Publications by authors named "Michael Nelson"

832 Publications

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.

bioRxiv 2021 Apr 10. Epub 2021 Apr 10.

Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within four days in 7 of 8 animals receiving 50 µg RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only ∼2-fold relative to USA-WA1. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-like betacoronavirus vaccine development.

Significance Statement: The emergence of SARS-CoV-2 variants of concern (VOC) that reduce the efficacy of current COVID-19 vaccines is a major threat to pandemic control. We evaluate a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model that addresses the need for a next-generation, efficacious vaccine with increased pan-SARS breadth of coverage. RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge. Neutralization activity against the B.1.351 VOC within two-fold of wild-type virus and against SARS-CoV-1 indicate exceptional breadth. Our results support consideration of RFN for SARS-like betacoronavirus vaccine development.
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http://dx.doi.org/10.1101/2021.04.09.439166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043445PMC
April 2021

Real-Time Cardiac Magnetic Resonance Imaging: A New Spin on the Evaluation of HFpEF.

Circulation 2021 Apr 12;143(15):1499-1501. Epub 2021 Apr 12.

Department of Kinesiology and Applied Physiology and Advanced Imaging Laboratory, University of Texas at Arlington (M.D.N.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053026DOI Listing
April 2021

Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates.

bioRxiv 2021 Mar 25. Epub 2021 Mar 25.

The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50 g) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response upon high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. SpFN's potent and broad immunogenicity profile and resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses.

One-sentence Summary: A SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates.
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http://dx.doi.org/10.1101/2021.03.24.436523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010721PMC
March 2021

Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection.

Open Forum Infect Dis 2020 Oct 12;7(10):ofaa429. Epub 2020 Sep 12.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.
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http://dx.doi.org/10.1093/ofid/ofaa429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958800PMC
October 2020

Pre-existing Immunity to Japanese Encephalitis Virus Alters CD4 T Cell Responses to Zika Virus Inactivated Vaccine.

Front Immunol 2021 24;12:640190. Epub 2021 Feb 24.

Cellular Immunology Section, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

The epidemic spread of Zika virus (ZIKV), associated with devastating neurologic syndromes, has driven the development of multiple ZIKV vaccines candidates. An effective vaccine should induce ZIKV-specific T cell responses, which are shown to improve the establishment of humoral immunity and contribute to viral clearance. Here we investigated how previous immunization against Japanese encephalitis virus (JEV) and yellow fever virus (YFV) influences T cell responses elicited by a Zika purified-inactivated virus (ZPIV) vaccine. We demonstrate that three doses of ZPIV vaccine elicited robust CD4 T cell responses to ZIKV structural proteins, while ZIKV-specific CD4 T cells in pre-immunized individuals with JEV vaccine, but not YFV vaccine, were more durable and directed predominantly toward conserved epitopes, which elicited Th1 and Th2 cytokine production. In addition, T cell receptor repertoire analysis revealed preferential expansion of cross-reactive clonotypes between JEV and ZIKV, suggesting that pre-existing immunity against JEV may prime the establishment of stronger CD4 T cell responses to ZPIV vaccination. These CD4 T cell responses correlated with titers of ZIKV-neutralizing antibodies in the JEV pre-vaccinated group, but not in flavivirus-naïve or YFV pre-vaccinated individuals, suggesting a stronger contribution of CD4 T cells in the generation of neutralizing antibodies in the context of JEV-ZIKV cross-reactivity.
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http://dx.doi.org/10.3389/fimmu.2021.640190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943459PMC
February 2021

Health Disparities in Allergic and Immunologic Conditions in Racial and Ethnic Underserved Populations: A Work Group Report of the AAAAI Committee on the Underserved.

J Allergy Clin Immunol 2021 Mar 10. Epub 2021 Mar 10.

University of Arkansas for Medical Sciences, Little Rock, Ark; Arkansas Children's Research Institute, Little Rock, Ark.

