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In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial (NCT02932566), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, -1.21%; 95% confidence interval, -2.12 to -0.31; P = 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials. In a double-blind, randomized phase 2 trial, treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the oral antifibrotic agent pirfenidone reduced myocardial fibrosis., Author(s): Gavin A. Lewis [sup.1] [sup.2] , Susanna Dodd [sup.3] , Dannii Clayton [sup.4] , Emma Bedson [sup.4] , Helen Eccleson [sup.4] , Erik B. Schelbert [sup.5] [sup.6] [sup.7] , [...]

Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells. TGF-β signaling also inhibited a cytotoxic program that includes granzymes and perforin expression at both early and late stages of infection in vivo and repressed the transcription factor eomesodermin. Overexpression of eomesodermin was sufficient to recapitulate in great part the phenotype of TGF-β receptor- deficient CD4 T cells, while SMAD4 was necessary for CD4 T cell accumulation and differentiation. TGF-β signaling also restricted accumulation and differentiation of CD4 T cells and reduced the expression of cytotoxic molecules in mice and humans infected with other persistent viruses. These data uncovered an eomesodermin-driven CD4 T cell program that is continuously suppressed by TGF-β signaling. During chronic viral infection, this program limits CD4 T cell responses while maintaining CD4 T helper cell identity., Introduction Chronic viral infections in both mice and humans create an immunosuppressive environment detrimental to both the on-going antiviral immune response as well as secondary immunity to unrelated pathogens or [...]

The Tertiary development of the Norwegian continental margin was dominated by the opening of the Arctic-North Atlantic Ocean. The correct identification of magnetic anomalies and their ages and the analysis of spreading rates during the formation of this ocean are important in understanding the development of the region and specifically the history of its passive margins. Three ocean domains, the AEgir, Reykjanes and Mohns regions, were investigated in an effort to understand the lateral changes in structural development of the passive margin after continental break-up. Spreading rates generally slowed down from 2 cm [a.sup.-1] after Early Eocene initiation of sea-floor spreading, to values around 0.5 cm [a.sup.-1] in Oligocene time. An increase in spreading rates to around 1 cm [a.sup.-1] coincided with the positioning of the Iceland hotspot under the North Atlantic mid-ocean ridge. At the same time, the European plate changed its absolute plate motion from a north-directed drift to a motion more towards the east. The location of inversion structures in the Voting and Faeroes Basin rather than in the More Basin is related to differences in spreading rates. The Mohns and the Reykjanes Ridges produced more ocean floor than the AEgir-Kolbeinsey Ridges. Asymmetric ocean-floor formation in the AEgir Ridge led to differential stress at the base of the lithosphere, which probably explains the absence of inversion features in the More Basin (less mantle drag). Furthermore, upper plate margins such as the Voting Basin and possibly the Faeroe Basin have a lower compressional strength than lower plate margins such as the More Basin, and therefore preferentially developed inversion structures. Along the transform boundaries separating the domains, additional stress probably built up along extension of the transform zones into the extended continental crust. This additional stress probably also assisted initiation of the inversion structures in the Voring Basin and the Faeroes area. The amplification of the inversion structures in the Voring Basin and the Faeroes Basin was subsequently caused by a variety of processes related to sedimentation and uplift-erosion. Keywords: Norwegian Sea, Tertiary, sea-floor spreading, passive margins, inversion tectonics.

'We have abandoned ideology. We simply do what works.' New Labour has made a virtue out of regularly claiming that it has no ideological or philosophical agenda. It has forsaken [...]