Characterization of emergent toxigenic M1UK Streptococcus pyogenes and associated sublineages.

Streptococcus pyogenes genotype emm1 is a successful, globally distributed epidemic clone that is regarded as inherently virulent. An emm1 sublineage, M1UK, that produces increased levels of SpeA toxin was associated with increased scarlet fever and invasive infections in England in 2015/2016. Defined by 27 SNPs in the core genome, M1UK is now dominant in England. To more fully characterize M1UK, we undertook comparative transcriptomic and proteomic analyses of M1UK and contemporary non-M1UK emm1 strains (M1global). Just seven genes were differentially expressed by M1UK compared with contemporary M1global strains. In addition to speA, five genes in the operon that includes glycerol dehydrogenase were upregulated in M1UK (gldA, mipB/talC, pflD, and phosphotransferase system IIC and IIB components), while aquaporin (glpF2) was downregulated. M1UK strains have a stop codon in gldA. Deletion of gldA in M1global abrogated glycerol dehydrogenase activity, and recapitulated upregulation of gene expression within the operon that includes gldA, consistent with a feedback effect. Phylogenetic analysis identified two intermediate emm1 sublineages in England comprising 13/27 (M113SNPs) and 23/27 SNPs (M123SNPs), respectively, that had failed to expand in the population. Proteomic analysis of invasive strains from the four phylogenetic emm1 groups highlighted sublineage-specific changes in carbohydrate metabolism, protein synthesis and protein processing; upregulation of SpeA was not observed in chemically defined medium. In rich broth, however, expression of SpeA was upregulated ~10-fold in both M123SNPs and M1UK sublineages, compared with M113SNPs and M1global. We conclude that stepwise accumulation of SNPs led to the emergence of M1UK. While increased expression of SpeA is a key indicator of M1UK and undoubtedly important, M1UK strains have outcompeted M123SNPs and other emm types that produce similar or more superantigen toxin. We speculate that an accumulation of adaptive SNPs has contributed to a wider fitness advantage in M1UK on an inherently successful emm1 streptococcal background.

Safety and efficacy of off-label use of ivabradine in patients with acute heart failure.

BACKGROUND: Ivabradine is approved to improve exercise tolerance and quality of life in patients with chronic heart failure; its use in acute heart failure (AHF) has not previously been studied. METHODS: Forty adult patients admitted with AHF were randomized into two groups; Group 1 patients were prescribed beta-blockers (BBs) and Group 2 patients were prescribed ivabradine. Both groups were given optimum anti-failure treatment for AHF. All patients were assessed for heart rate (HR), 6-minute walk test (6MWT), New York Heart Association (NYHA) classification, and Minnesota Living With Heart Failure Questionnaire (MLWHFQ) before and after 1 month of therapy. RESULTS: BBs or ivabradine among optimum medical therapy for AHF resulted in a significant improvement in all the studied parameters (NYHA class; 6MWT distance; HR and Borg scale dyspnea/fatigue score before and after the walk). The MLWHFQ was significantly worse during the follow-up in both groups. At the end of follow-up, there was a comparable beneficial effect attributed to the significant HR reduction observed in both groups. CONCLUSION: The results of this pilot study demonstrated the safety of the early use of ivabradine alone versus BBs when tolerated in patients admitted with AHF (both acutely decompensated as well as de novo). Both groups achieved comparable reduction in HR with improvement in functional capacity and exercise tolerance.