Health disparities are health differences linked with economic, social and environmental disadvantage. They adversely affect groups that have systematically experienced greater social or economic obstacles to health. Renewed efforts are needed to reduced health disparities in the US, highlighted by the disparate impact on racial minorities during the coronavirus pandemic. Institutional or systemic patterns of racism are promoted and legitimated through accepted societal standards and organizational processes within the field of medicine and contribute to health disparities. Herein, we review current evidence regarding health disparities in allergic rhinitis, asthma, atopic dermatitis, food allergy, drug allergy, and primary immune deficiency disease in racial and ethnic underserved populations. Best practices to address these disparities involve addressing social determinants of health and adopting policies to improve access to specialty care and treatment for the underserved through telemedicine and community partnerships, cross cultural provider training to reduce implicit bias, inclusion of underserved patients in research, implementation of culturally competent patient education, and recruitment and training of healthcare providers from underserved communities. Addressing health disparities requires a multi-level approach involving patients, health providers, local agencies, professional societies and national governmental agencies.
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http://dx.doi.org/10.1016/j.jaci.2021.02.034DOI Listing
March 2021

: Old World Leech Gut Microbial Community Structure Conserved in a New World Leech.

Appl Environ Microbiol 2021 Mar 5. Epub 2021 Mar 5.

Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, U.S.A.

Leeches are found in terrestrial, aquatic, and marine habitats on all continents. Sanguivorous leeches have been used in medicine for millennia. Modern scientific uses include studies of neurons, anticoagulants, and gut microbial symbioses. , the European medicinal leech, maintains a gut community dominated by two bacterial symbionts, and , which sometimes account for as much as 97% of the total crop microbiota. The highly simplified gut anatomy and microbiome of make it an excellent model organism for studying gut microbial dynamics. The North American medicinal leech, is a hirudinid leech native to Canada and the northern U.S.A. In this study we show that symbiont communities are very similar to those in We performed an extensive study using field-caught and purchased from two suppliers. Deep sequencing of the V4 region of the 16S rRNA gene allowed us to determine the core microbiome of as consisting of , and The analysis revealed that the composition of the gut microbiome of the two leech species was significantly different at all taxonomic levels. The R value was highest at the genus and ASV levels and much lower at phylum, class, and order taxonomic levels. The gut and bladder microbial communities were distinct. We propose that is an alternative to for studies of wild-caught animals and provide evidence for the conservation of digestive-tract and bladder symbionts in annelid models.Building evidence implicates the gut microbiome in critical animal functions such as regulating digestion, nutrition, immune regulation, and development. Simplified, phylogenetically diverse models for hypotheses testing are necessary because of the difficulty of assigning causative relationships in complex gut microbiomes. Previous research used as a tractable animal model of digestive-tract symbioses. Our data show that may work just as well without the drawback of being an endangered organism and with the added advantage of easy access to field-caught specimens. The similarity of the microbial community structure of species from two different continents reveals the highly-conserved nature of the microbial symbionts in sanguivorous leeches.
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http://dx.doi.org/10.1128/AEM.02082-20DOI Listing
March 2021

B cell engagement with HIV-1 founder virus envelope predicts development of broadly neutralizing antibodies.

Cell Host Microbe 2021 Apr 3;29(4):564-578.e9. Epub 2021 Mar 3.

U.S. Military HIV Research Program, Center of Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA. Electronic address:

Determining which immunological mechanisms contribute to the development of broad neutralizing antibodies (bNAbs) during HIV-1 infection is a major goal to inform vaccine design. Using samples from a longitudinal HIV-1 acute infection cohort, we found key B cell determinants within the first 14-43 days of viremia that predict the development of bNAbs years later. Individuals who develop neutralization breadth had significantly higher B cell engagement with the autologous founder HIV envelope (Env) within 1 month of initial viremia. A higher frequency of founder-Env-specific naive B cells was associated with increased B cell activation and differentiation and predictive of bNAb development. These data demonstrate that the initial B cell interaction with the founder HIV Env is important for the development of broadly neutralizing antibodies and provide evidence that events within HIV acute infection lead to downstream functional outcomes.
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http://dx.doi.org/10.1016/j.chom.2021.01.016DOI Listing
April 2021

TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption.

