Cytokines as potential novel therapeutic targets in severe inflammatory cardiomyopathy

BACKGROUND: Despite currently available state-of-the art therapies, a substantial proportion of patients with inflammatory cardiomyopathy progresses to advanced heart failure. There is an urgent need for novel therapies to improve outcomes. We hypothesized that elevated cyto-kine levels in inflammatory cardiomyopathy may lead to cardiac injury and that specific cyto-kines are associated with severely decreased left ventricular function consequently, thereby suggesting their potential as therapeutic targets. METHODS AND RESULTS: Blood samples collected from 529 patients at 2 registries were inves-tigated. First, in a derivation cohort of inflammatory cardiomyopathy from our medical center (n=63), we discovered cytokines that correlate inversely with severely decreased left ventricu-lar ejection fraction (LVEF). We confirmed reproducibility of our results in an independent cohort from a national registry (n=425) and to some degree generalizability in a small cohort of idiopathic dilated cardiomyopathy (IDCM, n=41). In total, we identified 82 cytokines asso-ciated with severely decreased LVEF (FDR < 0.05); a small portion had been previously pro-posed as therapeutic targets, while others emerged as novel discoveries. Finally, real-world data from electronic medical records further indicated the potential of inhibitors targeting cy-tokines of interest to confer a cardioprotective effect. CONCLUSIONS: We identified 82 cytokines associated with severe inflammatory cardiomyopa-thy. Our data were highly significant, reproducible, and generalizable to IDCM. The fact that some of the cytokines had been suggested as potential targets in prior literature supports va-lidity and plausibility of our data. Given that inhibition of cytokines is technically feasible, the identified proteins are compelling potential novel therapeutic targets

Male carriers of HLA-C*04:01 have increased risk of cardiac injury in COVID-19

Identification of factors that lead to the severe clinical course of COVID-19 is crucial for timely allocation of resources. The purpose of this study was to evaluate possible sex differences in cardiac injury associated with HLA-C*04:01. High sensitivity troponin T on admission (hs-TnTa) and maximum high sensitivity troponin T (hs-TnTmax) were used to assess for cardiac injury in patients with COVID-19 (n = 435). We tested for the association of elevated hs-TnT with HLA-C* 04:01 and evaluated for potential sex-specific differences. An association between hs-TnTa and the severity of clinical course was identified. In addition, our study revealed that hs-TnTmax was higher in men who were carriers of HLA-C*04:01 compared to men without the risk allele. Male carriers of HLA-C*04:01 with COVID-19 developed higher hs-TnTmax, suggesting a larger extent of cardiac injury. This association suggests the presence of different pathomechanisms in COVID-19 based on sex

Highly multiplexed immune repertoire sequencing links multiple lymphocyte classes with severity of response to COVID-19

BACKGROUND: Disease progression of subjects with coronavirus disease 2019 (COVID-19) varies dramatically. Understanding the various types of immune response to SARS-CoV-2 is critical for better clinical management of coronavirus outbreaks and to potentially improve future therapies. Disease dynamics can be characterized by deciphering the adaptive immune response. METHODS: In this cross-sectional study we analyzed 117 peripheral blood immune repertoires from healthy controls and subjects with mild to severe COVID-19 disease to elucidate the interplay between B and T cells. We used an immune repertoire Primer Extension Target Enrichment method (immunoPETE) to sequence simultaneously human leukocyte antigen (HLA) restricted T cell receptor beta chain (TRB) and unrestricted T cell receptor delta chain (TRD) and immunoglobulin heavy chain (IgH) immune receptor repertoires. The distribution was analyzed of TRB, TRD and IgH clones between healthy and COVID-19 infected subjects. Using McFadden's Adjusted R2 variables were examined for a predictive model. The aim of this study is to analyze the influence of the adaptive immune repertoire on the severity of the disease (value on the World Health Organization Clinical Progression Scale) in COVID-19. FINDINGS: Combining clinical metadata with clonotypes of three immune receptor heavy chains (TRB, TRD, and IgH), we found significant associations between COVID-19 disease severity groups and immune receptor sequences of B and T cell compartments. Logistic regression showed an increase in shared IgH clonal types and decrease of TRD in subjects with severe COVID-19. The probability of finding shared clones of TRD clonal types was highest in healthy subjects (controls). Some specific TRB clones seems to be present in severe COVID-19 (Figure S7b). The most informative models (McFadden´s Adjusted R2=0.141) linked disease severity with immune repertoire measures across all three cell types, as well as receptor-specific cell counts, highlighting the importance of multiple lymphocyte classes in disease progression. INTERPRETATION: Adaptive immune receptor peripheral blood repertoire measures are associated with COVID-19 disease severity

