Search

Many cardiac disorders result in regionally altered myocardial mechanics. Although myocardial strain distributions can be measured experimentally and clinically, regional wall stresses must be computed from computational models. Combining these approaches can provide insight into the structural basis of regional dysfunction under conditions such as acute myocardial infarction and ischemia-reperfusion. Recently, 3-dimensional computational models have helped to elucidate the structural basis of the functional border zone adjacent to acutely ischemic myocardium. They have also shown that heterogeneous dysfunction in ischemic-reperfused stunned myocardium does not necessarily imply heterogeneous myofilament injury. Now that computational models are able to reproduce many complex features of the 3-dimensional patterns of regional myocardial deformation observed experimentally, we suggest possible roles for such integrative models in clinical diagnosis. [ABSTRACT FROM AUTHOR]

Perfusion assessed in the cardiac catheterization laboratory predicts outcomes after myocardial infarction. The aim of this study was to investigate a novel method of assessing perfusion using digital subtraction angiography to generate a time-density curve (TDC) of myocardial blush, incorporating epicardial and myocardial perfusion. Seven pigs underwent temporary occlusion of the left anterior descending coronary artery for 60 minutes. Angiography was performed in the same projections before, during, and after occlusion. Perfusion parameters were obtained from the TDC and compared with Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade. In addition, safety and feasibility were tested in 8 patients after primary percutaneous coronary intervention. The contrast density differential between the proximal artery and the myocardium derived from the TDC correlated well with TIMI myocardial perfusion grade (R = 0.54, p <0.001). The arterial transit time derived from the TDC correlated with TIMI frame count (R = 0.435, p = 0.011). Using a cutoff of 2.4, the density/time ratio, a ratio of density differential to transit time, had sensitivity and specificity of 100% for coronary arterial occlusion. The positive and negative predictive values were 100%. The generation of a TDC was safe and feasible in 7 patients after acute myocardial infarctions, but the correlation between TDC-derived parameters and TIMI parameters did not reach statistical significance. In conclusion, this novel method of digital subtraction angiography with rapid, automated, quantitative assessment of myocardial perfusion in the cardiac catheterization laboratory correlates well with established angiographic measures of perfusion. Further studies to assess the prognostic value of this technique are warranted. [ABSTRACT FROM AUTHOR]

Background: Relationships between lifestyle risk factors and cardiovascular disease (CVD) risk in women with breast cancer (BC) are underexplored., Objectives: To evaluate the incidence of CVD in relation to the Life's Essential 8 (LE8) score among women with BC., Methods: Data from the Women's Health Initiative were utilized. The primary exposure was the LE8 score assessed prior to BC diagnosis. The LE8 score was stratified into low (0-59), moderate (60-79), and high (80-100) cardiovascular health (CVH). The primary endpoint was a composite of incident CVD events, which included coronary heart disease, defined as myocardial infarction along with coronary revascularization, CVD death, and stroke. We calculated the cumulative incidence of CVD and estimated hazard ratios., Results: Among 7,165 participants, the median age was 70.1 years at BC diagnosis. The mean LE8 score was 62.0 ± 12.2. Over a median follow-up period of 6 years, 490 composite CVD events occurred. The risk of CVD events was highest for low CVH compared with moderate and high CVH. Compared with low CVH, the hazard ratio for incident CVD was 0.57 (95% CI: 0.46-0.69) for moderate CVH and 0.34 (95% CI: 0.20-0.59) for high CVH. LE8, in conjunction with age, provided a C-statistic of 0.74 for the composite risk of CVD., Conclusions: Higher LE8 scores were associated with a lower risk of incident CVD among women with BC in the United States., Competing Interests: The WHI program is funded by National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was partially funded by a grant from Alpha Phi. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Ischemia with non-obstructive coronary arteries (INOCA) is a major clinical entity that involves potentially 20%-30% of patients with chest pain. INOCA is typically attributed either to coronary microvascular disease and/or vasospasm, but is likely distinct from classical coronary artery disease (CAD)., Objectives: To gain insights into the etiology of INOCA and CAD, RNA sequencing of whole blood from patients undergoing both stress testing and elective invasive coronary angiography (ICA) was conducted., Methods: Stress testing and ICA of 177 patients identified 40 patients (23%) with INOCA compared to 39 controls (stress-, ICA-). ICA+ patients divided into 38 stress- and 60 stress+. RNAseq was performed by Illumina with ribosomal RNA depletion. Transcriptome changes were analyzed by DeSeq2 and curated by manual and automated methods., Results: Differentially expressed genes for INOCA were associated with elevated levels of transcripts related to mucosal-associated invariant T (MAIT) cells, plasmacytoid dendritic cells (pcDC), and memory B cells, and were associated with autoimmune diseases such as rheumatoid arthritis. Decreased transcripts were associated with neutrophils, but neutrophil transcripts, per se , were not less abundant in INOCA. CAD transcripts were more related to T cell functions., Conclusions: Elevated transcripts related to pcDC, MAIT, and memory B cells suggest an autoimmune component to INOCA. Reduced neutrophil transcripts are likely attributed to chronic activation leading to increased translation and degradation. Thus, INOCA could result from stimulation of B cell, pcDC, invariant T cell, and neutrophil activation that compromises cardiac microvascular function., Competing Interests: TM, TJ, and IT have an equity interest in True Bearing Diagnostics, Inc., a diagnostics company developing RNA biomarkers for various diseases, including coronary artery disease. IT and TM are seeking patent protection for a commercial diagnostic test, without restriction for research uses. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Jaatinen, Shah, Mazhari, Hayden, Wargowsky, Jepson, Toma, Perkins and McCaffrey.)

Current serological tests cannot differentiate between total immunoglobulin A (IgA) and dimeric IgA (dIgA) associated with mucosal immunity. Here, we describe two new assays, dIgA-ELISA and dIgA-multiplex bead assay (MBA), that utilize the preferential binding of dIgA to a chimeric form of secretory component, allowing the differentiation between dIgA and monomeric IgA. dIgA responses elicited through severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were measured in (i) a longitudinal panel, consisting of 74 samples (n = 20 individuals) from hospitalized cases of coronavirus disease 2019 (COVID-19); (ii) a longitudinal panel, consisting of 96 samples (n = 10 individuals) from individuals with mild COVID-19; (iii) a cross-sectional panel with PCR-confirmed SARS-CoV-2 infection with mild COVID-19 (n = 199) and (iv) pre-COVID-19 samples (n = 200). The dIgA-ELISA and dIgA-MBA demonstrated a specificity for dIgA of 99% and 98.5%, respectively. Analysis of dIgA responses in the longitudinal panels revealed that 70% (ELISA) and 50% (MBA) of patients elicited a dIgA response by day 20 after PCR diagnosis with a SARS-CoV-2 infection. Individuals with mild COVID-19 displayed increased levels of dIgA within the first 3 weeks after diagnosis but responses appeared to be short lived, compared with sustained IgA levels. However, in samples from hospitalized patients with COVID-19 we observed high and sustained levels of dIgA, up to 245 days after PCR diagnosis. Our results suggest that severe COVID-19 infections are associated with sustained levels of plasma dIgA compared with mild cases., (© 2023 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Background: Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography either by invasive catheterization (ICA) or computed tomography (CTA). Prior studies employed single-molecule, amplification-independent RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. The present studies employed Illumina RNAseq and network co-expression analysis to identify systematic changes underlying CAD., Methods: Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by Illumina total RNA sequencing (RNAseq) to identify transcripts associated with CAD in 177 patients presenting for elective invasive coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs) and to identify patterns of changes through whole genome co-expression network analysis (WGCNA)., Results: The correlation between Illumina amplified RNAseq and the prior SeqLL unamplified RNAseq was quite strong (r = 0.87), but there was only 9 % overlap in the DEGs identified. Consistent with the prior RNAseq, the majority (93 %) of DEGs were down-regulated ~1.7-fold in patients with moderate to severe CAD (>20 % stenosis). DEGs were predominantly related to T cells, consistent with known reductions in Tregs in CAD. Network analysis did not identify pre-existing modules with a strong association with CAD, but patterns of T cell dysregulation were evident. DEGs were enriched for transcripts associated with ciliary and synaptic transcripts, consistent with changes in the immune synapse of developing T cells., Conclusions: These studies confirm and extend a novel mRNA signature of a Treg-like defect in CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse., Competing Interests: Declaration of competing interest TM, TJ, and IT have an equity interest in True Bearing Diagnostics, Inc., a diagnostics company developing RNA biomarkers for various diseases, including coronary artery disease. IT, GSL3, RK, and TM are seeking patent protection for a commercial diagnostic test, without restriction for research uses. DJ is the CEO of, and equity holder in SeqLL, Inc.