PLoS Pathog 2021 Feb 18;17(2):e1009339. Epub 2021 Feb 18.

Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.
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http://dx.doi.org/10.1371/journal.ppat.1009339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924766PMC
February 2021

Left ventricular diastolic dysfunction and exercise intolerance in obese heart failure with preserved ejection fraction.

Am J Physiol Heart Circ Physiol 2021 04 12;320(4):H1535-H1542. Epub 2021 Feb 12.

Department of Kinesiology, University of Texas at Arlington, Arlington, Texas.

This study tested the hypothesis that early left ventricular (LV) relaxation is impaired in older obese patients with heart failure with preserved ejection fraction (HFpEF), and related to decreased peak exercise oxygen uptake (peak V̇o). LV strain and strain rate were measured by feature tracking of magnetic resonance cine images in 79 older obese patients with HFpEF (mean age: 66 yr; mean body mass index: 38 kg/m) and 54 healthy control participants. LV diastolic strain rates were indexed to cardiac preload as estimated by echocardiography derived diastolic filling pressures (), and correlated to peak V̇o. LV circumferential early diastolic strain rate was impaired in HFpEF compared with controls (0.93 ± 0.05/s vs. 1.20 ± 0.07/s, = 0.014); however, we observed no group differences in early LV radial or longitudinal diastolic strain rates. Isolating myocardial relaxation by indexing all three early LV diastolic strain rates (i.e. circumferential, radial, and longitudinal) to amplified the group difference in early LV diastolic circumferential strain rate (0.08 ± 0.03 vs. 0.13 ± 0.05, < 0.0001), and unmasked differences in early radial and longitudinal diastolic strain rate. Moreover, when indexing to , early LV diastolic strain rates from all three principal strains, were modestly related with peak V̇o ( = 0.36, -0.27, and 0.35, respectively, all < 0.01); this response, however, was almost entirely driven by itself, ( = -0.52, < 0.001). Taken together, we found that although LV relaxation is impaired in older obese patients with HFpEF, and modestly correlates with their severely reduced peak exercise V̇o, LV filling pressures appear to play a much more important role in determining exercise intolerance. Using a multimodal imaging approach to uncouple tissue deformation from atrial pressure, we found that left ventricular (LV) relaxation is impaired in older obese patients with HFpEF, but only modestly correlates with their severely reduced peak V̇o. In contrast, the data show a much stronger relationship between elevated LV filling pressures and exercise intolerance, refocusing future therapeutic priorities.
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http://dx.doi.org/10.1152/ajpheart.00610.2020DOI Listing
April 2021

Hot Flashes and Cardiovascular Disease Risk Indices Among Women With HIV.

Open Forum Infect Dis 2021 Feb 12;8(2):ofab011. Epub 2021 Jan 12.

Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Women with HIV (WWH) transitioning through menopause have heightened cardiovascular disease (CVD) risk. In the general population, hot flash burden relates to CVD risk indices. We found higher hot flash burden among women with vs without HIV. Further, among WWH, hot flash burden related to select CVD risk indices.

Clinicaltrialsgov Registration: NCT02874703.
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http://dx.doi.org/10.1093/ofid/ofab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863866PMC
February 2021

Impact of changes in tissue optical properties on near-infrared diffuse correlation spectroscopy measures of skeletal muscle blood flow.

J Appl Physiol (1985) 2021 Apr 11;130(4):1183-1195. Epub 2021 Feb 11.

Applied Physiology and Advanced Imaging Laboratory, Department of Kinesiology, The University of Texas at Arlington, Arlington, Texas.

