152 research outputs found

    Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

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    Auteurs : the PRECISION investigatorsInternational audienceBackground Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. Methods PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12‚ÄĘ5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. Findings The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was-15‚ÄĘ3 (SE 0‚ÄĘ9) mm Hg for aprocitentan 12‚ÄĘ5 mg,-15‚ÄĘ2 (0‚ÄĘ9) mm Hg for aprocitentan 25 mg, and-11‚ÄĘ5 (0‚ÄĘ9) mm Hg for placebo, for a difference versus placebo of-3‚ÄĘ8 (1‚ÄĘ3) mm Hg (97‚ÄĘ5% CI-6‚ÄĘ8 to-0‚ÄĘ8, p=0‚ÄĘ0042) and-3‚ÄĘ7 (1‚ÄĘ3) mm Hg (-6‚ÄĘ7 to-0‚ÄĘ8; p=0‚ÄĘ0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was-4‚ÄĘ2 mm Hg (95% CI-6‚ÄĘ2 to-2‚ÄĘ1) and-5‚ÄĘ9 mm Hg (-7‚ÄĘ9 to-3‚ÄĘ8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5‚ÄĘ8 mm Hg, 95% CI 3‚ÄĘ7 to 7‚ÄĘ9, p<0‚ÄĘ0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12‚ÄĘ5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. Interpretation In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40

    DV-QKD coexistence with 1.6 terabit/s classical channels in free space using fiber-wireless-fiber terminals

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    We experimentally demonstrate for the first time the simultaneous transmission of a COW-based DV-QKD channel and an 8√ó200 Gpbs 16-QAM coherent optical channels, both operating in the C-band over 2.5 m of free space enabled by Fiber-Wireless-Fiber terminals

    Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

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    ¬© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study‚ÄĒa multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3¬∑85 [95% CI 2¬∑58‚Äď5¬∑75]; p<0¬∑0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63¬∑0% vs 82¬∑7%; OR 0¬∑35 [0¬∑23‚Äď0¬∑53]; p<0¬∑0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research

    Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy

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    Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5‚Ä≤ AMP-activated protein kinase (AMPKőĪ1/őĪ2/ő≤2/ő≥1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment

    Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries