1.4, p < 0.01) and 1.2 (95% CI 1.0-1.3, p < 0.05) times more likely to be seen than patients <27 during the pandemic, versus the 2019 and 2020 controls. Patients 54-82 were 1.3 (95% CI 1.1-1.5, p < 0.001) times more likely to be seen than patients <27 during the pandemic versus the 2019 control. Patients 27-54, 54-82, and 82+, respectively, were 3.3 (95% CI 2.6-4.2, p < 1e-20), 3.5 (95% CI 2.8-4.4, p < 1e-24), and 1.9 (95% CI 1.1-3.4, p < 0.05) times more likely to be seen by telemedicine than patients <27. Among pandemic telemedicine appointments, Black patients were 1.5 (95% CI 1.2-1.9, p < 1e-3) times more likely to be seen by audio-only telemedicine than White patients, as compared with video telemedicine. Conclusions: Telemedicine access barriers must be reduced to ensure that disparities during the pandemic do not persist.

Genome-wide repeat landscapes in cancer and cell-free DNA.

Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma samples from 1975 patients, including those with lung, breast, colorectal, ovarian, liver, gastric, head and neck, bladder, cervical, thyroid, or prostate cancer. We identified tumor-specific changes in these patients in 1280 repeat element types from the LINE, SINE, LTR, transposable element, and human satellite families. These included changes to known repeats and 820 elements that were not previously known to be altered in human cancer. Repeat elements were enriched in regions of driver genes, and their representation was altered by structural changes and epigenetic states. Machine learning analyses of genome-wide repeat landscapes and fragmentation profiles in cfDNA detected patients with early-stage lung or liver cancer in cross-validated and externally validated cohorts. In addition, these repeat landscapes could be used to noninvasively identify the tissue of origin of tumors. These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer.

DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation.

Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.

Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers.

Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I-IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I-IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

H2Bub1 loss is an early contributor to clear cell ovarian cancer progression.

Epigenetic aberrations, including posttranslational modifications of core histones, are major contributors to cancer. Here, we define the status of histone H2B monoubiquitylation (H2Bub1) in clear cell ovarian carcinoma (CCOC), low-grade serous carcinoma, and endometrioid carcinomas. We report that clear cell carcinomas exhibited profound loss, with nearly all cases showing low or negative H2Bub1 expression. Moreover, we found that H2Bub1 loss occurred in endometriosis and atypical endometriosis, which are established precursors to CCOCs. To examine whether dysregulation of a specific E3 ligase contributes to the loss of H2Bub1, we explored expression of ring finger protein 40 (RNF40), ARID1A, and UBR7 in the same case cohort. Loss of RNF40 was significantly and profoundly correlated with loss of H2Bub1. Using genome-wide DNA methylation profiles of 230 patients with CCOC, we identified hypermethylation of RNF40 in CCOC as a likely mechanism underlying the loss of H2Bub1. Finally, we demonstrated that H2Bub1 depletion promoted cell proliferation and clonogenicity in an endometriosis cell line. Collectively, our results indicate that H2Bub1 plays a tumor-suppressive role in CCOCs and that its loss contributes to disease progression.

Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.

Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.

Detecting Liver Cancer Using Cell-Free DNA Fragmentomes.

Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection. SIGNIFICANCE: There is a great need for accessible and sensitive screening approaches for HCC worldwide. We have developed an approach for examining genome-wide cfDNA fragmentation features to provide a high-performing and cost-effective approach for liver cancer detection. See related commentary Rolfo and Russo, p. 532. This article is highlighted in the In This Issue feature, p. 517.

A natural language processing and deep learning approach to identify child abuse from pediatric electronic medical records.

Child physical abuse is a leading cause of traumatic injury and death in children. In 2017, child abuse was responsible for 1688 fatalities in the United States, of 3.5 million children referred to Child Protection Services and 674,000 substantiated victims. While large referral hospitals maintain teams trained in Child Abuse Pediatrics, smaller community hospitals often do not have such dedicated resources to evaluate patients for potential abuse. Moreover, identification of abuse has a low margin of error, as false positive identifications lead to unwarranted separations, while false negatives allow dangerous situations to continue. This context makes the consistent detection of and response to abuse difficult, particularly given subtle signs in young, non-verbal patients. Here, we describe the development of artificial intelligence algorithms that use unstructured free-text in the electronic medical record-including notes from physicians, nurses, and social workers-to identify children who are suspected victims of physical abuse. Importantly, only the notes from time of first encounter (e.g.: birth, routine visit, sickness) to the last record before child protection team involvement were used. This allowed us to develop an algorithm using only information available prior to referral to the specialized child protection team. The study was performed in a multi-center referral pediatric hospital on patients screened for abuse within five different locations between 2015 and 2019. Of 1123 patients, 867 records were available after data cleaning and processing, and 55% were abuse-positive as determined by a multi-disciplinary team of clinical professionals. These electronic medical records were encoded with three natural language processing (NLP) algorithms-Bag of Words (BOW), Word Embeddings (WE), and Rules-Based (RB)-and used to train multiple neural network architectures. The BOW and WE encodings utilize the full free-text, while RB selects crucial phrases as identified by physicians. The best architecture was selected by average classification accuracy for the best performing model from each train-test split of a cross-validation experiment. Natural language processing coupled with neural networks detected cases of likely child abuse using only information available to clinicians prior to child protection team referral with average accuracy of 0.90±0.02 and average area under the receiver operator characteristic curve (ROC-AUC) 0.93±0.02 for the best performing Bag of Words models. The best performing rules-based models achieved average accuracy of 0.77±0.04 and average ROC-AUC 0.81±0.05, while a Word Embeddings strategy was severely limited by lack of representative embeddings. Importantly, the best performing model had a false positive rate of 8%, as compared to rates of 20% or higher in previously reported studies. This artificial intelligence approach can help screen patients for whom an abuse concern exists and streamline the identification of patients who may benefit from referral to a child protection team. Furthermore, this approach could be applied to develop computer-aided-diagnosis platforms for the challenging and often intractable problem of reliably identifying pediatric patients suffering from physical abuse.

SWIFT: A Deep Learning Approach to Prediction of Hypoxemic Events in Critically-Ill Patients Using SpO 2 Waveform Prediction.

Hypoxemia is a significant driver of mortality and poor clinical outcomes in conditions such as brain injury and cardiac arrest in critically ill patients, including COVID-19 patients. Given the host of negative clinical outcomes attributed to hypoxemia, identifying patients likely to experience hypoxemia would offer valuable opportunities for early and thus more effective intervention. We present SWIFT (SpO 2 W aveform I CU F orecasting T echnique), a deep learning model that predicts blood oxygen saturation (SpO 2 ) waveforms 5 and 30 minutes in the future using only prior SpO 2 values as inputs. When tested on novel data, SWIFT predicts more than 80% and 60% of hypoxemic events in critically ill and COVID-19 patients, respectively. SWIFT also predicts SpO 2 waveforms with average MSE below .0007. SWIFT provides information on both occurrence and magnitude of potential hypoxemic events 30 minutes in advance, allowing it to be used to inform clinical interventions, patient triaging, and optimal resource allocation. SWIFT may be used in clinical decision support systems to inform the management of critically ill patients during the COVID-19 pandemic and beyond.

Variation in SARS-CoV-2 outbreaks across sub-Saharan Africa.

A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (for example, warmer environments1, younger populations2-4) have yet to be framed within a comprehensive analysis. We synthesized factors hypothesized to drive the pace and burden of this pandemic in SSA during the period from 25 February to 20 December 2020, encompassing demographic, comorbidity, climatic, healthcare capacity, intervention efforts and human mobility dimensions. Large diversity in the probable drivers indicates a need for caution in interpreting analyses that aggregate data across low- and middle-income settings. Our simulation shows that climatic variation between SSA population centers has little effect on early outbreak trajectories; however, heterogeneity in connectivity, although rarely considered, is likely an important contributor to variance in the pace of viral spread across SSA. Our synthesis points to the potential benefits of context-specific adaptation of surveillance systems during the ongoing pandemic. In particular, characterizing patterns of severity over age will be a priority in settings with high comorbidity burdens and poor access to care. Understanding the spatial extent of outbreaks warrants emphasis in settings where low connectivity could drive prolonged, asynchronous outbreaks resulting in extended stress to health systems.

Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Layered self-assemblies for controlled drug delivery: A translational overview.

