Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition.

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4.

Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.

Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Association of the multi-biomarker disease activity score with arterial 18-fluorodeoxyglucose uptake in rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) and atherosclerosis share many common inflammatory pathways. We studied whether a multi-biomarker panel for RA disease activity (MBDA) would associate with changes in arterial inflammation in an interventional trial. METHODS: In the TARGET Trial, RA patients with active disease despite methotrexate were randomly assigned to the addition of either a TNF inhibitor or sulfasalazine+hydroxychloroquine (triple therapy). Baseline and 24-week follow-up 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography scans were assessed for change in arterial inflammation measured as the maximal arterial target-to-blood background ratio of FDG uptake in the most diseased segment of the carotid arteries or aorta (MDS-TBRmax). The MBDA test, measured at baseline and weeks 6, 18, and 24, was assessed for its association with the change in MDS-TBRmax. RESULTS: Interpretable scans were available at baseline and week 24 for n = 112 patients. The MBDA score at week 24 was significantly correlated with the change in MDR-TBRmax (Spearman's rho = 0.239; p= 0.011) and remained significantly associated after adjustment for relevant confounders. Those with low MBDA at week 24 had a statistically significant adjusted reduction in arterial inflammation of 0.35 units vs no significant reduction in those who did not achieve low MBDA. Neither DAS28-CRP nor CRP predicted change in arterial inflammation. The MBDA component with the strongest association with change in arterial inflammation was serum amyloid A (SAA). CONCLUSIONS: Among treated RA patients, achieved MBDA predicts of changes in arterial inflammation. Achieving low MBDA at 24 weeks was associated with clinically meaningful reductions in arterial inflammation, regardless of treatment.

A review of self-supervised, generative, and few-shot deep learning methods for data-limited magnetic resonance imaging segmentation.

Magnetic resonance imaging (MRI) is a ubiquitous medical imaging technology with applications in disease diagnostics, intervention, and treatment planning. Accurate MRI segmentation is critical for diagnosing abnormalities, monitoring diseases, and deciding on a course of treatment. With the advent of advanced deep learning frameworks, fully automated and accurate MRI segmentation is advancing. Traditional supervised deep learning techniques have advanced tremendously, reaching clinical-level accuracy in the field of segmentation. However, these algorithms still require a large amount of annotated data, which is oftentimes unavailable or impractical. One way to circumvent this issue is to utilize algorithms that exploit a limited amount of labeled data. This paper aims to review such state-of-the-art algorithms that use a limited number of annotated samples. We explain the fundamental principles of self-supervised learning, generative models, few-shot learning, and semi-supervised learning and summarize their applications in cardiac, abdomen, and brain MRI segmentation. Throughout this review, we highlight algorithms that can be employed based on the quantity of annotated data available. We also present a comprehensive list of notable publicly available MRI segmentation datasets. To conclude, we discuss possible future directions of the field-including emerging algorithms, such as contrastive language-image pretraining, and potential combinations across the methods discussed-that can further increase the efficacy of image segmentation with limited labels.

PTSD increases risk for major adverse cardiovascular events through neural and cardio-inflammatory pathways.

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], ß = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population.

Self-gated, dynamic contrast-enhanced magnetic resonance imaging with compressed-sensing reconstruction for evaluating endothelial permeability in the aortic root of atherosclerotic mice.

High-risk atherosclerotic plaques are characterized by active inflammation and abundant leaky microvessels. We present a self-gated, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) acquisition with compressed sensing reconstruction and apply it to assess longitudinal changes in endothelial permeability in the aortic root of Apoe-/- atherosclerotic mice during natural disease progression. Twenty-four, 8-week-old, female Apoe-/- mice were divided into four groups (n = 6 each) and imaged with self-gated DCE-MRI at 4, 8, 12, and 16 weeks after high-fat diet initiation, and then euthanized for CD68 immunohistochemistry for macrophages. Eight additional mice were kept on a high-fat diet and imaged longitudinally at the same time points. Aortic-root pseudo-concentration curves were analyzed using a validated piecewise linear model. Contrast agent wash-in and washout slopes (b1 and b2 ) were measured as surrogates of aortic root endothelial permeability and compared with macrophage density by immunohistochemistry. b2 , indicating contrast agent washout, was significantly higher in mice kept on an high-fat diet for longer periods of time (p = 0.03). Group comparison revealed significant differences between mice on a high-fat diet for 4 versus 16 weeks (p = 0.03). Macrophage density also significantly increased with diet duration (p = 0.009). Spearman correlation between b2 from DCE-MRI and macrophage density indicated a weak relationship between the two parameters (r = 0.28, p = 0.20). Validated piecewise linear modeling of the DCE-MRI data showed that the aortic root contrast agent washout rate is significantly different during disease progression. Further development of this technique from a single-slice to a 3D acquisition may enable better investigation of the relationship between in vivo imaging of endothelial permeability and atherosclerotic plaques' genetic, molecular, and cellular makeup in this important model of disease.

