Achieving regioselective materials binding using multidomain peptides

The ability to integrate two disparate materials-binding domains into a single ligand to achieve regiospecific binding would be powerful to direct material assembly; however, this has proven challenging to achieve due to cross-materials binding. Accomplishing this goal might be achieved by harnessing the precision of biology to exploit the recognition between peptides and specific nanomaterials. Here, a designed bifunctional molecule termed Biomolecular Exfoliant and Assembly Motifs (BEAM) is introduced, featuring two different materials-binding peptide domains, one for graphene and one for hexagonal boron nitride ( h -BN), at each end of the molecule, separated by a fatty acid spacer. The BEAM is demonstrated to bind strongly to both graphene and h -BN surfaces, and in each case the materials-binding peptide domain is shown to preferentially bind its target material. Critically, the two materials-binding domains exhibited limited cross-domain interaction. The BEAM design concept shows substantial potential to eventually guide self-organization of a range of materials in aqueous media

Prevalence, timing, and impact of early recurrence of atrial tachyarrhythmias after pulsed field ablation: a secondary analysis of the PULSED AF trial

Background: Early recurrence of atrial tachyarrhythmias (ERAT) within 3 months of thermal ablation for atrial fibrillation (AF) is common and often considered transient. Pulsed field ablation (PFA) is a nonthermal energy source in which ERAT is not well described. Objective: The purpose of this study was to analyze ERAT in patients with AF undergoing PFA in the Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF (PULSED AF) trial. Methods: This analysis included 154 (52.4%) paroxysmal AF and 140 (47.6%) persistent AF who had ≥10 rhythm assessments during the 90-day blanking period. ERAT was defined as any instance of ≥30 seconds of AF, atrial flutter, or atrial tachycardia on transtelephonic monitoring (weekly and symptomatic) or ≥10 seconds on electrocardiography (at 3 months), both within 90 days. Late recurrence of atrial tachyarrhythmias (LRAT) was defined as observed atrial tachyarrhythmias between 90 days and 12 months. Results: The overall prevalence of ERAT was 27.1% in patients with paroxysmal AF and 31.6% in patients with persistent AF. In patients with ERAT, 73% had ERAT onset within the first month of the procedure. The presence of ERAT was associated with LRAT in patients with paroxysmal AF (hazard ratio 6.4; 95% confidence interval 3.6-11.3) and patients with persistent AF (hazard ratio 3.8; 95% confidence interval 2.2-6.6). Yet, in 29.4% of patients with paroxysmal AF and 34.3% of patients with persistent AF with ERAT, LRAT was not observed. LRAT was positively correlated with the number of ERAT observations. Conclusion: ERAT after PFA predicted LRAT in patients with paroxysmal and persistent AF. However, the concept of a blanking period after PFA is still valid, as approximately one-third of patients with ERAT did not continue to have LRAT during follow-up and may not need reablation

Antibacterial Envelope to Prevent Cardiac Implantable Device Infection

Background Infections after placement of cardiac implantable electronic devices (CIEDs) are associated with substantial morbidity and mortality. There is limited evidence on prophylactic strategies, other than the use of preoperative antibiotics, to prevent such infections. Methods We conducted a randomized, controlled clinical trial to assess the safety and efficacy of an absorbable, antibiotic-eluting envelope in reducing the incidence of infection associated with CIED implantations. Patients who were undergoing a CIED pocket revision, generator replacement, or system upgrade or an initial implantation of a cardiac resynchronization therapy defibrillator were randomly assigned, in a 1:1 ratio, to receive the envelope or not. Standard-of-care strategies to prevent infection were used in all patients. The primary end point was infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary end point for safety was procedure-related or system-related complications within 12 months. Results A total of 6983 patients underwent randomization: 3495 to the envelope group and 3488 to the control group. The primary end point occurred in 25 patients in the envelope group and 42 patients in the control group (12-month Kaplan-Meier estimated event rate, 0.7% and 1.2%, respectively; hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P=0.04). The safety end point occurred in 201 patients in the envelope group and 236 patients in the control group (12-month Kaplan-Meier estimated event rate, 6.0% and 6.9%, respectively; hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P<0.001 for noninferiority). The mean (+/- SD) duration of follow-up was 20.7 +/- 8.5 months. Major CIED-related infections through the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98). Conclusions Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications

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

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•5 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•3 (SE 0•9) mm Hg for aprocitentan 12•5 mg,-15•2 (0•9) mm Hg for aprocitentan 25 mg, and-11•5 (0•9) mm Hg for placebo, for a difference versus placebo of-3•8 (1•3) mm Hg (97•5% CI-6•8 to-0•8, p=0•0042) and-3•7 (1•3) mm Hg (-6•7 to-0•8; p=0•0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was-4•2 mm Hg (95% CI-6•2 to-2•1) and-5•9 mm Hg (-7•9 to-3•8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5•8 mm Hg, 95% CI 3•7 to 7•9, p<0•0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12•5 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

A Survey of Empirical Results on Program Slicing

International audienceBACKGROUND:Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS:This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS:Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION:Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding