Acute cannabidiol administration reduces alcohol craving and cue-induced nucleus accumbens activation in individuals with alcohol use disorder: the double-blind randomized controlled ICONIC trial.

Although alcohol use disorder (AUD) is highly prevalent, only a few medications are approved for its treatment leaving much room for improvement. Cannabidiol (CBD) might be a particularly promising candidate, with preclinical data suggesting that CBD is effective in targeting AUD symptoms and disease processes that drive alcohol use and relapse, due to its anti-craving, stress-reducing, and anti-compulsive effects. Here we report data from the double-blind randomized controlled ICONIC trial that compared the effects of a single dose of 800 mg cannabidiol against placebo (PLC) in N = 28 individuals with AUD.

A reductionist perspective on HIF-1α's role in cell proliferation under non-hypoxic conditions.

The role of hypoxia-inducible factor (HIF)-1α in the control of proliferation under non-hypoxic conditions has been investigated in numerous studies, but does not yield a coherent picture. Therefore, we conducted this meta-analysis of existing literature to systematically evaluate the role of HIF-1α, based on a number of inclusion and exclusion criteria. Studies analyzing non-transformed, primary cells showed a largely heterogeneous distribution of pro-proliferative, anti-proliferative or absent functions for HIF-1α, which are co-determined by several parameters, including the type and age of the cell and its localization in tissues and organs.

A transient increase of HIF-1α during the G1 phase (G1-HIF) ensures cell survival under nutritional stress.

The family of hypoxia-inducible transcription factors (HIF) is activated to adapt cells to low oxygen conditions, but is also known to regulate some biological processes under normoxic conditions. Here we show that HIF-1α protein levels transiently increase during the G1 phase of the cell cycle (designated as G1-HIF) in an AMP-activated protein kinase (AMPK)-dependent manner. The transient elimination of G1-HIF by a degron system revealed its contribution to cell survival under unfavorable metabolic conditions.

MRI-based training model for left atrial appendage closure.

Purpose: Percutaneous closure of the left atrial appendage (LAA) reduces the risk of embolic stroke in patients with atrial fibrillation. Thereby, the optimal transseptal puncture (TSP) site differs due to the highly variable anatomical shape of the LAA, which is rarely considered in existing training models. Based on non-contrast-enhanced magnetic resonance imaging (MRI) volumes, we propose a training model for LAA closure with interchangeable and patient-specific LAA enabling LAA-specific identification of the TSP site best suited.

Testing the Effect of Histone Acetyltransferases on Local Chromatin Compaction.

Experiments determining the chromatin association of histone acetylases (HATs) and deacetylases (HDACs) at the genome-wide level provide precise maps of locus occupancy, but do not allow conclusions on the functional consequences of this locus-specific enrichment. Here we describe a protocol that allows tethering of HATs or HDACs to specific genomic loci upon fusion with a fluorescent protein and a DNA-binding protein such as the E. coli Lac repressor (LacI), which binds to genomically inserted lac operon sequences (lacO) via DNA/protein interactions.

SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression.

The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of metabolism and the hypoxic response, while their role in other signal-mediated processes such inflammatory gene expression remains to be defined. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression. The knockdown of SIAH1/2 modulated the expression of approximately one third of IL-1α-regulated genes.

Prognostic value of myocardial perfusion scintigraphy in asymptomatic patients with diabetes mellitus at high cardiovascular risk: 5-year follow-up of the prospective multicenter BARDOT trial.

Background: The Basel Asymptomatic High-Risk Diabetics' Outcome Trial (BARDOT) demonstrated that asymptomatic diabetic patients with an abnormal myocardial perfusion scintigraphy (MPS) were at increased risk of major adverse cardiovascular events (MACEs) at 2-year follow-up. It remains unclear whether this finding holds true even for a longer follow-up.

Methods: Four hundred patients with type 2 diabetes, neither history nor symptoms of coronary artery disease (CAD), were evaluated clinically and with MPS.

Long-Term Results After Drug-Eluting Versus Bare-Metal Stent Implantation in Saphenous Vein Grafts: Randomized Controlled Trial.

Background Efficacy data on drug-eluting stents (DES) versus bare-metal stents (BMS) in saphenous vein grafts are controversial. We aimed to compare DES with BMS among patients undergoing saphenous vein grafts intervention regarding long-term outcome. Methods and Results In this multinational trial, patients were randomized to paclitaxel-eluting or BMS.

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME-CHF trial.

Aim: Fibroblast growth factor 23 (FGF23) is an intensively studied biomarker at the crossroads of cardiovascular disease, heart failure (HF) and chronic kidney disease. Independent associations between increasing FGF23 levels and cardiovascular events were found in many, but not all studies. By analysing data from the TIME-CHF cohort, we sought to investigate the prognostic value of FGF23 in an elderly, multimorbid HF patient cohort.

[Palliative needs of geriatric patients].

In Germany, the group of geriatric patients is the biggest part of all decedents. That is the reason why the medical staff, who is taking care of elderly patients, needs not only curative, rehabilitative and preventive competencies but also palliative skills. Recently, three guidelines were published (national guideline palliative care for patients with incurable cancer diseases, national guideline pain assessment in resident homes and German guideline geriatric assessment level 2).

Do ultrathin strut bare-metal stents with passive coating improve efficacy in large coronary arteries? Insights from the randomized, multicenter BASKET-PROVE trials.