The combined effect of air and transportation noise pollution on atherosclerotic inflammation and risk of cardiovascular disease events.

BACKGROUND: Air pollution and noise exposures individually associate with major adverse cardiovascular events (MACE) via a mechanism involving arterial inflammation (ArtI); however, their combined impact on ArtI and MACE remains unknown. We tested whether dual (vs. one or neither) exposure associates with greater ArtI and MACE risk and whether MACE risk is mediated via ArtI. METHODS: Individuals (N = 474) without active cancer or known cardiovascular disease with clinical 18F-FDG-PET/CT imaging were followed for 5 years for MACE. ArtI was measured. Average air pollution (particulate matter ≤ 2.5 µm, PM2.5) and transportation noise exposure were determined at individual residences. Higher exposures were defined as noise > 55 dBA (World Health Organization cutoff) and PM2.5 ≥ sample median. RESULTS: At baseline, 46%, 46%, and 8% were exposed to high levels of neither, one, or both pollutants; 39 experienced MACE over a median 4.1 years. Exposure to an increasing number of pollutants associated with higher ArtI (standardized ß [95% CI: .195 [.052, .339], P = .008) and MACE (HR [95% CI]: 2.897 [1.818-4.615], P < .001). In path analysis, ArtI partially mediated the relationship between pollutant exposures and MACE (P < .05). CONCLUSION: Air pollution and transportation noise exposures contribute incrementally to ArtI and MACE. The mechanism linking dual exposure to MACE involves ArtI.

Targeting Trained Innate Immunity With Nanobiologics to Treat Cardiovascular Disease.

[Figure: see text].

Scan-rescan measurement repeatability of 18F-FDG PET/MR imaging of vascular inflammation.

Non-invasive positron emission tomography (PET) of vascular inflammation and atherosclerotic plaque by identifying increased uptake of 18F-fluordeoxyglucose (18F-FDG) is a powerful tool for monitoring disease activity, progression, and its response to therapy. 18F-FDG PET/computed tomography (PET/CT) of the aorta and carotid arteries has become widely used to assess changes in inflammation in clinical trials. However, the recent advent of hybrid PET/magnetic resonance (PET/MR) scanners has advantages for vascular imaging due to the reduction in radiation exposure and improved soft tissue contrast of MR compared to CT. Important for research and clinical use is an understanding of the scan-rescan repeatability of the PET measurement. While this has been studied for PET/CT, no data is currently available for vascular PET/MR imaging. In this study, we determined the scan-rescan measurement repeatability of 18F-FDG PET/MR in the aorta and carotid arteries was less than 5%, comparable to similar findings for 18F-FDG PET/CT.

18F-fluoride PET/MR in cardiac amyloid: A comparison study with aortic stenosis and age- and sex-matched controls.

OBJECTIVES: Cardiac MR is widely used to diagnose cardiac amyloid, but cannot differentiate AL and ATTR subtypes: an important distinction given their differing treatments and prognoses. We used PET/MR imaging to quantify myocardial uptake of 18F-fluoride in ATTR and AL amyloid patients, as well as participants with aortic stenosis and age/sex-matched controls. METHODS: In this prospective multicenter study, patients were recruited in Edinburgh and New York and underwent 18F-fluoride PET/MR imaging. Standardized volumes of interest were drawn in the septum and areas of late gadolinium enhancement to derive myocardial standardized uptake values (SUV) and tissue-to-background ratio (TBRMEAN) after correction for blood pool activity in the right atrium. RESULTS: 53 patients were scanned: 18 with cardiac amyloid (10 ATTR and 8 AL), 13 controls, and 22 with aortic stenosis. No differences in myocardial TBR values were observed between participants scanned in Edinburgh and New York. Mean myocardial TBRMEAN values in ATTR amyloid (1.13 ± 0.16) were higher than controls (0.84 ± 0.11, P = .0006), aortic stenosis (0.73 ± 0.12, P < .0001), and those with AL amyloid (0.96 ± 0.08, P = .01). TBRMEAN values within areas of late gadolinium enhancement provided discrimination between patients with ATTR (1.36 ± 0.23) and all other groups (e.g., AL [1.06 ± 0.07, P = .003]). A TBRMEAN threshold >1.14 in areas of LGE demonstrated 100% sensitivity (CI 72.25 to 100%) and 100% specificity (CI 67.56 to 100%) for ATTR compared to AL amyloid (AUC 1, P = .0004). CONCLUSION: Quantitative 18F-fluoride PET/MR imaging can distinguish ATTR amyloid from other similar phenotypes and holds promise in improving the diagnosis of this condition.

A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans.