Near-infrared diffuse correlation spectroscopy (DCS) is increasingly used to study relative changes in skeletal muscle blood flow. However, most diffuse correlation spectrometers assume that tissue optical properties-such as absorption (μ) and reduced scattering (μ') coefficients-remain constant during physiological provocations, which is untrue for skeletal muscle. Here, we interrogate how changes in tissue μ and μ' affect DCS calculations of blood flow index (BFI). We recalculated BFI using raw autocorrelation curves and μ/μ' values recorded during a reactive hyperemia protocol in 16 healthy young individuals. First, we show that incorrectly assuming baseline μ and μ' substantially affects peak BFI and BFI slope when expressed in absolute terms (cm/s, < 0.01), but these differences are abolished when expressed in relative terms (% baseline). Next, to evaluate the impact of physiologic changes in μ and μ', we compared peak BFI and BFI slope when μ and μ' were held constant throughout the reactive hyperemia protocol versus integrated from a 3-s rolling average. Regardless of approach, group means for peak BFI and BFI slope did not differ. Group means for peak BFI and BFI slope were also similar following ad absurdum analyses, where we simulated supraphysiologic changes in μ/μ'. In both cases, however, we identified individual cases where peak BFI and BFI slope were indeed affected, with this result being driven by relative changes in μ over μ'. Overall, these results provide support for past reports in which μ/μ' were held constant but also advocate for real-time incorporation of μ and μ' moving forward. We investigated how changes in tissue optical properties affect near-infrared diffuse correlation spectroscopy (NIR-DCS)-derived indices of skeletal muscle blood flow (BFI) during physiological provocation. Although accounting for changes in tissue optical properties has little impact on BFI on a group level, individual BFI calculations are indeed impacted by changes in tissue optical properties. NIR-DCS calculations of BFI should therefore account for real-time, physiologically induced changes in tissue optical properties whenever possible.
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http://dx.doi.org/10.1152/japplphysiol.00857.2020DOI Listing
April 2021

A multi-niche microvascularized human bone marrow (hBM) on-a-chip elucidates key roles of the endosteal niche in hBM physiology.

Biomaterials 2021 Mar 25;270:120683. Epub 2021 Jan 25.

The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; The Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA. Electronic address:

The human bone marrow (hBM) is a complex organ critical for hematopoietic and immune homeostasis, and where many cancers metastasize. Understanding the fundamental biology of the hBM in health and diseases remain difficult due to complexity of studying or manipulating the BM in humans. Accurate biomaterial-based in vitro models of the hBM microenvironment are critical to further our understanding of the BM-niche and advancing new clinical interventions. Here we report a unique, 96-well format, microfluidic hBM-on-a-chip that incorporates the endosteal, central marrow, and perivascular niches of the human BM. Osteogenic differentiation of donor human mesenchymal stromal cells (MSCs) produced robust mineralization on the bottom surface ("bone-like endosteal layer") of the device, and subsequent seeding of human endothelial cells and MSCs in a fibrin-collagen hydrogel network ("central marrow") on the top created an interconnected 3D microvascular network ("perivascular niche"). The 96-well format allows eight independent "chips" to be studied in one plate, thereby increasing throughput and reproducibility. We show that this complex, multi-niche microtissue accurately mimics hBM composition and microphysiology, while providing key insights on hematopoietic progenitor dynamics. Presence of the endosteal niche decreased the proliferation and increased maintenance of CD34 hematopoietic stem cells (HSCs). Upon exposure to radiation, HSCs in the hBM-chips containing endosteal niches were less frequently apoptotic, suggesting a potentially radio-protective role of the osteoblast surface. Our methods and results provide a broad platform for creating complex, multi-niche, high-throughput microphysiological (MPS) systems. Specifically, this hBM-on-a-chip opens new opportunities in human bone marrow research and therapeutics development, and can be used to better understand normal and impaired hematopoiesis, and various hBM pathologies, including cancer and BM failures.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120683DOI Listing
March 2021

Diastolic dysfunction in women with ischemia and no obstructive coronary artery disease: Mechanistic insight from magnetic resonance imaging.

Int J Cardiol 2021 May 2;331:1-7. Epub 2021 Feb 2.

The University of Texas at Arlington, Arlington, TX, USA; Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA. Electronic address:

Background: Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF); however, the mechanism(s) contributing to this progression remains unclear. Given that diastolic dysfunction is common in women with INOCA, defining mechanisms related to diastolic dysfunction in INOCA could identify therapeutic targets to prevent HFpEF.

Methods: Cardiac MRI was performed in 65 women with INOCA and 12 reference controls. Diastolic function was defined by left ventricular early diastolic circumferential strain rate (eCSRd). Contributors to diastolic dysfunction were chosen a priori as coronary vascular dysfunction (myocardial perfusion reserve index [MPRI]), diffuse myocardial fibrosis (extracellular volume [ECV]), and aortic stiffness (aortic pulse wave velocity [aPWV]).

Results: Compared to controls, eCSRd was lower in INOCA (1.61 ± 0.33/s vs. 1.36 ± 0.31/s, P = 0.016); however, this difference was not exaggerated when the INOCA group was sub-divided by low and high MPRI (P > 0.05) nor was ECV elevated in INOCA (29.0 ± 1.9% vs. 28.0 ± 3.2%, control vs. INOCA; P = 0.38). However, aPWV was higher in INOCA vs. controls (8.1 ± 3.2 m/s vs. 6.1 ± 1.5 m/s; P = 0.045), and was associated with eCSRd (r = -0.50, P < 0.001). By multivariable linear regression analysis, aPWV was an independent predictor of decreased eCSRd (standardized β = -0.39, P = 0.003), as was having an elevated left ventricular mass index (standardized β = -0.25, P = 0.024) and lower ECV (standardized β = 0.30, P = 0.003).

Conclusions: These data provide mechanistic insight into diastolic dysfunction in women with INOCA, identifying aortic stiffness and ventricular remodeling as putative therapeutic targets.
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http://dx.doi.org/10.1016/j.ijcard.2021.01.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026746PMC
May 2021

Factors influencing estimates of HIV-1 infection timing using BEAST.

PLoS Comput Biol 2021 Feb 1;17(2):e1008537. Epub 2021 Feb 1.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

While large datasets of HIV-1 sequences are increasingly being generated, many studies rely on a single gene or fragment of the genome and few comparative studies across genes have been done. We performed genome-based and gene-specific Bayesian phylogenetic analyses to investigate how certain factors impact estimates of the infection dates in an acute HIV-1 infection cohort, RV217. In this cohort, HIV-1 diagnosis corresponded to the first RNA positive test and occurred a median of four days after the last negative test, allowing us to compare timing estimates using BEAST to a narrow window of infection. We analyzed HIV-1 sequences sampled one week, one month and six months after HIV-1 diagnosis in 39 individuals. We found that shared diversity and temporal signal was limited in acute infection, and insufficient to allow timing inferences in the shortest HIV-1 genes, thus dated phylogenies were primarily analyzed for env, gag, pol and near full-length genomes. There was no one best-fitting model across participants and genes, though relaxed molecular clocks (73% of best-fitting models) and the Bayesian skyline (49%) tended to be favored. For infections with single founders, the infection date was estimated to be around one week pre-diagnosis for env (IQR: 3-9 days) and gag (IQR: 5-9 days), whilst the genome placed it at a median of 10 days (IQR: 4-19). Multiply-founded infections proved problematic to date. Our ability to compare timing inferences to precise estimates of HIV-1 infection (within a week) highlights that molecular dating methods can be applied to within-host datasets from early infection. Nonetheless, our results also suggest caution when using uniform clock and population models or short genes with limited information content.
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http://dx.doi.org/10.1371/journal.pcbi.1008537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877758PMC
February 2021

Longitudinal impact of a pre-populated default quantity on emergency department opioid prescriptions.

J Am Coll Emerg Physicians Open 2021 Feb 19;2(1):e12337. Epub 2020 Dec 19.

NorthShore University Health System Evanston IL USA.

Objective: Previously published studies indicate that a pre-populated default quantity may decrease opioid amounts on discharge prescriptions from the emergency department (ED). However, the longitudinal effect of defaulted quantities has not been described in the literature.

Methods: A retrospective review of electronic health record data from visits to 4 hospital EDs in a community health system examined opioid prescription dispense quantities 3.5 years pre- and 6.5 years post-implementation of a defaulted dispense quantity of seventeen. The primary purpose was to determine the percentage of ED discharge opioid prescriptions containing the prepopulated default dispense quantity after implementation. The longitudinal effect of a default quantity implementation on the average quantity prescribed (normalized per 1000 visits) was examined by comparing the pre-implementation period (January 1, 2009-July 31, 2012) to the post-implementation period (August 1, 2012-June 30, 2018).