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. METHODS: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ((n) = 135), Spain ((n) = 133), Switzerland ((n) = 20) and the United States ((n) = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). FINDINGS: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted (p)-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. INTERPRETATION: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2

Multicriteria evaluation of the use of multiband dynamic compressors in audio recording defects elimination

W pracy przedstawiono wielokryterialną ocenę czterech kompresorów dynamiki zastosowanych do usuwania defektów nagrań. Przyjęto pięć kryteriów oceny kompresorów. Ocenę kompresorów przeprowadzili eksperci (producenci nagrań i reżyserzy dźwięku). Po ocenie zgodności opinii ekspertów zbudowano ranking użyteczności kompresorów.This paper presents a multicriteria evaluation of four dynamic compressors used to audio recording's defects elimination. Five evaluation criteria has been chosen. The evaluation has been made by experts (music producers and sound engineers) in Likert scale from 0 to 5. After evaluation ofconformity of experts', a ranking of usability of compressor has been made

Structural and Mössbauer effect studies of Dy(Fe0.4Co0.6-x Alx)2 intermetallics

The magnetic hyperfine fields observed at the 57Fe nuclei (77 K) in the Dy(Mn1-xFex)2 and Dy(Fe1-xCox)2 intermetallics form a Slater-Pauling curve. In order to study the effect of cobalt atoms on crystal structure and hyperfine interactions, the new Co/Al substituted series Dy(Fe0.4Co0.6-xAlx)2 was prepared and data of X-ray powder analysis are presented (300 K). From the 57Fe Mössbauer measurements at 77 K the hyperfine parameters were obtained. The magnetic hyperfine fields form a branch of the Slater-Pauling curve

Hyperfine interactions in Ho(Fe1-xCox)2 compounds at 295 K

Synthesis of Ho(Fe1–xCox)2 intermetallic compounds, studies of their crystal structure and 57Fe Mössbauer effect analysis were carried out at 295 K. X-ray measurements evidence a pure cubic Fd3m, C15, MgCu2-type Laves phase. The unit cell parameter decreases non-linearly with composition parameter x. Mössbauer effect spectra for the Ho(Fe1–xCox)2 series were composed of a number of locally originated subspectra due to random Fe/Co nearest neighbourhoods. Hyperfine interaction parameters, i.e. isomer shift, the magnetic hyperfine field and a quadrupole interaction parameter were determined from the fitting procedure of the spectra, for both the individual nearest neighbourhoods, and for the sample as bulk. As a consequence of Fe/Co substitution a Slater-Pauling type curve for the average magnetic hyperfine field vs. x is observed. The correlation between the local magnetic hyperfine fields and the average magnetic hyperfine fields is related to weak and strong ferromagnetism of the transition metal sublattice

nr0466.p65

Abstract A consequence of the Fe/Ni substitution in the series of Dy(Fe 0.7−x Ni x Co 0.3 ) 2 was studied in the presented paper. The synthesis and X-ray analysis (300 K) of the Dy(Fe 0.7−x Ni x Co 0.3 ) 2 system were performed. The cubic, MgCu 2 -type, Fd3m crystal structure was evidenced for this solid solution