Efficacy and safety of low-dose digoxin in patients with heart failure. Rationale and design of the DECISION trial.

Aims: Digoxin is the oldest drug in cardiovascular (CV) medicine, and one trial conducted >25 years ago showed a reduction in heart failure (HF) hospitalizations but no effect on mortality. However, later studies suggested that the dose of digoxin used in that trial (and other studies) may have been too high. The DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) trial will examine the efficacy and safety of low-dose digoxin in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with a background of contemporary HF treatment.

Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles.

Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(β-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response.

Use of regional transmural agreements to support the right care in the right place for patients with chronic heart failure-a qualitative study.

Background: Chronic heart failure (CHF) poses a major challenge for healthcare systems. As these patients' needs vary over time in intensity and complexity, the coordination of care between primary and secondary care is critical for them to receive the right care in the right place. To support the continuum of care needed, Dutch regional transmural agreements (RTAs) between healthcare providers have been developed.

TOP2B's contributions to transcription.

Transcription is regulated and mediated by multiprotein complexes in a chromatin context. Transcription causes changes in DNA topology which is modulated by DNA topoisomerases, enzymes that catalyse changes in DNA topology via transient breaking and re-joining of one or both strands of the phosphodiester backbone. Mammals have six DNA topoisomerases, this review focuses on one, DNA topoisomerase II beta (TOP2B).

All together: Integrated care for youth with type 1 diabetes.

Objective: We describe the implementation and evaluation of an integrated, stepped care model aimed to identify and address the concerns of adolescents with type 1 diabetes (T1D) associated with diabetes-related quality of life (DRQoL), emotional well-being, and depression.

Research Design And Methods: The care model with 4 steps: (1) Systematic identification and discussion of concerns salient to adolescents; (2) Secondary screening for depressive symptoms when indicated; (3) Developing collaborative treatment plans with joint physical and mental health goals; and (4) Psychiatric assessment and embedded mental health treatment; was implemented into an ambulatory pediatric diabetes clinic and evaluated using quantitative and qualitative methods.

Results: There were 236 adolescents (aged 13-18 years) with T1D that were enrolled in the care model.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route.

Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site.

Discovery and optimization of pyrazolopyrimidine sulfamates as ATG7 inhibitors.

Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7.

Effects of the COVID-19 Outbreak on Elder Mistreatment and Response in New York City: Initial Lessons.

New York City is currently experiencing an outbreak of COVID-19, a highly contagious and potentially deadly virus, which is particularly dangerous for older adults. This pandemic has led to public health policies including social distancing and stay-at-home orders. We explore here the impact of this unique crisis on victims of elder mistreatment and people at risk of victimization.

Cognitive Decline Over Time in Patients With Systolic Heart Failure: Insights From WARCEF.

Objectives: This study sought to characterize cognitive decline (CD) over time and its predictors in patients with systolic heart failure (HF).

Background: Despite the high prevalence of CD and its impact on mortality, predictors of CD in HF have not been established.

Methods: This study investigated CD in the WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) trial, which performed yearly Mini-Mental State Examinations (MMSE) (higher scores indicate better cognitive function; e.

Association between mortality and implantable cardioverter-defibrillators by aetiology of heart failure: a propensity-matched analysis of the WARCEF trial.

Aims: There is debate on whether the beneficial effect of implantable cardioverter-defibrillators (ICDs) is attenuated in patients with non-ischaemic cardiomyopathy (NICM). We assess whether any ICD benefit differs between patients with NICM and those with ischaemic cardiomyopathy (ICM), using data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial.

Methods And Results: We performed a post hoc analysis using WARCEF (N = 2293; ICM, n = 991 vs.

Pulse pressure and prognosis in patients with heart failure with reduced ejection fraction.

Background: A high pulse pressure (PP) is associated with adverse cardiovascular (CV) outcomes; however, this relationship may be reversed in patients with heart failure with reduced ejection fraction (HFREF).

Methods: Patients from the WARCEF trial with left ventricular ejection fraction ≤35% were included. PP was divided into tertiles: ≤42, 42-54 and >54 mm Hg.

Geriatric rehabilitation in older patients with cardiovascular disease: a feasibility study.

Purpose: Cardiac rehabilitation in older patients after hospitalization because of cardiovascular disease is recommended. However, many older patients do not receive cardiac rehabilitation in daily practice, due to lack of referral and poor adherence. This can be related to impaired clinical and functional status of these patients, who are more likely to present with frailty, frequent comorbidities, and disability.

Pharmacological inhibition of store-operated calcium entry in MDA-MB-468 basal A breast cancer cells: consequences on calcium signalling, cell migration and proliferation.

