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Noninvasive vagus nerve stimulation as acute therapy for migraine. The randomized PRESTO study

Objective: To evaluate the efficacy, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS; gammaCore; electroCore, LLC, Basking Ridge, NJ) for the acute treatment of migraine in a multicenter, double-blind, randomized, sham-controlled trial. Methods: A total of 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 minutes from pain onset. Participants were to repeat treatment if pain had not improved in 15 minutes. Results: nVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 minutes (12.7% vs 4.2%; p = 0.012) and 60 minutes (21.0% vs 10.0%; p = 0.023) but not at 120 minutes (30.4% vs 19.7%; p = 0.067; primary endpoint; logistic regression) after the first treated attack. A post hoc repeatedmeasures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 minutes (odds ratio 2.3; 95% confidence interval 1.2, 4.4; p = 0.012). nVNS demonstrated benefits across other endpoints including pain relief at 120minutes and was safe and well-tolerated. Conclusion: This randomized sham-controlled trial supports the abortive efficacy of nVNS as early as 30 minutes and up to 60 minutes after an attack. Findings also suggest effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine

TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS

Reduced Cardiocirculatory Complications With Unrestrictive Visiting Policy in an Intensive Care Unit

Background— Observational studies suggest that open visiting policies are preferred by most patients and visitors in intensive care units (ICUs), but no randomized trial has compared the safety and health outcomes of unrestrictive (UVP) and restrictive (RVP) visiting policies. The aim of this pilot, randomized trial was to compare the complications associated with UVP (single visitor with frequency and duration chosen by patient) and RVP (single visitor for 30 minutes twice a day). Methods and Results— Two-month sequences of the 2 visiting policies were randomly alternated for 2 years in a 6-bed ICU, with 226 patients enrolled (RVP/UVP, n=115/111). Environmental microbial contamination, septic and cardiovascular complications, emotional profile, and stress hormones response were systematically assessed. Patients admitted during the randomly scheduled periods of UVP received more frequent (3.2±0.2 versus 2.0±0.0 visits per day, mean±SEM) and longer (2.6±0.2 versus 1.0±0.0 h/d) visits ( P <0.001 for both comparisons). Despite significantly higher environmental microbial contamination during the UVP periods, septic complications were similar in the 2 periods. The risk of cardiocirculatory complications was 2-fold (odds ratio 2.0; 95% CI, 1.1 to 3.5; P =0.03) in the RVP periods, which were also associated with a nonsignificantly higher mortality rate (5.2% versus 1.8%; P =0.28). The UVP was associated with a greater reduction in anxiety score and a significantly lower increase in thyroid stimulating hormone from admission to discharge. Conclusions— Despite greater environmental microbial contamination, liberalizing visiting hours in ICUs does not increase septic complications, whereas it might reduce cardiovascular complications, possibly through reduced anxiety and more favorable hormonal profile