As progress towards malaria elimination continues, the challenge posed by the parasite species Plasmodium vivax has become more evident. In many regions co-endemic for P. vivax and Plasmodium falciparum , as transmission has declined the proportion of cases due to P. vivax has increased. Novel tools that directly target P. vivax are thus warranted for accelerated elimination. There is currently no advanced vaccine for P. vivax and only a limited number of potential candidates in the pipeline. In this study we aimed to identify promising P. vivax proteins that could be used as part of a subunit vaccination approach. We screened 342 P . vivax protein constructs for their ability to induce IgG antibody responses associated with protection from clinical disease in a cohort of children from Papua New Guinea. This approach has previously been used to successfully identify novel candidates. We were able to confirm previous results from our laboratory identifying the proteins reticulocyte binding protein 2b and StAR-related lipid transfer protein, as well as at least four novel candidates with similar levels of predicted protective efficacy. Assessment of these P. vivax proteins in further studies to confirm their potential and identify functional mechanisms of protection against clinical disease are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mazhari, Takashima, Longley, Ruybal-Pesantez, White, Kanoi, Nagaoka, Kiniboro, Siba, Tsuboi and Mueller.)

Objectives: This study aims to compare veterans and non-veterans undergoing transcatheter aortic valve replacement (TAVR) using data from the Society for Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) registry., Methods: Patients undergoing TAVR at George Washington University (GWU) and veterans treated at Washington DC Veterans Affairs Medical Center (VAMC) who underwent TAVR at GWU from 2014-2020 were included. All patients were reported in the TVT registry. Emergency and valve-in-valve TAVR were excluded. Cohorts were divided based on veteran status. Operators were the same for both groups. Outcomes were compared at 30 days and 1 year. The primary outcome was mortality and secondary outcomes were morbidity metrics., Results: A total of 299 patients (91 veterans, 208 non-veterans) were included. Veterans had higher rates of hypertension (87.9% vs 77.9%; P=.04), diabetes (46.7% vs 28.9%; P<.01), and lung disease (2.4% vs 11.0%; P<.001). Outcomes were not significantly different between veterans and non-veterans, including 30-day mortality (0% vs 2.9%, respectively; P=.18), 1-year mortality (9.8% vs 10.7%, respectively; P=.61), stroke incidence (0% vs 2.5%, respectively; P=.73), median intensive care unit stay (24 hours in both groups), and overall hospital stay (2 days in both groups)., Conclusions: The affiliation between a VAMC and an academic medical center allowed for direct comparison between veterans and non-veterans undergoing TAVR by the same operators using the TVT registry. Despite significantly higher rates of comorbidities, veterans had equivalent outcomes compared with non-veterans. This may be in part due to the comprehensive care that veterans receive in the VAMC and this institution's integrated heart center team.

Serological markers are a promising tool for surveillance and targeted interventions for Plasmodium vivax malaria. P. vivax is closely related to the zoonotic parasite P. knowlesi, which also infects humans. P. vivax and P. knowlesi are co-endemic across much of South East Asia, making it important to design serological markers that minimize cross-reactivity in this region. To determine the degree of IgG cross-reactivity against a panel of P. vivax serological markers, we assayed samples from human patients with P. knowlesi malaria. IgG antibody reactivity is high against P. vivax proteins with high sequence identity with their P. knowlesi ortholog. IgG reactivity peaks at 7 days post-P. knowlesi infection and is short-lived, with minimal responses 1 year post-infection. We designed a panel of eight P. vivax proteins with low levels of cross-reactivity with P. knowlesi. This panel can accurately classify recent P. vivax infections while reducing misclassification of recent P. knowlesi infections., Competing Interests: Declaration of interests R.L., M.W., T.T., and and I.M. are inventors on filed patent PCT/US17/67926 on a system, method, apparatus, and diagnostic test for P. vivax. M.H. was an employee of the company CellFree Sciences Co., Ltd., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Plasmodium vivax is emerging as the dominant and prevalent species causing malaria in near-elimination settings outside of Africa. Hypnozoites, the dormant liver stage parasite of P. vivax, are undetectable to any currently available diagnostic test, yet are a major reservoir for transmission. Advances have been made to harness the naturally acquired immune response to identify recent exposure to P. vivax blood-stage parasites and, therefore, infer the presence of hypnozoites. This in-development diagnostic is currently able to detect infections within the last 9-months with 80% sensitivity and 80% specificity. Further work is required to optimize protein expression and protein constructs used for antibody detection., Methods: The antibody response against the top performing predictor of recent infection, P. vivax reticulocyte binding protein 2b (PvRBP2b), was tested against multiple fragments of different sizes and from different expression systems. The IgG induced against the recombinant PvRBP2b fragments in P. vivax infected individuals was measured at the time of infection and in a year-long observational cohort; both conducted in Thailand., Results: The antibody responses to some but not all different sized fragments of PvRBP2b protein are highly correlated with each other, significantly higher 1-week post-P. vivax infection, and show potential for use as predictors of recent P. vivax infection., Conclusions: To achieve P. vivax elimination goals, novel diagnostics are required to aid in detection of hidden parasite reservoirs. PvRBP2b was previously shown to be the top candidate for single-antigen classification of recent P. vivax exposure and here, it is concluded that several alternative recombinant PvRBP2b fragments can achieve equal sensitivity and specificity at predicting recent P. vivax exposure., (© 2022. The Author(s).)

