The involvement of toll-like receptor 9 (TLR9), a receptor for bacterial DNA, in septic cardiac depression has not been clarified in vivo. Thus, the aim of the study was to test possible TLR9 inhibitors (H154-thioate, IRS954-thioate, and chloroquine) for their ability to protect the cardiovascular system in a murine model of CpG oligodeoxynucleotide- (ODN-) dependent systemic inflammation. Sepsis was induced by i.p. application of the TLR9 agonist 1668-thioate in C57BL/6 wild type (WT) and TLR9-deficient (TLR9-D) mice. Thirty minutes after stimulation TLR9 antagonists were applied i.v. Survival was monitored up to 18 h after stimulation. Cardiac mRNA expression of inflammatory mediators was analyzed 2 h and 6 h after stimulation with 1668-thioate and hemodynamic parameters were monitored at the later time point. Stimulation with 1668-thioate induced a severe sepsis-like state with significant drop of body temperature and significantly increased mortality in WT animals. Additionally, there was a time-dependent increase of inflammatory mediators in the heart accompanied by development of septic heart failure. These effects were not observed in TLR9-D mice. Inhibition of TLR9 by the suppressive ODN H154-thioate significantly ameliorated cardiac inflammation, preserved cardiac function, and improved survival. This suppressive ODN was the most efficient inhibitor of the tested substances.
A 3 4 7 -A 7 6 6 implement NICE recommendations. Similar results have been observed in France, where costs associated to NOAC prescriptions dispensed in the non-hospital setting have increased from € 56.3M in 2012 to € 309,8M in 2015. In response to increasing NOAC prescription, the ANSM and Assurance Maladie consider there is a need for increased vigilance in their use. These findings highlight the considerable increase in NOAC prescriptions and costs in both England and France, and should inform future policy efforts to encourage adequate use of NOACs in order to control increasing expenditure. ConClusions: Between 2012 and 2015, there was a considerable increase in NOAC drug expenditures from prescriptions dispensed in the non-hospital setting, in both England and France, which suggests that policies aimed at incentivizing NOAC prescriptions have been effective, but should further factor in the increasing economic impact of these treatments.
were excluded. Follow-up began after index date and continued until end of first drug exposure, end of continuous enrollment, all-cause death, or end of data, whichever was first. Multivariable Cox proportional hazard and Poisson regression was used to compare the effects of oral treprostinil to selexipag on PH-related hospitalization risk and rates, respectively. RESULTS: The study population included 99 patients treated with oral treprostinil and 123 patients treated with selexipag. The study population, on average, was 61 years old and predominately female (71%). After adjusting for confounders, selexipag reduced the risk for first PH-related hospitalization by 47% compared to oral treprostinil (hazard ratio: 0.53; 95% CI (confidence interval): 0.31, 0.93; p-value: 0.03). Compared to oral treprostinil, PH-related hospitalization rate with selexipag was reduced by 46% after adjusting for confounders (rate ratio: 0.54; 95% CI: 0.35, 0.82; p-value: 0.004). CONCLUSIONS: Selexipag is associated with lower PHrelated hospitalization risk and rates compared to oral treprostinil.
OBJECTIVES:A popular approach to estimate treatment effects is the meta-analysis of individual participant data (IPD). This study aimed to assess through IPD the impact of exercise-based cardiac rehabilitation (ExCR) on exercise capacity and health-related quality of life (HRQoL) and identify subgroups of patients with heart failure (HF) that may respond differently to ExCR. METHODS: The Exercise Training Meta-Analysis of Trials for Chronic Heart Failure (ExTraMATCH II) collected IPD from RCTs that compared exercise rehabilitation with a non-exercise control and a minimum follow-up of 6 months. Outcomes of interest were the 6 Minutes Walk Test (6MWT), peak volume of oxygen consumption (pVO2), the Minnesota Living with Heart Failure (MLHF) or other HRQoL questionnaires. The primary analyses included one-stage and two-stage IPD meta-analyses carried out at 6 and 12 months. All primary analyses used IPD hierarchical random effects regression models, adjusted for the baseline value of the outcome measure. RESULTS: Thirteen studies provided anonymised IPD for 3,000 patients (1,496 ExCR, 1,504 control) with a median followup of 33 weeks. Compared to control, average treatment effects from the one-stage meta-analysis over 12 months showed a significant improvement in MLHF: 5.94 (95% CI 1.0 to 10.9), standardised HRQoL score: 0.20 (95% CI 0.03 to 0.37), 6MWT: 21.0 (95% CI 1.57 to 40.4) and standardised exercise capacity score: 0.27 (95% CI 0.11 to 0.43) for patients assigned to ExCR. No significant difference in peak VO2 was observed: 1.01 (95% CI -0.42 to 2.44). Interaction analyses revealed no consistent interaction between the effect of ExCR and the predefined subgroups. CONCLUSIONS: Access to individual data from several RCTs allows to address important questions on the benefits of ExCR in HF failure. Results from this IPD must be discussed in light of findings from previous aggregate data meta-analyses on the same topic.
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