AIMS: Air pollution [i.e. particulate matter with diameter <2.5 µm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE. METHODS AND RESULTS: Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual's home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE. CONCLUSIONS: Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.

Magnetization-prepared GRASP MRI for rapid 3D T1 mapping and fat/water-separated T1 mapping.

PURPOSE: This study aimed to (i) develop Magnetization-Prepared Golden-angle RAdial Sparse Parallel (MP-GRASP) MRI using a stack-of-stars trajectory for rapid free-breathing T1 mapping and (ii) extend MP-GRASP to multi-echo acquisition (MP-Dixon-GRASP) for fat/water-separated (water-specific) T1 mapping. METHODS: An adiabatic non-selective 180° inversion-recovery pulse was added to a gradient-echo-based golden-angle stack-of-stars sequence for magnetization-prepared 3D single-echo or 3D multi-echo acquisition. In combination with subspace-based GRASP-Pro reconstruction, the sequence allows for standard T1 mapping (MP-GRASP) or fat/water-separated T1 mapping (MP-Dixon-GRASP), respectively. The accuracy of T1 mapping using MP-GRASP was evaluated in a phantom and volunteers (brain and liver) against clinically accepted reference methods. The repeatability of T1 estimation was also assessed in the phantom and volunteers. The performance of MP-Dixon-GRASP for water-specific T1 mapping was evaluated in a fat/water phantom and volunteers (brain and liver). RESULTS: ROI-based mean T1 values are correlated between the references and MP-GRASP in the phantom (R2 = 1.0), brain (R2 = 0.96), and liver (R2 = 0.73). MP-GRASP achieved good repeatability of T1 estimation in the phantom (R2 = 1.0), brain (R2 = 0.99), and liver (R2 = 0.82). Water-specific T1 is different from in-phase and out-of-phase composite T1 (composite T1 when fat and water signal are mixed in phase or out of phase) both in the phantom and volunteers. CONCLUSION: This work demonstrated the initial performance of MP-GRASP and MP-Dixon-GRASP MRI for rapid 3D T1 mapping and 3D fat/water-separated T1 mapping in the brain (without motion) and in the liver (during free breathing). With fat/water-separated T1 estimation, MP-Dixon-GRASP could be potentially useful for imaging patients with fatty-liver diseases.

Whole-Body Atherosclerosis Imaging by Positron Emission Tomography/Magnetic Resonance Imaging: From Mice to Nonhuman Primates.

Cardiovascular disease due to atherosclerosis is still the main cause of morbidity and mortality worldwide. This disease is a complex systemic disorder arising from a network of pathological processes within the arterial vessel wall, and, outside of the vasculature, in the hematopoietic system and organs involved in metabolism. Recent years have seen tremendous efforts in the development and validation of quantitative imaging technologies for the noninvasive evaluation of patients with atherosclerotic cardiovascular disease. Specifically, the advent of combined positron emission tomography and magnetic resonance imaging scanners has opened new exciting opportunities in cardiovascular imaging. In this review, we will describe how combined positron emission tomography/magnetic resonance imaging scanners can be leveraged to evaluate atherosclerotic cardiovascular disease at the whole-body level, with specific focus on preclinical animal models of disease, from mouse to nonhuman primates. We will broadly describe 3 major areas of application: (1) vascular imaging, for advanced atherosclerotic plaque phenotyping and evaluation of novel imaging tracers or therapeutic interventions; (2) assessment of the ischemic heart and brain; and (3) whole-body imaging of the hematopoietic system. Finally, we will provide insights on potential novel technical developments which may further increase the relevance of integrated positron emission tomography/magnetic resonance imaging in preclinical atherosclerosis studies.

Atherosclerosis Immunoimaging by Positron Emission Tomography.

The immune system's role in atherosclerosis has long been an important research topic and is increasingly investigated for therapeutic and diagnostic purposes. Therefore, noninvasive imaging of hematopoietic organs and immune cells will undoubtedly improve atherosclerosis phenotyping and serve as a monitoring method for immunotherapeutic treatments. Among the available imaging techniques, positron emission tomography's unique features make it an ideal tool to quantitatively image the immune response in the context of atherosclerosis and afford reliable readouts to guide medical interventions in cardiovascular disease. Here, we summarize the state of the art in the field of atherosclerosis positron emission tomography immunoimaging and provide an outlook on current and future applications.

Assessing the qualitative and quantitative impacts of simple two-class vs multiple tissue-class MR-based attenuation correction for cardiac PET/MR.