The CYP2D6 enzyme is estimated to metabolize 25% of commonly used pharmaceuticals and is of intense pharmacogenetic interest due to the polymorphic nature of the CYP2D6 gene. Accurate allele typing of CYP2D6 has proved challenging due to frequent copy number variants (CNVs) and paralogous pseudogenes. SNP-arrays, qPCR and short-read sequencing have been employed to interrogate CYP2D6, however these technologies are unable to capture longer range information. Long-read sequencing using the PacBio Single Molecule Real Time (SMRT) sequencing platform has yielded promising results for CYP2D6 allele typing. However, previous studies have been limited in scale and have employed nascent data processing pipelines. We present a robust data processing pipeline "PLASTER" for accurate allele typing of SMRT sequenced amplicons. We demonstrate the pipeline by typing CYP2D6 alleles in a large cohort of 377 Solomon Islanders. This pharmacogenetic method will improve drug safety and efficacy through screening prior to drug administration., (© 2022. The Author(s).)

Serology tests are extremely useful for assessing whether a person has been infected with a pathogen. Since the onset of the COVID-19 pandemic, measurement of anti-SARS-CoV-2-specific antibodies has been considered an essential tool in identifying seropositive individuals and thereby understanding the extent of transmission in communities. The Luminex system is a bead-based technology that has the capacity to assess multiple antigens simultaneously using very low sample volumes and is ideal for high-throughput studies. We have adapted this technology to develop a COVID-19 multi-antigen serological assay. This protocol described here carefully outlines recommended steps to optimize and establish this method for COVID-19-specific antibody measurement in plasma and in saliva. However, the protocol can easily be customized and thus the assay is broadly applicable to measure antibodies to other pathogens.

Background: Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography. Surprisingly, despite well-established clinical indications, up to 40% of the one million invasive cardiac catheterizations return a result of 'no blockage'. The present studies employed RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD., Methods: Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by single-molecule sequencing of RNA (RNAseq) to identify transcripts associated with CAD (TRACs) in a discovery group of 96 patients presenting for elective coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs)., Results: Surprisingly, 98% of DEGs/TRACs were down-regulated ~ 1.7-fold in patients with mild to severe CAD (> 20% stenosis). The TRACs were independent of comorbid risk factors for CAD, such as sex, hypertension, and smoking. Bioinformatic analysis identified an enrichment in transcripts such as FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A that are likely markers of regulatory T cells (Treg), consistent with known reductions in Tregs in CAD. A validation cohort of 80 patients confirmed the overall pattern (92% down-regulation) and supported many of the Treg-related changes. TRACs were enriched for transcripts associated with stress granules, which sequester RNAs, and ciliary and synaptic transcripts, possibly consistent with changes in the immune synapse of developing T cells., Conclusions: These studies identify a novel mRNA signature of a Treg-like defect in CAD patients and provides a blueprint for a diagnostic test for CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse., (© 2021. The Author(s).)

Multiplexed bead-based assays that use Luminex® xMAP® technology have become popular for measuring antibodies against proteins of interest in many fields, including malaria and more recently SARS-CoV-2/COVID-19. There are currently two formats that are widely used: non-magnetic beads or magnetic beads. Data are lacking regarding the comparability of results obtained using these two types of beads, and for assays run on different instruments. Whilst non-magnetic beads can only be run on flow-based instruments (such as the Luminex® 100/200™ or Bio-Plex® 200), magnetic beads can be run on both these and the newer MAGPIX® instruments. In this study we utilized a panel of purified recombinant Plasmodium vivax proteins and samples from malaria-endemic areas to measure P. vivax-specific IgG responses using different combinations of beads and instruments. We directly compared: i) non-magnetic versus magnetic beads run on a Bio-Plex® 200, ii) magnetic beads run on the Bio-Plex® 200 versus MAGPIX® and iii) non-magnetic beads run on a Bio-Plex® 200 versus magnetic beads run on the MAGPIX®. We also performed an external comparison of our optimized assay. We observed that IgG antibody responses, measured against our panel of P. vivax proteins, were moderately-strongly correlated in all three of our comparisons (pearson r>0.5 for 18/19 proteins), however higher amounts of protein were required for coupling to magnetic beads. Our external comparison indicated that results generated in different laboratories using the same coupled beads are also highly comparable (pearson r>0.7), particularly if a reference standard curve is used., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RJL, TT and IM are inventors on patent application PCT/US17/67926 on a system, method, apparatus and diagnostic test for Plasmodium vivax. MH is a paid employee of CellFree Sciences Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