Results: After implementation in 2012, the acceptance rate of the default dispense quantity increased each year, up to 48% in 2016 and maintained through 2018. A significant decrease in prescribed opioid quantities post-default quantity implementation was sustained, with the average quantity prescribed from 2015-2018 maintained at 17 or lower.

Conclusion: A pre-populated default quantity impacts discharge opioid prescribing as evidenced by a high sustained rate of prescriber utilization over years and reduction in the per prescription average pill quantity. The acceptance of a pre-populated default quantity may allow for selection of even a lower quantity to influence prescribing patterns of opioid analgesics.
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http://dx.doi.org/10.1002/emp2.12337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819264PMC
February 2021

Monitoring and Synchronization of Cardiac and Respiratory Traces in Magnetic Resonance Imaging: A Review.

IEEE Rev Biomed Eng 2021 Jan 29;PP. Epub 2021 Jan 29.

Synchronization of human vital signs, namely the cardiac cycle and respiratory excursions, is necessary during magnetic resonance imaging of the cardiovascular system and the abdominal cavity to achieve optimal image quality with minimized artifacts. This review summarizes techniques currently available in clinical practice, as well as methods under development, outlines the benefits and disadvantages of each approach, and offers some unique solutions for consideration.
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http://dx.doi.org/10.1109/RBME.2021.3055550DOI Listing
January 2021

Draft Genome Sequences of sp. Strains BGC7 and HGC4, Isolated from the Hindgut of a Lower Termite.

Microbiol Resour Announc 2021 Jan 28;10(4). Epub 2021 Jan 28.

Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, USA

spp. are facultative heterotrophs which colonize diverse environments, including the hindgut of the lower termite genomes are enriched for genes involving oligo- and polysaccharide utilization, enabling modification of a wide array of complex glycans. Here, we report draft genome sequences for sp. strains BGC7 and HGC4.
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http://dx.doi.org/10.1128/MRA.01427-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844080PMC
January 2021

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes.

EBioMedicine 2021 Jan 12;63:103175. Epub 2021 Jan 12.

Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States. Electronic address:

Background: During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV).

Methods: Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome.

Findings: MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures.

Interpretation: Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection.

Funding: A full list of the funding sources is detailed in the Acknowledgment section of the manuscript.
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http://dx.doi.org/10.1016/j.ebiom.2020.103175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811131PMC
January 2021

Emotion as a source of moral understanding in conservation.

Conserv Biol 2021 Jan 6. Epub 2021 Jan 6.

Centre for Compassionate Conservation, School of Life Sciences, University of Technology Sydney, Ultimo, NSW, 2007, Australia.

Recent debates around the meaning and implications of compassionate conservation suggest that some conservationists consider emotion a false and misleading basis for moral judgment and decision making. We trace these beliefs to a long-standing, gendered sociocultural convention and argue that the disparagement of emotion as a source of moral understanding is both empirically and morally problematic. According to the current scientific and philosophical understanding, reason and emotion are better understood as partners, rather than opposites. Nonetheless, the two have historically been seen as separate, with reason elevated in association with masculinity and emotion (especially nurturing emotion) dismissed or delegitimated in association with femininity. These associations can be situated in a broader, dualistic, and hierarchical logic used to maintain power for a dominant male (White, able-bodied, upper class, heterosexual) human class. We argue that emotion should be affirmed by conservationists for the novel and essential insights it contributes to conservation ethics. We consider the specific example of compassion and characterize it as an emotional experience of interdependence and shared vulnerability. This experience highlights conservationists' responsibilities to individual beings, enhancing established and widely accepted beliefs that conservationists have a duty to protect populations, species, and ecosystems (or biodiversity). We argue compassion, thus understood, should be embraced as a core virtue of conservation.
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http://dx.doi.org/10.1111/cobi.13689DOI Listing
January 2021

RNA-Seq identifies genes whose proteins are upregulated during syncytia development in murine C2C12 myoblasts and human BeWo trophoblasts.

