Synthesis and structure of palladium(II) complexes supported by bis-NHC pincer ligands for the electrochemical activation of CO2.

A series of bis-NHC pincer complexes of palladium(II) have been prepared and characterized. These pyridyl-spaced dicarbene complexes ([(PDCR)Pd(MeCN)](PF6)2 ) were synthesized with substituents of varying steric bulk at the wingtip positions, which include R = methyl, ethyl, isopropyl, cyclohexyl, mesityl and 2,6-diisopropylphenyl. The synthesis of this library of complexes was accomplished either by direct metallation of the prerequisite pyridyl-spaced bis-imidazolium proligands with Pd(OAc)2 or via treatment with Ag2O to afford the corresponding silver carbenes, which were then transmetallated onto palladium. Solid-state structures for each of the [(PDCR)Pd(MeCN)](PF6)2 derivatives were obtained via X-ray crystallography and allowed for the steric properties of each PDCR ligand to be evaluated by two methods. These analyses, which included calculation of the percent buried volume (%VBur) and solid angles of the PDCR ligands, served to characterize the steric environment around the palladium center in each of the complexes that was prepared. Finally, voltammetry and controlled potential electrolysis studies were performed to characterize the redox chemistry of the [(PDCR)Pd(MeCN)](PF6)2 derivatives and assess if they could electrocatalyze the reduction of CO2. The influence of the steric properties of the PDCR ligand on the electrochemistry of the resulting complexes [(PDCR)Pd(MeCN)](PF6)2 is also discussed.

Dietary ω-3 fatty acids and the incidence of atrial fibrillation in the Million Veteran Program.

BACKGROUND: Although recent large randomized clinical trials have reported an increased risk of atrial fibrillation (AF) with marine ω-3 fatty acid supplements, it is unclear whether dietary marine ω-3 fatty acids assessed through food frequency questionnaires are associated with AF risk. OBJECTIVES: We sought to test the hypothesis that dietary eicosapentaenoic acid/docosahexaenoic acid/docosapentaecnoic acid (EPA/DHA/DPA) is associated with a higher risk of AF in a large prospective cohort of US Veterans. METHODS: We analyzed data from Million Veteran Program participants who completed self-reported food frequency questionnaires. We used multivariable Cox regression to estimate the HRs of AF across quintiles of ω-3 fatty acid consumption and a cubic spline analysis to assess the dose-response relations between ω-3 fatty acids and AF. RESULTS: Of the 301,294 veterans studied, the median intake of ω-3 fatty acids (EPA/DHA/DPA) was 219 mg/d (IQR: 144-575), and the mean age was 64.9 y (SD: 12.0); 91% were men, and 84% were White. Consumption of EPA/DHA/DPA exhibited a nonlinear inverse relation with incident AF characterized by an initial decline to 11% at 750 mg/d of marine ω-3 fatty acid intake followed by a plateau. CONCLUSIONS: Contrary to our hypothesis, dietary EPA/DHA/DPA was not associated with a higher risk of AF but was inversely related to AF risk in a nonlinear manner.

Predictive value of ASCVD risk score for mortality and major adverse cardiovascular events in the year following a COVID-19 infection among US Veterans.

BACKGROUND: Morbidity and mortality following COVID-19 infection may be influenced by baseline atherosclerotic cardiovascular disease (ASCVD) risk, yet limited data are available to identify those at highest risk. We examined the association between baseline ASCVD risk with mortality and major adverse cardiovascular events (MACE) in the year following COVID-19 infection. METHODS: We evaluated a nationwide retrospective cohort of US Veterans free of ASCVD who were tested for COVID-19. The primary outcome was absolute risk of all-cause mortality in the year following a COVID-19 test among those hospitalized vs. not stratified by baseline VA-ASCVD risk scores. Secondarily, risk of MACE was examined. RESULTS: There were 393,683 Veterans tested for COVID-19 and 72,840 tested positive. Mean age was 57 years, 86% were male, and 68% were white. Within 30 days following infection, hospitalized Veterans with VA-ASCVD scores >20% had an absolute risk of death of 24.6% vs. 9.7% (P ≤0.0001) for those who tested positive and negative for COVID-19 respectively. In the year following infection, risk of mortality attenuated with no difference in risk after 60 days. The absolute risk of MACE was similar for Veterans who tested positive or negative for COVID-19. CONCLUSIONS: Veterans without clinical ASCVD experienced an increased absolute risk of death within 30 days of a COVID-19 infection compared to Veterans with the same VA-ASCVD risk score who tested negative, but this risk attenuated after 60 days. Whether cardiovascular preventive medications can lower the risk of mortality and MACE in the acute period following COVID-19 infection should be evaluated.

Performance of EHR classifiers for patient eligibility in a clinical trial of precision screening.

BACKGROUND: Validated computable eligibility criteria use real-world data and facilitate the conduct of clinical trials. The Genomic Medicine at VA (GenoVA) Study is a pragmatic trial of polygenic risk score testing enrolling patients without known diagnoses of 6 common diseases: atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer. We describe the validation of computable disease classifiers as eligibility criteria and their performance in the first 16 months of trial enrollment. METHODS: We identified well-performing published computable classifiers for the 6 target diseases and validated these in the target population using blinded physician review. If needed, classifiers were refined and then underwent a subsequent round of blinded review until true positive and true negative rates ≥80% were achieved. The optimized classifiers were then implemented as pre-screening exclusion criteria; telephone screens enabled an assessment of their real-world negative predictive value (NPV-RW). RESULTS: Published classifiers for type 2 diabetes and breast and prostate cancer achieved desired performance in blinded chart review without modification; the classifier for atrial fibrillation required two rounds of refinement before achieving desired performance. Among the 1077 potential participants screened in the first 16 months of enrollment, NPV-RW of the classifiers ranged from 98.4% for coronary artery disease to 99.9% for colorectal cancer. Performance did not differ by gender or race/ethnicity. CONCLUSIONS: Computable disease classifiers can serve as efficient and accurate pre-screening classifiers for clinical trials, although performance will depend on the trial objectives and diseases under study.