Store-operated Ca entry is a pathway that is remodelled in a variety of cancers, and altered expression of the components of store-operated Ca entry is a feature of breast cancer cells of the basal molecular subtype. Studies of store-operated Ca entry in breast cancer cells have used non-specific pharmacological inhibitors, complete depletion of intracellular Ca stores and have mostly focused on MDA-MB-231 cells (a basal B breast cancer cell line). These studies compared the effects of the selective store-operated Ca entry inhibitors Synta66 and YM58483 (also known as BTP2) on global cytosolic free Ca ([Ca]) changes induced by physiological stimuli in a different breast cancer basal cell line model, MDA-MB-468.

Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial).

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction.

Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment.

Aims: Left atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement.

Comparison of Outcomes and Intervention Among Patients With Non-ST-Segment Elevation Acute Myocardial Infarction of Those With a Left Circumflex Versus Those With a Non-Left Circumflex-Related Coronary Artery (From the ELISA-3 Trial).

Previous studies found that patients with an acute coronary syndrome (ACS) due to occlusion of the left circumflex (LC) coronary artery often present without ST-elevation, leading to a delay in diagnosis and revascularization, a larger infarct size, and a worse prognosis. In this subgroup analysis of the ELISA-3 study (early or late intervention in high-risk non-ST-segment elevation acute coronary syndromes [NSTE-ACS]) incidence, characteristics and prognosis of LC-related NSTE-ACS was investigated, and the outcome of early versus late invasive strategy was compared. In 383 of 542 patients the culprit vessel could be identified, with the LC artery in 112 (29%) of them.

Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients: From the WARCEF Trial.

Objectives: The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).

Background: Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue.

Resting Heart Rate and Ischemic Stroke in Patients with Heart Failure.

Background: Although high resting heart rate (RHR) is known to be associated with an increased risk of mortality and hospital admission in patients with heart failure, the relationship between RHR and ischemic stroke remains unclear. This study is aimed at investigating the relationship between RHR and ischemic stroke in patients with heart failure in sinus rhythm.

Methods: We examined 2,060 patients with systolic heart failure in sinus rhythm from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial.

Two-year outcome after early or late Intervention in non-ST elevation acute coronary syndrome.

Objective: To compare long-term outcome of an early to a delayed invasive strategy in high-risk patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

Methods: This prospective, multicentre trial included patients with NSTE-ACS and at least two out of three of the following high-risk criteria: (1) evidence of extensive myocardial ischaemia on ECG, (2) elevated biomarkers for myocardial necrosis and (3) age above 65 years. Patients were randomised to either an early (angiography and revascularisation if appropriate <12 hours) or a delayed invasive strategy (>48 hours after randomisation).

What Are Effective Program Characteristics of Self-Management Interventions in Patients With Heart Failure? An Individual Patient Data Meta-analysis.

Background: To identify those characteristics of self-management interventions in patients with heart failure (HF) that are effective in influencing health-related quality of life, mortality, and hospitalizations.

Methods And Results: Randomized trials on self-management interventions conducted between January 1985 and June 2013 were identified and individual patient data were requested for meta-analysis. Generalized mixed effects models and Cox proportional hazard models including frailty terms were used to assess the relation between characteristics of interventions and health-related outcomes.

Early or late intervention in patients with transient ST-segment elevation acute coronary syndrome: Subgroup analysis of the ELISA-3 trial.

Objectives: To investigate incidence and patient characteristics of transient ST-segment elevation (TSTE) ACS and to compare outcome of early versus late invasive treatment.

Background: Optimal timing of treatment in TSTE-ACS patients is not outlined in current guidelines and no prospective randomized trials have been done so far.

Methods: Post hoc subgroup analysis of patients with TSTE randomized in the ELISA 3 trial.

CHA DS -VASc score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm.

Aims: The aim of this study was to determine whether the CHA DS -VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm.

Methods And Results: CHA DS -VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage.

Left Ventricular Ejection Fraction and Risk of Stroke and Cardiac Events in Heart Failure: Data From the Warfarin Versus Aspirin in Reduced Ejection Fraction Trial.

Background And Purpose: In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments.

Development of a novel noncapillary plasma microsampling device for ultra-low volume of blood collection.

The desire for serial microsampling in mice has led to extensive research in this field within the pharmaceutical industry. The ability to profile a compound's in vivo properties with less material and fewer mice has obvious advantages. A new device and workflow was developed at the Takeda Oncology site to allow scientists to isolate plasma from very low volumes of mouse blood (as low as 20 μl) collected using standard microsampling techniques.