Physiol Rep 2021 Jan;9(1):e14671

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.

The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA-Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly upregulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5. These findings provide avenues for further understanding of the mechanisms underlying mammalian placental syncytiotrophoblast development.
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http://dx.doi.org/10.14814/phy2.14671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786548PMC
January 2021

International society of sports nutrition position stand: caffeine and exercise performance.

J Int Soc Sports Nutr 2021 Jan 2;18(1). Epub 2021 Jan 2.

Performance & Physique Enhancement Laboratory, University of South Florida, Tampa, FL, 33612, USA.

Following critical evaluation of the available literature to date, The International Society of Sports Nutrition (ISSN) position regarding caffeine intake is as follows: 1. Supplementation with caffeine has been shown to acutely enhance various aspects of exercise performance in many but not all studies. Small to moderate benefits of caffeine use include, but are not limited to: muscular endurance, movement velocity and muscular strength, sprinting, jumping, and throwing performance, as well as a wide range of aerobic and anaerobic sport-specific actions. 2. Aerobic endurance appears to be the form of exercise with the most consistent moderate-to-large benefits from caffeine use, although the magnitude of its effects differs between individuals. 3. Caffeine has consistently been shown to improve exercise performance when consumed in doses of 3-6 mg/kg body mass. Minimal effective doses of caffeine currently remain unclear but they may be as low as 2 mg/kg body mass. Very high doses of caffeine (e.g. 9 mg/kg) are associated with a high incidence of side-effects and do not seem to be required to elicit an ergogenic effect. 4. The most commonly used timing of caffeine supplementation is 60 min pre-exercise. Optimal timing of caffeine ingestion likely depends on the source of caffeine. For example, as compared to caffeine capsules, caffeine chewing gums may require a shorter waiting time from consumption to the start of the exercise session. 5. Caffeine appears to improve physical performance in both trained and untrained individuals. 6. Inter-individual differences in sport and exercise performance as well as adverse effects on sleep or feelings of anxiety following caffeine ingestion may be attributed to genetic variation associated with caffeine metabolism, and physical and psychological response. Other factors such as habitual caffeine intake also may play a role in between-individual response variation. 7. Caffeine has been shown to be ergogenic for cognitive function, including attention and vigilance, in most individuals. 8. Caffeine may improve cognitive and physical performance in some individuals under conditions of sleep deprivation. 9. The use of caffeine in conjunction with endurance exercise in the heat and at altitude is well supported when dosages range from 3 to 6 mg/kg and 4-6 mg/kg, respectively. 10. Alternative sources of caffeine such as caffeinated chewing gum, mouth rinses, energy gels and chews have been shown to improve performance, primarily in aerobic exercise. 11. Energy drinks and pre-workout supplements containing caffeine have been demonstrated to enhance both anaerobic and aerobic performance.
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http://dx.doi.org/10.1186/s12970-020-00383-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777221PMC
January 2021

Hemodynamic consequences of incomplete uterine spiral artery transformation in human pregnancy, with implications for placental dysfunction and preeclampsia.

J Appl Physiol (1985) 2021 Feb 24;130(2):457-465. Epub 2020 Dec 24.

Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.