Self-assembly is a prominent phenomenon observed in nature. Inspired by this thermodynamically favorable approach, several natural and synthetic materials have been investigated to develop functional systems for various biomedical applications, including drug delivery. Furthermore, layered self-assembled systems provide added advantages of tunability and multifunctionality which are crucial for controlled and targeted drug release. Layer-by-layer (LbL) deposition has emerged as one of the most popular, well-established techniques for tailoring such layered self-assemblies. This review aims to provide a brief overview of drug delivery applications using LbL deposition, along with a discussion of associated scalability challenges, technological innovations to overcome them, and prospects for commercial translation of this versatile technique. Additionally, alternative self-assembly techniques such as metal-phenolic networks (MPNs) and Liesegang rings are also reviewed in the context of their recent utilization for controlled drug delivery. Blending the sophistication of these self-assembly phenomena with material science and technological advances can provide a powerful tool to develop smart drug carriers in a scalable manner.

High variation expected in the pace and burden of SARS-CoV-2 outbreaks across sub-Saharan Africa.

A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (e.g., warmer environments1, younger populations2-4) have yet to be framed within a comprehensive analysis accounting for factors that may offset the effects of climate and demography. Here, we synthesize factors hypothesized to shape the pace of this pandemic and its burden as it moves across SSA, encompassing demographic, comorbidity, climatic, healthcare and intervention capacity, and human mobility dimensions of risk. We find large scale diversity in probable drivers, such that outcomes are likely to be highly variable among SSA countries. While simulation shows that extensive climatic variation among SSA population centers has little effect on early outbreak trajectories, heterogeneity in connectivity is likely to play a large role in shaping the pace of viral spread. The prolonged, asynchronous outbreaks expected in weakly connected settings may result in extended stress to health systems. In addition, the observed variability in comorbidities and access to care will likely modulate the severity of infection: We show that even small shifts in the infection fatality ratio towards younger ages, which are likely in high risk settings, can eliminate the protective effect of younger populations. We highlight countries with elevated risk of 'slow pace', high burden outbreaks. Empirical data on the spatial extent of outbreaks within SSA countries, their patterns in severity over age, and the relationship between epidemic pace and health system disruptions are urgently needed to guide efforts to mitigate the high burden scenarios explored here.

Study Protocol: A Cross-Sectional Examination of Socio-Demographic and Ecological Determinants of Nutrition and Disease Across Madagascar.

Madagascar has experienced significant environmental change since 1960, particularly through forest clearing for agricultural expansion. Climatic patterns are undergoing change in Madagascar as well, with increasing temperatures, droughts, and cyclonic activity. The impact of these environmental and climatic changes will pose threats to food availability, income generation, and local ecosystems, with significant potential effects on the spatial and temporal distribution of disease burden. This study seeks to describe the health status of a large sample of geographically and socially diverse Malagasy communities through multiple clinical measurements, detailed social surveys, and paired data on regional variation in local ecologies. With an increased understanding of the current patterns of variation in human health and nutrition, future studies will be better able to identify associations with climate and anticipate and mitigate the burdens expected from larger, longer-term changes. Our mixed-method approach included an observational cross-sectional study. Research subjects were men, women, and children from 1,125 households evenly distributed across 24 communities in four ecologically and socio-demographically distinct regions of Madagascar. For these 1,125 households, all persons of both sexes and all ages therein (for a total of 6,292 individuals) were recruited into the research study and a total of 5,882 individuals were enrolled. Through repeated social survey recalls and focus group meetings, we obtained social and demographic data, including broad categories of seasonal movements, and characterized the fluctuation of income generation, food production and dietary consumption. Through collection of clinical and biological samples for both point-of-care diagnoses and laboratory analyses, we obtained detailed occurrence (and importantly co-occurrence) data on micronutrient nutritional, infectious disease, and non-communicable disease status. Our research highlights the highly variable social, cultural, and environmental contexts of health conditions in Madagascar, and the tremendous inter-regional, inter-community, and intra-community variation in nutritional and disease status. More than 30% of the surveyed population was afflicted by anemia and 14% of the population had a current malaria infection. This type of rich metadata associated with a suite of biological samples and nutritional and disease outcome data should allow disentangling some of the underlying drivers of ill health across the changing landscapes of Madagascar.

