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Background: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. Design: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (e.g., severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The two independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the two co-primary outcomes. Summary: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery. Population Health Research Institute

ImportanceIn patients with multivessel coronary artery disease (CAD) presenting with ST-segment elevation myocardial infarction (STEMI), complete revascularization reduces major cardiovascular events compared with culprit lesion–only percutaneous coronary intervention (PCI). Whether complete revascularization also improves angina-related health status is unknown.ObjectiveTo determine whether complete revascularization improves angina status in patients with STEMI and multivessel CAD.Design, Setting, and ParticipantsThis secondary analysis of a randomized, multinational, open label trial of patient-reported outcomes took place in 140 primary PCI centers in 31 countries. Patients presenting with STEMI and multivessel CAD were randomized between February 1, 2013, and March 6, 2017. Analysis took place between July 2021 and December 2021.InterventionsFollowing PCI of the culprit lesion, patients with STEMI and multivessel CAD were randomized to receive either complete revascularization with additional PCI of angiographically significant nonculprit lesions or to no further revascularization.Main Outcomes and MeasuresSeattle Angina Questionnaire Angina Frequency (SAQ-AF) score (range, 0 [daily angina] to 100 [no angina]) and the proportion of angina-free individuals by study end.ResultsOf 4041 patients, 2016 were randomized to complete revascularization and 2025 to culprit lesion–only PCI. The mean (SD) age of patients was 62 (10.7) years, and 3225 (80%) were male. The mean (SD) SAQ-AF score increased from 87.1 (17.8) points at baseline to 97.1 (9.7) points at a median follow-up of 3 years in the complete revascularization group (score change, 9.9 [95% CI, 9.0-10.8]; P P P = .006). Overall, 1457 patients (87.5%) were free of angina (SAQ-AF score, 100) in the complete revascularization group compared with 1376 patients (84.3%) in the culprit lesion–only group (absolute difference, 3.2% [95% CI, 0.7%-5.7%]; P = .01). This benefit was observed mainly in patients with nonculprit lesion stenosis severity of 80% or more (absolute difference, 4.7%; interaction P = .02).Conclusions and RelevanceIn patients with STEMI and multivessel CAD, complete revascularization resulted in a slightly greater proportion of patients being angina-free compared with a culprit lesion–only strategy. This modest incremental improvement in health status is in addition to the established benefit of complete revascularization in reducing cardiovascular events.

Background: In some randomized clinical trials, transradial access (TRA) compared with transfemoral access (TFA) was associated with lower mortality in patients with coronary artery disease undergoing invasive management. We analyzed the effects of TRA versus TFA across multicenter randomized clinical trials and whether these associations are modified by patient or procedural characteristics. Methods: We performed an individual patient data meta-analysis of multicenter randomized clinical trials comparing TRA with TFA among patients undergoing coronary angiography with or without percutaneous coronary intervention. The primary outcome was all-cause mortality and the co–primary outcome was major bleeding at 30 days. The primary analysis was conducted by 1-stage mixed-effects models on the basis of the intention-to-treat cohort. The effect of access site on mortality and major bleeding was assessed further by multivariable analysis. The relationship among access site, bleeding, and mortality was investigated by natural effect model mediation analysis with multivariable adjustment. Results: A total of 21 600 patients (10 775 TRA, 10 825 TFA) from 7 randomized clinical trials were included. The median age was 63.9 years, 31.9% were women, 95% presented with acute coronary syndrome, and 75.2% underwent percutaneous coronary intervention. All-cause mortality (1.6% versus 2.1%; hazard ratio, 0.77 [95% CI, 0.63–0.95]; P =0.012) and major bleeding (1.5% versus 2.7%; odds ratio, 0.55 [95% CI, 0.45–0.67]; P P interaction =0.003), indicating that the benefit of TRA was substantial in patients with moderate or severe anemia, whereas it was not significant in patients with milder or no baseline anemia. After adjustment, TRA remained associated with 24% and 51% relative risk reduction of all-cause mortality and major bleeding, respectively. A mediation analysis showed that the benefit of TRA on mortality was only partially driven by major bleeding prevention and ancillary mechanisms are required to fully explain the causal association. Conclusions: TRA is associated with lower all-cause mortality and major bleeding at 30 days compared with TFA. The effect on mortality was driven by patients with anemia. The reduction in major bleeding only partially explains the mortality benefit. Registration: URL: https://www.crd.york.ac.uk/prospero ; Unique identifier: CRD42018109664.

Background: Women have a worse prognosis after ST-segment elevation myocardial infarction (STEMI) than men. The prognostic role of thrombus burden (TB) in influencing the sex-related differences in clinical outcomes after STEMI has not been clearly investigated. Objectives: The aim of this study was to assess the sex-related differences in TB and its clinical implications in patients with STEMI. Methods: Individual patient data from the 3 major randomized clinical trials of manual thrombus aspiration were analyzed, encompassing a total of 19,047 patients with STEMI, of whom 13,885 (76.1%) were men and 4,371 (23.9%) were women. The primary outcome of interest was 1-year cardiovascular (CV) death. The secondary outcomes of interest were recurrent myocardial infarction, heart failure, all-cause mortality, stroke, stent thrombosis (ST), and target vessel revascularization at 1 year. Results: Patients with high TB (HTB) had worse 1-year outcomes compared with those presenting with low TB (adjusted HR for CV death: 1.52; 95% CI: 1.10-2.12; P = 0.01). In unadjusted analyses, female sex was associated with an increased risk for 1-year CV death regardless of TB. After adjustment, the risk for 1-year CV death was higher only in women with HTB (HR: 1.23; 95% CI: 1.18-1.28; P < 0.001), who also had an increased risk for all-cause death and ST than men. Conclusions: In patients with STEMI, angiographic evidence of HTB negatively affected prognosis. Among patients with HTB, women had an excess risk for ST, CV, and all-cause mortality than men. Further investigations are warranted to better understand the pathophysiological mechanisms leading to excess mortality in women with STEMI and HTB.

Study Design A clinical randomized control trial. Objective To compare the efficacy and safety of Hybrid arch bar (HAB) with Erich arch bar (EAB) in fracture management of the mandible. Methods In this randomized clinical trial, 44 patients were divided into 2 groups:- Group 1, N = 23 (EAB group) and Group 2, N = 21 (HAB group). The primary outcome was time taken for the application of arch bar, while the inner and outer glove puncture, operator prick, oral hygiene, arch bar stability, complications of HAB, and cost comparison were secondary outcomes. Results The time taken for the application of arch bar in group 2 was significantly shorter than group 1 (55.66 ± 17.869 min vs 82.04 ± 12.197 min) and the frequency of outer glove puncture was also significantly lesser for group 2 (0 punctures vs 9 punctures). Better oral hygiene was found in group 2. EAB was cost-effective than HAB (Rs 700 ± 239.79 vs Rs 1742.50 ± 257.14). The stability of the arch bar was comparable in both groups. Group 2 had associated complications of root injury in 2 out of 252 screws placed and the screw head got covered by soft tissue in 137 out of 252 screws placed. Conclusions Thus, HAB was better than EAB with a shorter time of application, less risk of prick injury, and improved oral hygiene. Clinical trial registry name- clinical trials registry- India, URL- http://ctri.nic.in , registration number- CTRI/2020/06/025966.

Background: Chronic total occlusions (CTO) are common and are associated with lower percutaneous coronary intervention (PCI) success rates, often due to failure of antegrade guidewire crossing. Local, intralesional delivery of collagenase (MZ-004) may facilitate guidewire crossing in CTO. Aims: To evaluate the effect of MZ-004 in facilitating antegrade wire crossing in CTO angioplasty. Methods: A total of 76 patients undergoing CTO PCI were enrolled at 13 international sites: 38 in the randomized training stage (collagenase [MZ-004] 900 or 1200 μg) and 38 in the placebo-controlled stage (MZ-004 900 or 1200 μg or placebo). Patients received the MZ-004 or identical volume saline (placebo group) in a double-blind design, injected via microcatheter directly into the proximal cap of the CTO. The following day patients underwent CTO PCI using antegrade wire techniques only. Results: Patients were generally similar except for a trend for higher Japanese chronic total occlusion (J-CTO) score in the MZ-004 group (MZ-004 J-CTO score 1.9 vs. 1.4, p = 0.07). There was a numerical increase in the rates of guidewire crossing in the MZ-004 groups compared to placebo (74% vs. 63%, p = 0.52). Guidewire crossing with a soft-tip guidewire (≤1.5 g tip load) was significantly higher in the MZ-004 groups (0% in placebo, 17% in 900 μg, and 29% in 1200 μg MZ-004 group, p = 0.03). Rates of the major adverse cardiovascular event were similar between groups. Conclusion: Local delivery of MZ-004 into coronary CTOs appears safe and may facilitate CTO crossing, particularly with softer tipped guidewires. These data support the development of a pivotal trial to further evaluate this agent.

Organocatalytic ring-opening polymerization of cyclic carbonate monomers derivatized with metallocenes is described for the rapid synthesis of high Mn metallopolymers.

BACKGROUND The radial artery is recommended by international guidelines as the default vascular access in patients with acute coronary syndromes (ACS) managed invasively. However, crossover from radial to femoral access is required in 4-10% of cases and has been associated with worse outcomes. No standardised algorithm exists to predict the risk of radial crossover. AIMS We sought to derive and externally validate a risk score to predict radial crossover in patients with ACS managed invasively. METHODS The derivation cohort consisted of 4,197 patients with ACS undergoing invasive management via the randomly allocated radial access from the MATRIX trial. Using logistic regression, we selected predictors of radial crossover and developed a numerical risk score. External validation was accomplished among 3,451 and 491 ACS patients managed invasively and randomised to radial access from the RIVAL and RIFLE-STEACS trials, respectively. RESULTS The MATRIX score (age, height, smoking, renal failure, prior coronary artery bypass grafting, ST-segment elevation myocardial infarction, Killip class, radial expertise) showed a c-index for radial crossover of 0.71 (95% CI: 0.67-0.75) in the derivation cohort. Discrimination ability was modest in the RIVAL (c-index: 0.64; 95% CI: 0.59-0.67) and RIFLE-STEACS (c-index: 0.66; 95% CI: 0.57-0.75) cohorts. A cut-off of ≥41 points was selected to identify patients at high risk of radial crossover. CONCLUSIONS The MATRIX score is a simple eight-item risk score which provides a standardised tool for the prediction of radial crossover among patients with ACS managed invasively. This tool can assist operators in anticipating and better addressing difficulties related to transradial procedures, potentially improving outcomes.

Background Women have a worse prognosis after ST-segment elevation myocardial infarction (STEMI) than men. The prognostic role of thrombus burden (TB) in influencing the sex-related differences in clinical outcomes after STEMI has not been clearly investigated. Objectives The aim of this study was to assess the sex-related differences in TB and its clinical implication in patients with STEMI. Methods We analyzed individual patient data from the 3 major randomized clinical trials of manual thrombus aspiration, encompassing a total of 19,047 patients with STEMI, of whom 13,885 (76.1%) were men and 4,371 (23.9%) were women. The primary outcome of interest was 1-year cardiovascular (CV) death. The secondary outcomes of interest were recurrent myocardial infarction, heart failure, all-cause mortality, stroke, stent thrombosis (ST), and target vessel revascularization at 1 year. Results Patients with high TB (HTB) had worse 1-year outcomes compared with those presenting with low TB (adjusted HR for CV death; 1.52; 95% CI: 1.10-2.12; P=0.01). In unadjusted analyses, female sex was associated with an increased risk for 1-year CV death regardless of TB. After adjustment, this risk for 1-year CV death was higher only in women with HTB (HR 1.23, 95% CI: 1.18-1.28; P Conclusion In patients with STEMI, angiographic evidence of HTB negatively affected prognosis. Among patients with HTB, women had an excess risk for stent thrombosis, CV and all-cause mortality than men. Further investigations are warranted to better understand the pathophysiological mechanisms leading to excess mortality in women with STEMI and HTB.

The introduction of basic computational chemistry concepts is becoming an integral part of any complete undergraduate curriculum in chemistry. The advanced organic chemistry course affords laboratory time in which some focused study of computational chemistry is possible. Although learning how to carry out basic computational manipulations is important, interest in computational chemistry can be instilled by carrying out a research-like experience. We incorporated a course-based undergraduate research experience (CURE) into our advanced organic chemistry lab course in which students, as a group, studied the spontaneous formation of strained propellane compounds from the corresponding anionic bridgehead bromide precursor compounds. Completing the calculations and data analysis as a class simulated a true research project, and led to the discovery of results from which interesting conclusions were drawn. Student feedback was generally very positive and suggested that this project gave them a strong sense for how computational chemistry research is conducted.

In patients with ST-segment elevation myocardial infarction (STEMI), early initiation of high-intensity statin therapy, regardless of low-density lipoprotein (LDL) cholesterol levels, is the standard of practice worldwide. Aims: We sought to determine the effect of a similar early initiation strategy, using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to the high-intensity statin, on LDL cholesterol in acute STEMI.In a randomised, double-blind trial we assigned 68 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) to early treatment with alirocumab 150 mg subcutaneously or to a matching sham control. The first injection was given before primary PCI regardless of the baseline LDL level, then at 2 and 4 weeks. The primary outcome was the percent reduction in direct LDL cholesterol up to 6 weeks, analysed using a linear mixed model. Results: High-intensity statin use was 97% and 100% in the alirocumab and sham-control groups, respectively. At a median of 45 days, the primary outcome of LDL cholesterol decreased by 72.9% with alirocumab (2.97 mmol/L to 0.75 mmol/L) versus 48.1% with the sham control (2.87 mmol/L to 1.30 mmol/L), for a mean between-group difference of -22.3% (p0.001). More patients achieved the European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guideline target of LDL ≤1.4 mmol/L in the alirocumab group (92.1% vs 56.7%; p0.001). Within the first 24 hours, LDL declined slightly more rapidly in the alirocumab group than in the sham-control group (-0.01 mmol/L/hour; p=0.03) with similar between-group mean values. Conclusions: In this randomised trial of routine early initiation of PCSK9 inhibitors in patients undergoing primary PCI for STEMI, alirocumab reduced LDL cholesterol by 22% compared with sham control on a background of high-intensity statin therapy. A large trial is needed to determine if this simplified approach followed by long-term therapy improves cardiovascular outcomes in patients with acute STEMI. (ClinicalTrials.gov: NCT03718286).

Background Recently the distal radial access (DRA) technique has been introduced for coronary angiography and intervention as an alternative to the conventional radial access (RA). Purpose The aim of this study was to provide a quantitative appraisal of the effects of DRA vs conventional RA for coronary angiography with or without intervention. Methods The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for randomised clinical trials (RCT) comparing DRA versus RA for coronary angiography and/or intervention. Data were pooled by meta-analysis using a random-effects model. The number of patients needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) were calculated. The primary endpoint was radial artery occlusion (RAO) at the longest available follow-up. Additional secondary outcomes were assessed. Results A total of 13 RCT including 4,901 patients were identified and included in the final analysis. Coronary angiography alone was performed in 3 studies, percutaneous coronary intervention was performed in a variable proportion of patients ranging from 24% to 100% across studies. Study population included patients with chronic coronary syndrome in the large majority, and the proportion of acute coronary syndrome ranged from to 31% to 100% across studies. Compared with RA, DRA was associated with a significant lower risk of RAO, either detected at the longest follow-up (risk ratio [RR]: 0.36; 95% CI: 0.23 to 0.58; p Conclusions Compared with RA, DRA is associated with lower risks of RAO and EASY ≥ II hematoma, but requires longer time for radial artery puncture and sheath insertion, more puncture attempts and a higher access site crossover. Funding Acknowledgement Type of funding sources: None.

This paper studies the dissipative generalized surface quasi-geostrophic equations in a supercritical regime where the order of the dissipation is small relative to order of the velocity, and the velocities are less regular than the advected scalar by up to one order of derivative. We also consider a non-degenerate modification of the endpoint case in which the velocity is less smooth than the advected scalar by slightly more than one order. The existence and uniqueness theory of these equations in the borderline Sobolev spaces is addressed, as well as the instantaneous smoothing effect of their corresponding solutions. In particular, it is shown that solutions emanating from initial data belonging to these Sobolev classes immediately enter a Gevrey class. Such results appear to be the first of its kind for a quasilinear parabolic equation whose coefficients are of higher order than its linear term; they rely on an approximation scheme which modifies the flux in such a way that preserves the underlying commutator structure lost by having to work in the critical space setting, as well as delicate adaptations of well-known commutator estimates to Gevrey classes., 34 pages and 1 figure

Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.

Aims Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE). Methods and results We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61–0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64–0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34–0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66–0.90; P Conclusion Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

BACKGROUND More than half of patients undergoing percutaneous coronary intervention (PCI) have multivessel disease (MVD). The prognostic significance of PCI in stable patients has recently been debated, but little data exists about the potential benefit of complete revascularization (CR) in stable MVD. We investigated the prognostic benefit of CR in patients undergoing PCI for stable disease. METHODS We compared CR versus incomplete revascularization (IR) in 8,436 patients with MVD. The primary outcome was all-cause mortality at 5 years. RESULTS A total of 1,399 patients (17%) underwent CR during the index PCI procedure for stable disease. CR was associated with lower mortality (6.2 vs. 10.7%, p

The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19.The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing.Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions.The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19.Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation.For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Digital, Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging.Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of antiinflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials., Contexte : Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n’est pas facile de realiser des essais à repartition aleatoire dans un contexte pandemique.Methodologie : Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d’inscription de 3 500 patients externes et de 2 500 patients hospitalises presentant une COVID-19 symptomatique. L’essai mene auprès de patients externes visait à evaluer la colchicine par rapport aux soins habituels, et l’aspirine par rapport aux soins habituels. Le paramètre d’evaluation principal au terme de la repartition aleatoire des patients etait l’hospitalisation ou le decès dans le groupe traite par la colchicine, et la thrombose majeure, l’hospitalisation ou le decès dans le groupe traite par l’aspirine. L’essai mene auprès de patients hospitalises visant à evaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l’aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d’evaluation principal au terme de la repartition aleatoire des patients etait le recours à l’oxygenotherapie à haut debit ou à la ventilation mecanique ou le decès dans le groupe traite par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l’oxyg enotherapie à haut debit ou à la ventilation m ecanique ou le decès dans le groupe traite par l’association rivaroxaban-aspirine. Resultats : À la fin de la periode d’inscription, le 10 fevrier 2022, 3 917 patients externes et 2 611 patients hospitalises formaient la population des essais. Certains aspects se sont reveles problematiques, notamment le manque de donnees preliminaires sur les interventions à evaluer, les incertitudes liees aux taux d´evenements prevus, les retards touchant les approbations reglementaires et ethiques et les interventions de recherche, de même que l’evolution de la pandemie de COVID-19. Conclusions : Les essais ACT d etermineront l’efficacite du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l’aspirine, administree seule ou en association avec le rivaroxaban, contre la COVID-19 legère, moderee ou sevère. Les leçons tirees de ces essais orienteront la planification d’essais ulterieurs., Ciencias Médicas y de la Salud

The stereoselective synthesis of terminal bromo-substituted propargylamines via in situ generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral N-tert-butanesulfinyl aldimines is reported. Modest to good yields (43-85%) and diastereoselectivity (dr = 3:1 to >20:1) were achieved for a range of aryl, heteroaryl, alkyl, and α,β-unsaturated substrates. Terminal bromo-substituted propargylamines prepared via this method can be directly used in the frequently employed Cadiot-Chodkiewicz coupling to produce functionalized diynes. The method reported here increases the structural diversity of chiral terminal bromo-substituted propargylamines that can be readily synthesized as previous methods for the stereoselective synthesis of these compounds rely on amino acid precursors from the chiral pool.

Funder: John Simon Guggenheim Memorial Foundation; doi: https://doi.org/10.13039/100005851, Funder: Einstein Visiting Fellow Program, The Rayleigh–Bénard system with stress-free boundary conditions is shown to have a global attractor in each affine space where velocity has fixed spatial average. The physical problem is shown to be equivalent to one with periodic boundary conditions and certain symmetries. This enables a Gronwall estimate on enstrophy. That estimate is then used to bound the L 2 norm of the temperature gradient on the global attractor, which, in turn, is used to find a bounding region for the attractor in the enstrophy–palinstrophy plane. All final bounds are algebraic in the viscosity and thermal diffusivity, a significant improvement over previously established estimates. The sharpness of the bounds are tested with numerical simulations.

Background: It is unclear whether more effective forms of thrombus removal than current aspiration catheters would lead to improved outcomes. We sought to evaluate the prognostic role of residual thrombus burden (rTB), after manual thrombectomy, in patients undergoing primary percutaneous coronary intervention with routine manual thrombectomy in the TOTAL trial (Thrombectomy Versus PCI Alone). Methods: This is a single-arm analysis of patients from the TOTAL trial who underwent routine manual aspiration thrombectomy. The rTB was quantified by an angiographic core laboratory using the Thrombolysis in Myocardial Infarction criteria and validated using existing optical coherent tomography data. Large rTB was defined as grade ≥3. The primary outcome was death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or new or worsening heart failure within 180 days. Results: Of 5033 patients randomized to routine thrombectomy, 2869 patients had quantifiable rTB (1014 [35%] had large rTB). Patients with large rTB were more likely to have hypertension, previous percutaneous coronary intervention, myocardial infarction, or Killip class III on presentation but less likely to have Killip class I. The primary outcome occurred more frequently in patients with large rTB, even after adjustment for known risk predictors (8.6% versus 4.6%; adjusted hazard ratio, 1.83 [95% CI, 1.34–2.48]). These patients also had a higher risk of cardiovascular death (adjusted hazard ratio, 1.83 [95% CI, 1.13–2.95]), cardiogenic shock (adjusted hazard ratio, 2.02 [95% CI, 1.08–3.76]), and heart failure (adjusted hazard ratio, 1.74 [95% CI, 1.02–2.96]) but not myocardial infarction or stroke. Conclusions: Large rTB is a common finding in primary percutaneous coronary intervention and is associated with increased risk of adverse cardiovascular outcomes, including cardiovascular death. Future technologies offering better thrombus removal than current devices may decrease or even eliminate the risk associated with rTB. This, potentially, can turn into a strategic option to be studied in clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01149044.

Biodegradable polymers are desirable to mitigate the environmental impact of plastic waste in the environment. Over the past several decades, the development of organocatalytic ring-opening polymerization (OROP) has made the synthesis of many new types of biodegradable polymers possible. In this research article, the first example of an oxygen atom transfer reagent pendant on a biodegradable polymer backbone is reported. The monomers for the polycarbonate backbone are sourced from the biodegradable 2,2-bis(hydroxymethyl) propionic acid molecule, and an iodoaryl group is installed pendant to the cyclic monomer for post-polymerization modification into an iodosylaryl oxygen atom transfer reagent. The key I-O bond is characterized by XPS spectroscopy, and a test reaction to triphenylphosphine demonstrates the ability of the polymer to engage in an oxygen atom transfer reaction with a substrate.