Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Differences in Bacterial Small RNAs in Stool Samples from Hypercholesterolemic and Normocholesterolemic Subjects

Cholesterol metabolism is important at the physiological level as well as in several diseases, with small RNA being an element to consider in terms of its epigenetic control. Thus, the aim of this study was to identify differences between bacterial small RNAs present at the gut level in hypercholesterolemic and normocholesterolemic individuals. Twenty stool samples were collected from hypercholesterolemic and normocholesterolemic subjects. RNA extraction and small RNA sequencing were performed, followed by bioinformatics analyses with BrumiR, Bowtie 2, BLASTn, DESeq2, and IntaRNA, after the filtering of the reads with fastp. In addition, the prediction of secondary structures was obtained with RNAfold WebServer. Most of the small RNAs were of bacterial origin and presented a greater number of readings in normocholesterolemic participants. The upregulation of small RNA ID 2909606 associated with Coprococcus eutactus (family Lachnospiraceae) was presented in hypercholesterolemic subjects. In addition, a positive correlation was established between small RNA ID 2149569 from the species Blautia wexlerae and hypercholesterolemic subjects. Other bacterial and archaeal small RNAs that interacted with the LDL receptor (LDLR) were identified. For these sequences, the prediction of secondary structures was also obtained. There were significant differences in bacterial small RNAs associated with cholesterol metabolism in hypercholesterolemic and normocholesterolemic participants

Core non-coding RNAs of <i>Piscirickettsia salmonis</i>

<div><p><i>Piscirickettsia salmonis</i>, a fastidious Gram-negative intracellular facultative bacterium, is the causative agent o Piscirickettsiosis. <i>P</i>. <i>salmonis</i> has broad host range with a nearly worldwide distribution, causing significant mortality. The molecular regulatory mechanisms of <i>P</i>. <i>salmonis</i> pathogenesis are relatively unknown, mainly due to its difficult <i>in vitro</i> culture and genomic differences between genogroups. Bacterial non-coding RNAs (ncRNAs) are important post-transcriptional regulators of bacterial physiology and virulence that are predominantly transcribed from intergenic regions (<i>trans</i>-acting) or antisense strand of open reading frames (<i>cis</i>-acting). The repertoire of ncRNAs present in the genome of <i>P</i>. <i>salmonis</i> and its possible role in bacterial physiology and pathogenesis are unknown. Here, we predicted and analyzed the core ncRNAs of <i>P</i>. <i>salmonis</i> base on structure and correlate this prediction to RNA sequencing data. We identified a total of 69 ncRNA classes related to tRNAs, rRNA, thermoregulators, antitoxins, ribozymes, riboswitches, miRNAs and antisense-RNAs. Among these ncRNAs, 29 classes of ncRNAs are shared between all <i>P</i>. <i>salmonis</i> genomes, constituting the core ncRNAs of <i>P</i>. <i>salmonis</i>. The ncRNA core of <i>P</i>. <i>salmonis</i> could serve to develop diagnostic tools and explore the role of ncRNA in fish pathogenesis.</p></div

Predicted <i>P</i>. <i>salmonis</i> GacS/GacA-CsrA/CsrB/CsrC regulatory system.

<p>Predicted <i>P</i>. <i>salmonis</i> GacS/GacA-CsrA/CsrB/CsrC regulatory system.</p

Number of ncRNA per family, the most abundant RNA families as was expected where tRNA, rRNA and sRNA.

<p>The number of rRNA in certain genomes varies attributable to the number of contigs. Also in all the analyzed genomes were predicted miRNA-like.</p

Hierarchical clustering of RNA family content in each <i>P</i>. <i>salmonis</i> strain.

<p>Presence of ncRNA classes are represented in red and the absence in white.</p

Clustering based on ncRNAs classes.

<p>Similarities between each <i>P</i>. <i>salmonis</i> strain was calculated based on Euclidean distance, using ncRNAs classes content between each <i>P</i>. <i>salmonis</i> strain are represented in each square. Low distance (in red) means a similar ncRNAs classes content and a high distance (in black) means many differences in ncRNAs classes.</p

Genomes of <i>P</i>. <i>salmonis</i> utilized in this study.

<p>Genomes of <i>P</i>. <i>salmonis</i> utilized in this study.</p

Windmill ncRNAs.

<p><b>A.</b> Graphic representation of the ncrNAs core in <i>P</i>. <i>salmonis</i>. In middle shows the number of ncRNAs present in all genomes of <i>P</i>. <i>salmonis</i> and in the leaves are the number of ncRNAs for genome. <b>B.</b> Venn diagram between predictions by structure from StructRNAfinder and sRNA-Detected by transcriptomics analysis.</p

ncRNA core predicted in <i>P</i>. <i>salmonis</i>.

<p>ncRNA core predicted in <i>P</i>. <i>salmonis</i>.</p