Myoglobin for Detection of High-Risk Patients with Acute Myocarditis

There is an unmet need for accurate and practical screening to detect myocarditis. We sought to test the hypothesis that the extent of acute myocarditis, measured by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR), can be estimated based on routine blood markers. A total of 44 patients were diagnosed with acute myocarditis and included in this study. There was strong correlation between myoglobin and LGE (rs = 0.73 [95% CI 0.51; 0.87], p < 0.001), while correlation was weak between LGE and TnT-hs (rs = 0.37 [95% CI 0.09; 0.61], p = 0.01). Receiver operating curve (ROC) analysis determined myoglobin ≥ 87 μg/L as cutoff to identify myocarditis (92% sensitivity, 80% specificity). The data were reproduced in an established model of coxsackievirus B3 myocarditis in mice (n = 26). These data suggest that myoglobin is an accurate marker of acute myocarditis. Graphical Abstract Receiver operating curve analysis determined myoglobin ≥ 87 μg/L as cutoff to identify myocarditis and these data were reproduced in an established model of coxsackievirus B3 myocarditis in mice: CMRI, cardiac magnetic resonance imaging; Mb, myoglobin; LGE, late gadolinium enhancement; ROC, receiver operating curve analysis

Sex and age differences in sST2 in cardiovascular disease

AimsThe goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs).MethodsWe examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234).ResultsMyocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p &lt; 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02).ConclusionWe found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs

Simultaneous, Multi-Wavelength Variability Characterization of the Free-Floating Planetary Mass Object PSO J318.5-22

We present simultaneous HST WFC3 + Spitzer IRAC variability monitoring for the highly-variable young ($\sim$20 Myr) planetary-mass object PSO J318.5-22. Our simultaneous HST + Spitzer observations covered $\sim$2 rotation periods with Spitzer and most of a rotation period with HST. We derive a period of 8.6$\pm$0.1 hours from the Spitzer lightcurve. Combining this period with the measured $v sin i$ for this object, we find an inclination of 56.2$\pm 8.1^{\circ}$. We measure peak-to-trough variability amplitudes of 3.4$\pm$0.1$\%$ for Spitzer Channel 2 and 4.4 - 5.8$\%$ (typical 68$\%$ confidence errors of $\sim$0.3$\%$) in the near-IR bands (1.07-1.67 $\mu$m) covered by the WFC3 G141 prism -- the mid-IR variability amplitude for PSO J318.5-22 one of the highest variability amplitudes measured in the mid-IR for any brown dwarf or planetary mass object. Additionally, we detect phase offsets ranging from 200--210$^{\circ}$ (typical error of $\sim$4$^{\circ}$) between synthesized near-IR lightcurves and the Spitzer mid-IR lightcurve, likely indicating depth-dependent longitudinal atmospheric structure in this atmosphere. The detection of similar variability amplitudes in wide spectral bands relative to absorption features suggests that the driver of the variability may be inhomogeneous clouds (perhaps a patchy haze layer over thick clouds), as opposed to hot spots or compositional inhomogeneities at the top-of-atmosphere level.Comment: 48 pages, 22 figures, accepted to A