Modeling the Impact of Newcastle Disease Virus Vaccinations on Chicken Production Systems in Northeastern Madagascar.

Chickens are a key source of nutrition for rural Malagasy communities. Due to high endemic rates of Newcastle disease, it remains challenging to raise sustainable chicken flocks as a consistent food source. Here, we explore the impact of triannual Newcastle disease virus (NDV) vaccine interventions on the growth and herd immunity acquisition of Malagasy chicken flocks. Between 2011 and 2018 we collected longitudinal data to assess the population dynamics of chicken populations in remote Malagasy communities. In 2016, we launched a pilot campaign for vaccination in six rural communities to determine the impacts on chicken survivorship and productivity. We used these data to specify a mathematical model of realistic Malagasy chicken population dynamics under a triannual vaccination regime. The mathematical model represents an extension to conventional SIR models that allows for modeling the impact of specific vaccinations on chicken flock dynamics, rather than estimation of parameters. Understanding chicken population dynamics is important for realizing the potential for domestic chicken flocks to serve as sustainable food sources. The results suggested that vaccination coverage of at least ~40% is necessary over 5+ years to achieve population doubling, while complete herd immunity may not be possible given the short duration of effectiveness of vaccination, and the high levels of births and deaths in the chicken flocks.

Conjugate-SELEX: A High-throughput Screening of Thioaptamer-liposomal Nanoparticle Conjugates for Targeted Intracellular Delivery of Anticancer Drugs.

Patients with advanced head and neck squamous cell carcinoma receiving chemotherapy have a poor prognosis partly due to normal tissue toxicity; therefore, development of a tumor-targeted drug delivery platform to minimize collateral toxicity is a goal of cancer nanomedicine. Aptamers can achieve this purpose. While conventional Systematic Evolution of Ligands by Exponential Enrichment (SELEX) screens aptamer-only libraries and conjugates them to delivery vehicles after selection, we hypothesized that specific delivery requires screening libraries with aptamer-nanoparticle conjugates. We designed a procedure called, "Conjugate-SELEX", where liposomal nanoparticles (LNP) conjugated with aptamers is screened to identify aptamers that carried attached LNPs to the human head and neck squamous cell carcinoma cell cytosol. Aptamer-LNPs were simultaneously selected for a low affinity to human hepatocytes, minimizing hepatoxicity and LNP clearance. Post-SELEX Next Generation sequencing demonstrated convergence to a family of sequences with one base difference. Affinity pulldown and proteomics analysis identified the uptake-mediating surface receptor as the neuroblast differentiation-associated protein AHNAK (Desmoyokin), a ubiquitous intracellular protein expressed in certain epithelial cell types. Uptake studies with the lead aptamer-conjugates showed enhanced uptake and increased cytotoxicity induced by doxorubicin in cells treated with aptamer-conjugated LNPs over LNP controls. Conjugate-SELEX identifies aptamers capable of targeted cytosolic delivery of attached LNPs payload, while minimizing off-target delivery. The technique lends itself to identification of uptake-mediating surface receptors.

Dual-energy computed tomography imaging of atherosclerotic plaques in a mouse model using a liposomal-iodine nanoparticle contrast agent.

BACKGROUND: The accumulation of macrophages in inflamed atherosclerotic plaques has long been recognized. In an attempt to develop an imaging agent for detection of vulnerable plaques, we evaluated the feasibility of a liposomal-iodine nanoparticle contrast agent for computed tomography imaging of macrophage-rich atherosclerotic plaques in a mouse model. METHODS AND RESULTS: Liposomal-iodine formulations varying in particle size and polyethylene glycol coating were fabricated and shown to stably encapsulate the iodine compound. In vitro uptake studies using optical and computed tomography imaging in the RAW 264.7 macrophage cell line identified the formulation that promoted maximal uptake. Dual-energy computed tomography imaging using this formulation in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and control C57BL/6 mice (n=6) followed by spectral decomposition of the dual-energy images enabled imaging of the liposomes localized in the plaque. Imaging cytometry confirmed the presence of liposomes in the plaque and their colocalization with a small fraction (≈2%) of the macrophages in the plaque. CONCLUSIONS: The results demonstrate the feasibility of imaging macrophage-rich atherosclerotic plaques using a liposomal-iodine nanoparticle contrast agent and dual-energy computed tomography.