Normal human pregnancy requires a dramatic increase in uteroplacental blood flow, which is achieved by a transformation in the geometry of uterine spiral arteries, a key element in this blood supply system. The transformation is mediated by trophoblast invasion directed at converting a portion of the spiral artery into an open funnel, thereby greatly reducing resistance to flow. The converted portion lies within the depth of the decidua and part of the myometrium. Insufficient depth of trophoblast invasion in early pregnancy predisposes to inadequate perfusion of the developing placenta and fetus and may lead to preeclampsia, fetal growth restriction, and preterm delivery, sometimes referred to as the "Great Obstetrical Syndromes." We examine the hemodynamic consequences of spiral artery transformation in human pregnancy and the relationship between the degree of transformation and the corresponding change in flow rate and resistance to flow. We identify two key variables in determining the hemodynamic change: the longitudinal converted fraction of the spiral artery and the relative downstream diameter of the open funnel. Our results indicate that there is a critical threshold in the value of the converted fraction required to achieve the marked increase in uteroplacental blood flow in normal pregnancy. This finding validates common clinical observations that the depth of trophoblast invasion reflects the "adequacy" of the increase in uteroplacental blood supply required in normal human pregnancy. Our results provide a quantitative measure of that adequacy and may serve as a future diagnostic marker for high-risk pregnancy. Human pregnancy requires dramatic increase in uteroplacental blood supply achieved by geometric transformation of uterine spiral arteries and facilitated by trophoblast invasion of these arteries to greatly reduce resistance to flow. Incomplete transformation has been associated with failed pregnancies, preeclampsia, and other pathologies, but a quantitative measure of "incompleteness" has been unavailable so far. We use a mathematical model to obtain a numerical threshold for this measure which may serve as a future diagnostic marker.
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http://dx.doi.org/10.1152/japplphysiol.00504.2020DOI Listing
February 2021

Challenges at the intersection of conservation and ethics: Reply to Meyer et al. 2021.

Conserv Biol 2021 Feb 22;35(1):373-377. Epub 2020 Dec 22.

Centre for Compassionate Conservation, Faculty of Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia.

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http://dx.doi.org/10.1111/cobi.13666DOI Listing
February 2021

A Multifunctional LNA Oligonucleotide-Based Strategy Blocks AR Expression and Transactivation Activity in PCa Cells.

Mol Ther Nucleic Acids 2021 Mar 27;23:63-75. Epub 2020 Oct 27.

Department of Medical Oncology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.

The androgen receptor (AR) plays a critical role in the development of prostate cancer (PCa) through the activation of androgen-induced cellular proliferation genes. Thus, blocking AR-mediated transcriptional activation is expected to inhibit the growth and spread of PCa. Using tailor-made splice-switching locked nucleic acid (LNA) oligonucleotides (SSOs), we successfully redirected splicing of the AR precursor (pre-)mRNA and destabilized the transcripts via the introduction of premature stop codons. Furthermore, the SSOs simultaneously favored production of the AR45 mRNA in lieu of the full-length AR. AR45 is an AR isoform that can attenuate the activity of both full-length and oncogenic forms of AR by binding to their common N-terminal domain (NTD), thereby blocking their transactivation potential. A large screen was subsequently used to identify individual SSOs that could best perform this dual function. The selected SSOs powerfully silence AR expression and modulate the expression of AR-responsive cellular genes. This bi-functional strategy that uses a single therapeutic molecule can be the basis for novel PCa treatments. It might also be customized to other types of therapies that require the silencing of one gene and the simultaneous expression of a different isoform.
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http://dx.doi.org/10.1016/j.omtn.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723773PMC
March 2021

Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

NPJ Breast Cancer 2020 Nov 27;6(1):63. Epub 2020 Nov 27.

University of California, San Francisco, CA, USA.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.
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http://dx.doi.org/10.1038/s41523-020-00203-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695723PMC
November 2020

RV144 HIV-1 vaccination impacts post-infection antibody responses.

PLoS Pathog 2020 12 8;16(12):e1009101. Epub 2020 Dec 8.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection.
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http://dx.doi.org/10.1371/journal.ppat.1009101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748270PMC
December 2020

N-Terminal pro-B-type natriuretic peptide and coronary microvascular dysfunction in women with preserved ejection fraction: A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

PLoS One 2020 3;15(12):e0243213. Epub 2020 Dec 3.

Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.

Background: Women with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD), often have coronary microvascular dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population.

Methods: We evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables.

Results: Overall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = <0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively).

Conclusion: Among women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243213PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714343PMC
January 2021

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project.

Int J Cardiol 2021 Mar 14;327:25-30. Epub 2020 Nov 14.

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA. Electronic address:

Aims: Women with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction.

Methods And Results: Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02-1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73-0.96 95%CI] vs. 0.65 [0.60-0.71 95%CI], respectively, P = 0.007).

Conclusion: The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.006DOI Listing
March 2021