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).Supported by a grant (PI19/00545, to Dr. Martín) from the Ministry of Science and Innovation through the Carlos III Institute of Health–Fondo de Investigación Sanitaria; by a grant from the Biomedical Research Networking Center on Cardiovascular Diseases (to Drs. Martín, Sánchez-Madrid, and Ibáñez); by grants (S2017/BMD-3671-INFLAMUNE-CM, to Drs. Martín and Sánchez-Madrid; and S2017/BMD-3867-RENIM-CM, to Dr. Ibáñez) from Comunidad de Madrid; by a grant (20152330 31, to Drs. Martín, Sánchez-Madrid, and Alfonso) from Fundació La Marató de TV3; by grants (ERC-2011-AdG 294340-GENTRIS, to Dr. Sánchez-Madrid; and ERC-2018-CoG 819775-MATRIX, to Dr. Ibáñez) from the European Research Council; by grants (SAF2017-82886R, to Dr. Sánchez-Madrid; RETOS2019-107332RB-I00, to Dr. Ibáñez; and SAF2017-90604-REDT-NurCaMeIn and RTI2018-095928-BI00, to Dr. Ricote) from the Ministry of Science and Innovation; by Fondo Europeo de Desarrollo Regional (FEDER); and by a 2016 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation to Dr. Martín. The National Center for Cardiovascular Research (CNIC) is supported by the Carlos III Institute of Health, the Ministry of Science and Innovation, the Pro CNIC Foundation, and by a Severo Ochoa Center of Excellence grant (SEV-2015-0505). Mr. Blanco-Domínguez is supported by a grant (FPU16/02780) from the Formación de Profesorado Universitario program of the Spanish Ministry of Education, Culture, and Sports. Ms. Linillos-Pradillo is supported by a fellowship (PEJD-2016/BMD-2789) from Fondo de Garantía de Empleo Juvenil de Comunidad de Madrid. Dr. Relaño is supported by a grant (BES-2015-072625) from Contratos Predoctorales Severo Ochoa para la Formación de Doctores of the Ministry of Economy and Competitiveness. Dr. Alonso-Herranz is supported by a fellowship from La Caixa–CNIC. Dr. Caforio is supported by Budget Integrato per la Ricerca dei Dipartimenti BIRD-2019 from Università di Padova. Dr. Das is supported by grants (UG3 TR002878 and R35 HL150807) from the National Institutes of Health and the American Heart Association through its Strategically Focused Research Networks.S

From Data to Software to Science with the Rubin Observatory LSST

The Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) dataset will dramatically alter our understanding of the Universe, from the origins of the Solar System to the nature of dark matter and dark energy. Much of this research will depend on the existence of robust, tested, and scalable algorithms, software, and services. Identifying and developing such tools ahead of time has the potential to significantly accelerate the delivery of early science from LSST. Developing these collaboratively, and making them broadly available, can enable more inclusive and equitable collaboration on LSST science. To facilitate such opportunities, a community workshop entitled "From Data to Software to Science with the Rubin Observatory LSST" was organized by the LSST Interdisciplinary Network for Collaboration and Computing (LINCC) and partners, and held at the Flatiron Institute in New York, March 28-30th 2022. The workshop included over 50 in-person attendees invited from over 300 applications. It identified seven key software areas of need: (i) scalable cross-matching and distributed joining of catalogs, (ii) robust photometric redshift determination, (iii) software for determination of selection functions, (iv) frameworks for scalable time-series analyses, (v) services for image access and reprocessing at scale, (vi) object image access (cutouts) and analysis at scale, and (vii) scalable job execution systems. This white paper summarizes the discussions of this workshop. It considers the motivating science use cases, identified cross-cutting algorithms, software, and services, their high-level technical specifications, and the principles of inclusive collaborations needed to develop them. We provide it as a useful roadmap of needs, as well as to spur action and collaboration between groups and individuals looking to develop reusable software for early LSST science.Comment: White paper from "From Data to Software to Science with the Rubin Observatory LSST" worksho

From Data to Software to Science with the Rubin Observatory LSST

editorial reviewedThe Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) dataset will dramatically alter our understanding of the Universe, from the origins of the Solar System to the nature of dark matter and dark energy. Much of this research will depend on the existence of robust, tested, and scalable algorithms, software, and services. Identifying and developing such tools ahead of time has the potential to significantly accelerate the delivery of early science from LSST. Developing these collaboratively, and making them broadly available, can enable more inclusive and equitable collaboration on LSST science. To facilitate such opportunities, a community workshop entitled "From Data to Software to Science with the Rubin Observatory LSST" was organized by the LSST Interdisciplinary Network for Collaboration and Computing (LINCC) and partners, and held at the Flatiron Institute in New York, March 28-30th 2022. The workshop included over 50 in-person attendees invited from over 300 applications. It identified seven key software areas of need: (i) scalable cross-matching and distributed joining of catalogs, (ii) robust photometric redshift determination, (iii) software for determination of selection functions, (iv) frameworks for scalable time-series analyses, (v) services for image access and reprocessing at scale, (vi) object image access (cutouts) and analysis at scale, and (vii) scalable job execution systems. This white paper summarizes the discussions of this workshop. It considers the motivating science use cases, identified cross-cutting algorithms, software, and services, their high-level technical specifications, and the principles of inclusive collaborations needed to develop them. We provide it as a useful roadmap of needs, as well as to spur action and collaboration between groups and individuals looking to develop reusable software for early LSST science