BACKGROUND: Hybrid PET/MR imaging has significant potential in cardiology due to its combination of molecular PET imaging and cardiac MR. Multi-tissue-class MR-based attenuation correction (MRAC) is necessary for accurate PET quantification. Moreover, for thoracic PET imaging, respiration is known to lead to misalignments of MRAC and PET data that result in PET artifacts. These factors can be addressed by using multi-echo MR for tissue segmentation and motion-robust or motion-gated acquisitions. However, the combination of these strategies is not routinely available and can be prone to errors. In this study, we examine the qualitative and quantitative impacts of multi-class MRAC compared to a more widely available simple two-class MRAC for cardiac PET/MR. METHODS AND RESULTS: In a cohort of patients with cardiac sarcoidosis, we acquired MRAC data using multi-echo radial gradient-echo MR imaging. Water-fat separation was used to produce attenuation maps with up to 4 tissue classes including water-based soft tissue, fat, lung, and background air. Simultaneously acquired 18F-fluorodeoxyglucose PET data were subsequently reconstructed using each attenuation map separately. PET uptake values were measured in the myocardium and compared between different PET images. The inclusion of lung and subcutaneous fat in the MRAC maps significantly affected the quantification of 18F-fluorodeoxyglucose activity in the myocardium but only moderately altered the appearance of the PET image without introduction of image artifacts. CONCLUSION: Optimal MRAC for cardiac PET/MR applications should include segmentation of all tissues in combination with compensation for the respiratory-related motion of the heart. Simple two-class MRAC is adequate for qualitative clinical assessment.

Cardiovascular 18F-fluoride positron emission tomography-magnetic resonance imaging: A comparison study.

BACKGROUND: 18F-Fluoride uptake denotes calcification activity in aortic stenosis and atherosclerosis. While PET/MR has several advantages over PET/CT, attenuation correction of PET/MR data is challenging, limiting cardiovascular application. We compared PET/MR and PET/CT assessments of 18F-fluoride uptake in the aortic valve and coronary arteries. METHODS AND RESULTS: 18 patients with aortic stenosis or recent myocardial infarction underwent 18F-fluoride PET/CT followed immediately by PET/MR. Valve and coronary 18F-fluoride uptake were evaluated independently. Both standard (Dixon) and novel radial GRE) MR attenuation correction (AC) maps were validated against PET/CT with results expressed as tissue-to-background ratios (TBRs). Visually, aortic valve 18F-fluoride uptake was similar on PET/CT and PET/MR. TBRMAX values were comparable with radial GRE AC (PET/CT 1.55±0.33 vs. PET/MR 1.58 ± 0.34, P = 0.66; 95% limits of agreement - 27% to + 25%) but performed less well with Dixon AC (1.38 ± 0.44, P = 0.06; bias (-)14%; 95% limits of agreement - 25% to + 53%). In native coronaries, 18F-fluoride uptake was similar on PET/MR to PET/CT regardless of AC approach. PET/MR identified 28/29 plaques identified on PET/CT; however, stents caused artifact on PET/MR making assessment of 18F-fluoride uptake challenging. CONCLUSION: Cardiovascular PET/MR demonstrates good visual and quantitative agreement with PET/CT. However, PET/MR is hampered by stent-related artifacts currently limiting clinical application.

Factors Associated With Longitudinal Psychological and Physiological Stress in Health Care Workers During the COVID-19 Pandemic: Observational Study Using Apple Watch Data.

BACKGROUND: The COVID-19 pandemic has resulted in a high degree of psychological distress among health care workers (HCWs). There is a need to characterize which HCWs are at an increased risk of developing psychological effects from the pandemic. Given the differences in the response of individuals to stress, an analysis of both the perceived and physiological consequences of stressors can provide a comprehensive evaluation of its impact. OBJECTIVE: This study aimed to determine characteristics associated with longitudinal perceived stress in HCWs and to assess whether changes in heart rate variability (HRV), a marker of autonomic nervous system function, are associated with features protective against longitudinal stress. METHODS: HCWs across 7 hospitals in New York City, NY, were prospectively followed in an ongoing observational digital study using the custom Warrior Watch Study app. Participants wore an Apple Watch for the duration of the study to measure HRV throughout the follow-up period. Surveys measuring perceived stress, resilience, emotional support, quality of life, and optimism were collected at baseline and longitudinally. RESULTS: A total of 361 participants (mean age 36.8, SD 10.1 years; female: n=246, 69.3%) were enrolled. Multivariate analysis found New York City's COVID-19 case count to be associated with increased longitudinal stress (P=.008). Baseline emotional support, quality of life, and resilience were associated with decreased longitudinal stress (P<.001). A significant reduction in stress during the 4-week period after COVID-19 diagnosis was observed in the highest tertial of emotional support (P=.03) and resilience (P=.006). Participants in the highest tertial of baseline emotional support and resilience had a significantly different circadian pattern of longitudinally collected HRV compared to subjects in the low or medium tertial. CONCLUSIONS: High resilience, emotional support, and quality of life place HCWs at reduced risk of longitudinal perceived stress and have a distinct physiological stress profile. Our findings support the use of these characteristics to identify HCWs at risk of the psychological and physiological stress effects of the pandemic.