CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation ...is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.
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•ARID1A-containing cBAF opens enhancers in effector CD8+ T cells during infection•cBAF establishes binding sites of many effector TFs, including T-bet and BATF•cBAF is necessary for late-stage differentiation of TE and Trm cells•Circulating memory cells form without cBAF, but are functionally impaired
Chromatin remodeling is a critical step for cellular differentiation. McDonald et al. show that the canonical BAF complex mediates chromatin remodeling to establish de novo enhancers in recently activated virus-specific CD8+ T cells, which, in turn, allows the activated cells to acquire specialized effector and memory cell fates.
N-Alkyl 2-pyridones and other enolizable heterocycles are important synthetic constructs, due to their prevalence in natural products and pharmaceutical targets and their capacity to serve as models ...for a number of biological and chemical processes. The disclosed Au(I)-catalyzed reaction utilizes 2-propargyloxypyridines to access N-alkylated 2-pyridone products derived from both 5-exo and 6-endo addition of the nitrogen to the pendent alkyne. Experimental and computational studies suggest that the desired 5-exo N-alkenyl 2-pyridonyl ethers are formed reversibly in the transformation. After extensive optimization, biaryl Au(I) catalyst 21 was found to overcome the inherent preference for the 6-endo pathway and provide the highest combination of 5-exo selectivity and yield. Herein, we report the application of this new Au(I)-catalyzed C–N bond formation to the preparation of a variety of N-alkenyl 2-pyridonyl ether analogues, which have the potential to serve as an entry point for the synthesis of complex N-alkyl 2-pyridone-containing frameworks.
BackgroundAccording to the Medical Research Council (MRC) framework, the theorisation of how multilevel, multicomponent interventions work and the understanding of their interaction with their ...implementation context are necessary to be able to evaluate them beyond their complexity. More research is needed to provide good examples following this approach in order to produce evidence-based information on implementation practices.ObjectivesThis article reports on the results of the process evaluation of a complex mental health intervention in small and medium enterprises (SMEs) tested through a pilot study. The overarching aim is to contribute to the evidence base related to the recruitment, engagement and implementation strategies of applied mental health interventions in the workplace.MethodThe Mental Health Promotion and Intervention in Occupational Settings (MENTUPP) intervention was pilot tested in 25 SMEs in three work sectors and nine countries. The evaluation strategy of the pilot test relied on a mixed-methods approach combining qualitative and quantitative research methods. The process evaluation was inspired by the RE-AIM framework and the taxonomy of implementation outcomes suggested by Proctor and colleagues and focused on seven dimensions: reach, adoption, implementation, acceptability, appropriateness, feasibility and maintenance.ResultsFactors facilitating implementation included the variety of the provided materials, the support provided by the research officers (ROs) and the existence of a structured plan for implementation, among others. Main barriers to implementation were the difficulty of talking about mental health, familiarisation with technology, difficulty in fitting the intervention into the daily routine and restrictions caused by COVID-19.ConclusionsThe results will be used to optimise the MENTUPP intervention and the theoretical framework that we developed to evaluate the causal mechanisms underlying MENTUPP. Conducting this systematic and comprehensive process evaluation contributes to the enhancement of the evidence base related to mental health interventions in the workplace and it can be used as a guide to overcome their contextual complexity.Trial registration numberISRCTN14582090.
Causes of death among patients with heart failure with reduced ejection fraction (HFrEF) with and without diabetes (DM) have not been well described. We used data from a multinational HFrEF cohort to ...evaluate the specific causes (COD) of death in patients with and without DM.
Combined patient level data from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial and the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry were used in this analysis. Overall, 6182 patients with LVEF ≤ 35% were used. All COD were independently adjudicated. Sub distribution models were used to evaluate the risk of each COD between patients with and without DM.
There were 2,445 (40%) patients with DM and 3,737 (60%) patients without DM. Among patients with DM there were 527 deaths: 322 CV (61% of deaths); 80 non CV (15% of deaths); 125 unknown (24% of deaths). Among patients without DM there were 607 deaths: 380 CV (63% of deaths); 73 non-CV (12% of deaths); 154 unknown (25% of deaths). Sudden death was the most common COD, occurring in 22% and 30% of deaths in patients with/without DM, respectively. There were modest differences in COD among patients with/without diabetes (figure). After adjusting for baseline variables, DM was not associated with an increased risk of CV death (subdistribution HR sHR 1.13; 95% CI 0.90-1.43); sudden death (sHR 0.87; 95% CI 0.60-1.27); HF death (sHR 1.08; 95% CI 0.73-1.59). DM was associated with an increased risk of MI/stroke death (sHR 2.22 95% CI 1.23 - 3.99). Results were consistent across the individual HF-ACTION and ASIAN-HF cohorts.
Among a well characterized multinational HFrEF cohort, the most common adjudicated COD in patients with and without DM was sudden death. Patients with DM, compared to without DM, did not have an increased risk of CV death, sudden death or HF death. While the presence of DM was associated with an increased risk of MI/stroke death, this accounted for only a small portion. Therapies to reduce the risk of sudden death and HF death should be evaluated in all HFrEF patients, regardless of DM status.
Continued structure−activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an ...imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-à-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo1,2-apyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
Objective.— To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis.
Background.— ...There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication.
Methods.— This was a worldwide, randomized, placebo‐controlled, double‐blind, multiple‐attack study in adults with a >1‐year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10‐mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2‐hour pain relief.
Results.— Two‐hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2‐24 hours (32.6% vs 11.1%, P < .001), 2‐hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 15.8% with rizatriptan, 3 3.2% with placebo); none were serious.
Conclusion.— Rizatriptan 10‐mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.
Objective.— To examine the efficacy of rizatriptan 10‐mg orally disintegrating tablet (ODT) for treating migraines of mild intensity soon after onset, with or without patient‐specific migraine ...education.
Background.— Studies have shown rizatriptan tablet efficacy in early migraine treatment.
Methods.— In this randomized, placebo‐controlled, double‐blind, factorial design study, adults with a history of migraine were assigned to rizatriptan 10‐mg ODT ± patient education (personalized summary of early migraine signs and symptoms) or placebo ± patient education in a 1 : 1 : 1 : 1 ratio. Patients were instructed to treat 1 attack at the earliest time they knew that their headache was a migraine, while pain was mild. During the next 24 hours, patients assessed pain severity, associated symptoms, functional disability, use of rescue medication, and treatment satisfaction. The primary endpoint was pain freedom at 2 hours; a key secondary endpoint was 24‐hour sustained pain freedom.
Results.— Of 207 patients randomized to treatment, 188 (91%) treated a study migraine. Significantly more patients taking rizatriptan reported pain freedom at 2 hours compared with placebo (66.3% vs 28.1%, P < .001). Similarly, significantly more patients taking rizatriptan reported 24‐hour sustained pain freedom (52.2% vs 17.7%, P < .001). A greater proportion of patients in the rizatriptan + education group reported pain freedom at 2 hours compared with those in the rizatriptan + no education group (71.7% vs 60.9%, P = .430). Few adverse events were reported.
Conclusion.— Rizatriptan 10‐mg ODT, when taken early, while headache pain is mild, was superior to placebo at providing pain freedom at 2 hours and 24‐hour sustained pain freedom (NCT00516737).
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