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement

Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in NEU1 which encodes lysosomal sialidase (neuraminidase 1). Lysosomal neuraminidase catalyzes the removal of terminal sialic acid molecules from glycolipids, glycoproteins and oligosaccharides. Sialidosis is classified into two types, based on phenotype and age of onset. Patients with the milder type 1 typically present late, usually in the second or third decade, with myoclonus, ataxia and visual defects. Type 2 is more severe and presents earlier with coarse facial features, developmental delay, hepatosplenomegaly and dysostosis multiplex. Presentation and severity of the disease are related to whether lysosomal sialidase is inactive or there is some residual activity. Diagnosis is suspected based on clinical features and increased urinary bound sialic acid excretion and confirmed by genetic testing showing pathogenic variants in NEU1. We report a patient with type 1 sialidosis who presented mainly with ataxia and both generalized and myoclonic seizures but no visual involvement. Whole exome sequencing of the proband detected compound heterozygous likely pathogenic variants (S182G and G227R) in NEU1. Keywords: Sialidosis, Ataxia, Myoclonus, Neurodeaminiase, NEU

A Possible Newly Defined and Treatable Secondary Cause of Early Morning Wake-Up Headaches in an Older Hypermobile Woman: Nutcracker Physiology with Spinal Epidural Venous Congestion

Introduction Left renal vein compression (nutcracker physiology) with secondary spinal epidural venous congestion is a newly recognized cause of daily persistent headache. Presently only women with underlying symptomatic hypermobility issues appear to develop headache from this anatomic issue. The hypothesized etiology is an abnormal reset of the patient’s cerebrospinal fluid (CSF) pressure to an elevated state. Headaches that occur during sleep can have a varied differential diagnosis, one of which is elevated CSF pressure. We present the case of an older woman who began to develop severe wake-up headaches at midnight. She was found to have left renal vein compression and spinal epidural venous congestion on imaging. After treatment with lumbar vein coil embolization, which alleviated the spinal cord venous congestion, her headaches alleviated. Case Presentation A 61-year-old woman with a history of hypermobile Ehlers-Danlos syndrome, began to be awakened with severe head pain at midnight at least several times per week. The headache was a holocranial, pressure sensation, which worsened in the supine position. The headaches were mostly eliminated with acetazolamide. Because of her hypermobility issues and pressure-like headache she was investigated for underlying nutcracker physiology and spinal epidural venous congestion. This was confirmed using magnetic resonance (MR) angiography and conventional venography, and after lumbar vein coil embolization her wake-up headaches ceased. Conclusion The case report suggests a possible new underlying and treatable cause for early morning, wake-up, headaches: nutcracker physiology with secondary spinal epidural venous congestion. The case expands on the clinical headache presentation of nutcracker physiology

Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

Abstract Registry data worldwide indicate an overall female predominance for pulmonary arterial hypertension (PAH) of 2–4 over men. Genetic predisposition accounts for only 1–5% of PAH cases, while autoimmune diseases and infections are closely linked to PAH. Idiopathic PAH may include patients with undiagnosed autoimmune diseases based on the relatively high presence of autoantibodies in this group. The two largest PAH registries to date report a sex ratio for autoimmune connective tissue disease-associated PAH of 9:1 female to male, highlighting the need for future studies to analyze subgroup data according to sex. Autoimmune diseases that have been associated with PAH include female-dominant systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and thyroiditis as well as male-dominant autoimmune diseases like myocarditis which has been linked to HIV-associated PAH. The sex-specific association of PAH to certain infections and autoimmune diseases suggests that sex hormones and inflammation may play an important role in driving the pathogenesis of disease. However, there is a paucity of data on sex differences in inflammation in PAH, and more research is needed to better understand the pathogenesis underlying PAH in men and women. This review uses data on sex differences in PAH and PAH-associated autoimmune diseases from registries to provide insight into the pathogenesis of disease