Influence of Additives on the Reversible Oxygen Reduction Reaction/Oxygen Evolution Reaction in the Mg²⁺‐Containing Ionic Liquid N ‐Butyl‐N ‐Methylpyrrolidinium Bis(Trifluoromethanesulfonyl)imide

The influence of different additives on the oxygen reduction reaction/oxygen evolution reaction (ORR/OER) in magnesium‐containing N ‐butyl‐N ‐methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([BMP][TFSI]) on a glassy carbon electrode was investigated to gain a better understanding of the electrochemical processes in Mg–air batteries. 18‐Crown‐6 was used as a complexing agent for Mg ions to hinder the passivation caused by their reaction with ORR products such as superoxide and peroxide anions. Furthermore, borane dimethylamine complex (NBH) was used as a potential water‐removing agent to inhibit electrode passivation by reacting with trace impurities of water. The electrochemical processes were characterized by differential electrochemical mass spectrometry to monitor the consumed and evolved O2 in the ORR/OER and determine the number of transferred electrons. Crown ether and NBH efficiently masked Mg$^{2+}$. A stochiometric excess of crown ether resulted in reduced formation of a passivation layer, whereas at too high concentrations the reversibility of the ORR/OER was diminished

Ionic Liquid Electrolytes for Metal-Air Batteries: Interactions between O2, Zn2+ and H2O Impurities

Motivated by the potential of ionic liquids (ILs) to replace traditional aqueous electrolytes in Zn-air batteries, we investigated the effects arising from mutual interactions between O₂ and Zn(TFSI)₂ as well as the influence of H₂O impurities in the oxygen reduction/oxygen evolution reaction (ORR/OER) and in Zn deposition/dissolution on a glassy carbon (GC) electrode in the ionic liquid N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)-imide (BMP-TFSI) by differential electrochemical mass spectrometry. This allowed us to determine the number of electrons transferred per reduced/evolved O₂ molecule. In O₂ saturated neat BMP-TFSI the ORR and OER were found to be reversible, in Zn²⁺containing IL Zn deposition/stripping proceeds reversibly as well. Simultaneous addition of O₂ and Zn²⁺ suppresses Zn metal deposition, instead ZnO₂ is formed in the ORR, which is reversible only after excursions to very negative potentials (−1.4 V). The addition of water leads to an enhancement of all processes described above, which is at least partly explained by a higher mobility of O₂ and Zn²⁺ in the water containing electrolytes. Consequences for the operation of Zn-air batteries in these electrolytes are discussed

Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Reduced Trial.

BACKGROUND: There is limited published information on outcome adjudication in heart failure (HF). OBJECTIVES: The authors sought to compare investigator reports (IRs) to a Clinical Events Committee (CEC) and the impact of SCTI (Standardized Clinical Trial Initiative) criteria. METHODS: In the EMPEROR-Reduced trial, the authors compared IRs to the CEC for concordance; treatment effect on primary composite outcome events; and the components first event hospitalization primarily for HF or cardiovascular mortality (CVM), prognosis after hospitalization for heart failure (HHF), total HHFs, and trial duration with and without SCTI criteria. RESULTS: The CEC confirmed 76.3% of IR events for the primary outcome (CVM: 89.1%; HHF: 73.7%). The HR for treatment effect did not differ between adjudication methods for the primary outcome (IR: 0.75 [95% CI: 0.66-0.85]; CEC: 0.75 [95% CI: 0.65-0.86]), its components, or total HHFs. The prognosis after first HHF for all-cause mortality and CVM also did not differ between IR or CEC. Interestingly, IR primary HHF with different CEC primary cause had the highest subsequent fatal event rate. Full SCTI criteria were present in 90% of CEC HHFs-with a similar treatment effect to non-SCTI. The IR primary event reached the protocol target number (841) 3 months earlier than CEC (4 months with full SCTI criteria). CONCLUSIONS: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation. The use of granular (SCTI) criteria did not improve trial performance. Finally, our data suggest that consideration be given to broadening the HHF definition to include "for or with" worsening disease. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. METHODS: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56-0.78; P<0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P<0.0001). CONCLUSIONS: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. METHODS: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. RESULTS: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. CONCLUSIONS: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977

Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.

AIMS: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials. METHODS AND RESULTS: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300?pg/mL in patients without and >900?pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72?±?9?years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12?months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54?±?9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists. CONCLUSION: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021

Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951)

Functional dissociations in top-down control dependent neural repetition priming.

Contains fulltext : 53560.pdf (publisher's version ) (Closed access)Little is known about the neural mechanisms underlying top-down control of repetition priming. Here, we use functional brain imaging to investigate these mechanisms. Study and repetition tasks used a natural/man-made forced choice task. In the study phase subjects were required to respond to either pictures or words that were presented superimposed on each other. In the repetition phase only words were presented that were new, previously attended or ignored, or picture names that were derived from previously attended or ignored pictures. Relative to new words we found repetition priming for previously attended words. Previously ignored words showed a reduced priming effect, and there was no significant priming for pictures repeated as picture names. Brain imaging data showed that neural priming of words in the left prefrontal cortex (LIPFC) and left fusiform gyrus (LOTC) was affected by attention, semantic compatibility of superimposed stimuli during study and cross-modal priming. Neural priming reduced for words in the LIPFC and for words and pictures in the LOTC if stimuli were previously ignored. Previously ignored words that were semantically incompatible with a superimposed picture during study induce increased neural priming compared to semantically compatible ignored words (LIPFC) and decreased neural priming of previously attended pictures (LOTC). In summary, top-down control induces dissociable effects on neural priming by attention, cross-modal priming and semantic compatibility in a way that was not evident from behavioral results

Functional dissociations in top-down control dependent neural repetition priming.

Little is known about the neural mechanisms underlying top-down control of repetition priming. Here, we use functional brain imaging to investigate these mechanisms. Study and repetition tasks used a natural/man-made forced choice task. In the study phase subjects were required to respond to either pictures or words that were presented superimposed on each other. In the repetition phase only words were presented that were new, previously attended or ignored, or picture names that were derived from previously attended or ignored pictures. Relative to new words we found repetition priming for previously attended words. Previously ignored words showed a reduced priming effect, and there was no significant priming for pictures repeated as picture names. Brain imaging data showed that neural priming of words in the left prefrontal cortex (LIPFC) and left fusiform gyrus (LOTC) was affected by attention, semantic compatibility of superimposed stimuli during study and cross-modal priming. Neural priming reduced for words in the LIPFC and for words and pictures in the LOTC if stimuli were previously ignored. Previously ignored words that were semantically incompatible with a superimposed picture during study induce increased neural priming compared to semantically compatible ignored words (LIPFC) and decreased neural priming of previously attended pictures (LOTC). In summary, top-down control induces dissociable effects on neural priming by attention, cross-modal priming and semantic compatibility in a way that was not evident from behavioral results