γδ T cells play an essential role in the immune response to many pathogens, including Plasmodium . However, long-lasting effects of infection on the γδ T cell population still remain inadequately understood. This study focused on assessing molecular and functional changes that persist in the γδ T cell population following resolution of malaria infection. We investigated transcriptional changes and memory-like functional capacity of malaria pre-exposed γδ T cells using a Plasmodium chabaudi infection model. We show that multiple genes associated with effector function (chemokines, cytokines and cytotoxicity) and antigen-presentation were upregulated in P. chabaudi -exposed γδ T cells compared to γδ T cells from naïve mice. This transcriptional profile was positively correlated with profiles observed in conventional memory CD8 + T cells and was accompanied by enhanced reactivation upon secondary encounter with Plasmodium -infected red blood cells in vitro . Collectively our data demonstrate that Plasmodium exposure result in "memory-like imprints" in the γδ T cell population and also promotes γδ T cells that can support antigen-presentation during subsequent infections., (Copyright © 2020 Kumarasingha, Ioannidis, Abeysekera, Studniberg, Wijesurendra, Mazhari, Poole, Mueller, Schofield, Hansen and Eriksson.)

This study describes an approach to support decisions on the acquisition of innovative nursing technologies. The approach focusses a participatory design that involves nursing staff from the beginning of the process and aims at achieving positive results regarding identification with the decision of implementation and use of technologies by nursing staff.

A long-standing challenge in malaria is the limited understanding of B cell immunity, previously hampered by lack of tools to phenotype rare antigen-specific cells. Our aim was to develop a method for identifying carbohydrate-specific B cells within lymphocyte populations and to determine whether a candidate vaccine generated functional memory B cells (MBCs) that reactivated upon challenge with Plasmodium (pRBCs). To this end, a new flow cytometric probe was validated and used to determine the kinetics of B cell activation against the candidate vaccine glycosylphosphatidylinositol conjugated to Keyhole Limpet Haemocyanin (GPI-KLH). Additionally, immunized C57BL/6 mice were rested (10 weeks) and challenged with pRBCs or GPI-KLH to assess memory B cell recall against foreign antigen. We found that GPI-specific B cells were detectable in GPI-KLH vaccinated mice, but not in Plasmodium -infected mice. Additionally, in previously vaccinated mice GPI-specific IgG1 MBCs were reactivated against both pRBCs and synthetic GPI-KLH, which resulted in increased serum levels of anti-GPI IgG in both challenge approaches. Collectively our findings contribute to the understanding of B cell immunity in malaria and have important clinical implications for inclusion of carbohydrate conjugates in malaria vaccines.

Transcatheter aortic valve implantation (TAVI) is an acceptable treatment for severe aortic stenosis in high or intermediate risk patients. Conduction abnormalities are a known complication of TAVI. Most abnormalities occur perioperatively but can develop later. The predictors of delayed conduction abnormalities are unknown. Patients who underwent TAVI at our institution were reviewed. Patients with a pre-existing pacemaker were excluded. Baseline, in-hospital, and 30-day follow-up ECGs were reviewed. Patient and procedural characteristics were analyzed to look for predictors of acute and delayed abnormalities. Ninety-eight patients were included. All valves implanted were balloon expandable, most commonly SAPIEN S3 (78%). Thirty-seven (37.7%) patients developed abnormalities before discharge. Of these patients, 20 (57.1%) had complete resolution at 30-day follow-up. No patients with new conduction abnormalities during hospitalization had additional abnormalities at 30-day follow-up. Five (5.1%) patients developed new conduction abnormalities following discharge. Overall, 22 (22.4%) patients had conduction abnormalities at 30-day follow-up which were not present at baseline. Predilatation (p = 0.003), higher ratios of balloon (p = 0.03) or valve (p = 0.05) size to left ventricular outflow tract, and previous myocardial infarction (p = 0.034) were predictive of acute conduction abnormalities. Baseline right bundle branch block (p = 0.002), longer baseline (p <0.001) and discharge (p = 0.004) QRS duration, moderate, or severe aortic insufficiency (p = 0.002) and atrial fibrillation (p = 0.031) were predictors of new conduction abnormalities after discharge. In conclusion, most new in-hospital conduction abnormalities resolve by 30-day follow-up. In-hospital conduction abnormalities are related to technical aspects of TAVI while delayed conduction abnormalities are related to baseline conduction system disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)