Background: The new generation thinner-strut silicon carbide (SiC) coated cobalt chromium (CoCr) bare-metal stents (BMS) are designed to accelerate rapid endothelialisation and reduce thrombogenicity when implanted in coronary arteries. However, smaller studies suggest higher rates of symptomatic restenosis in patients receiving the newer generation BMS. We investigated the efficacy of a newer generation ultrathin strut silicon-carbide coated cobalt-chromium (CoCr) BMS (SCC-BMS) as compared to an older thin-strut uncoated CoCr BMS (UC-BMS) in patients presenting with coronary artery disease requiring stenting of large vessels (≥3.

Drug-eluting stents in large coronary vessels improve both safety and efficacy compared with bare-metal stents in women: a pooled analysis of the BASKET-PROVE I and II trials.

Background: Drug-eluting stents (DES) have proven superior to bare-metal stents (BMS) in terms of safety and efficacy. However, inference to the female subgroup has been limited by low enrolment rates of women in clinical trials. The objective of this study was to investigate the safety and efficacy of DES versus BMS in women and men.

Prognostic Significance of Longitudinal Clinical Congestion Pattern in Chronic Heart Failure: Insights From TIME-CHF Trial.

Background: The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure.

Methods: A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class ≥II from the TIME-CHF study were included.

Competing risks of major bleeding and thrombotic events with prasugrel-based dual antiplatelet therapy after stent implantation - An observational analysis from BASKET-PROVE II.

Background: Dual antiplatelet therapy (DAPT) prevents thrombotic events after coronary stent implantation but may induce bleedings, specifically in elderly patients. However, a competitive risk analysis is lacking.

Objectives: To assess the determinants of major bleeding and the balance between the competing risks of major bleeding and thrombotic events during prasugrel-based DAPT after stent implantation.

Is the clinical presentation of chronic heart failure different in elderly versus younger patients and those with preserved versus reduced ejection fraction?

Background: Whether the clinical presentation and in particular prevalence of symptoms and signs of heart failure (HF) is different in elderly versus younger patients and in those with reduced (HFrEF) versus preserved (HFpEF) left ventricular ejection fraction (LVEF) is a matter of ongoing debate.

Aims: To compare detailed clinical characteristics of these important subgroups and to develop a prediction rule for the differentiation of HFpEF and HFrEF based on clinical parameters.

Methods: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising 622 patients ≥60 years with HF including the whole LVEF spectrum.

Novel concept to guide systolic heart failure medication by repeated biomarker testing-results from TIME-CHF in context of predictive, preventive, and personalized medicine.

Background: It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF.

Methods: This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged ≥ 60 years, LVEF ≤ 45%, and NYHA ≥ II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, β-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis.

Prasugrel vs. clopidogrel in contemporary Western European patients with acute coronary syndromes receiving drug-eluting stents: Comparative cost-effectiveness analysis from the BASKET-PROVE cohorts.

Background: Clinical and cost-effectiveness of prasugrel vs. clopidogrel in acute coronary syndrome (ACS) was only evaluated using TRITON-TIMI 38 event rates. A comparative analysis of both drugs in contemporary European ACS patients is lacking.

Prognostic Usefulness of Cardiac Stress Test Modalities in Patients With Type 2 Diabetes Mellitus Who Underwent Myocardial Perfusion Scintigraphy (from the Basel Asymptomatic High-Risk Diabetics' Outcome Trial).

Our study aimed to assess predictors of the stress test technique used and to evaluate the impact of exercise level achieved on risk stratification in patients with asymptomatic type 2 diabetes without a previous coronary artery disease. Little is known whether co-morbidities of these patients predict the stress technique and whether physical performance provides risk stratification: 400 patients underwent clinical evaluation and myocardial perfusion scintigraphy (MPS) using physical or pharmacological stress. Physical patients were divided into 2 groups: achieving <6 and ≥6 METs, respectively.

Predictors and prognostic impact of silent coronary artery disease in asymptomatic high-risk patients with diabetes mellitus.

Aims: Evaluation of predictors of silent coronary artery disease (SCAD) in high-risk asymptomatic diabetic patients and to evaluate their two-year outcome.

Methods And Results: Four hundred diabetic patients without prior CAD but at high CAD risk underwent myocardial perfusion scintigraphy (MPS) in this prospective multicentre outcome trial. MPS were abnormal in 22% of patients.

Second generation drug-eluting stents versus bare-metal stents for percutaneous coronary intervention of the proximal left anterior descending artery: An analysis of the BASKET-PROVE I and II trials.

Objectives: To compare mid-term outcomes between patients undergoing proximal left anterior descending artery (LAD) percutaneous coronary intervention (PCI) with second generation drug-eluting stent (DES) or bare-metal stent (BMS).

Background: PCI with BMS and first-generation DES have shown to be safe options for the treatment of proximal LAD stenosis, however associated with considerable reintervention rates. Overall, second-generation DES has proven to be superior to BMS and first-generation DES, nevertheless, its effect for proximal LAD PCI has not previously been reported.

Management of Skull Base Defects After Surgical Resection of Sinonasal and Ventral Skull Base Malignancies.

Over the past 2 decades, there has been a significant increase in the resection of larger and more complex ventral skull base malignancies. The resection of these lesions has resulted in the creation of larger and more difficult to repair skull base defects. There are many available options for ventral skull base reconstruction.

Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).

Aims: While the conditions of heart failure (HF) with reduced (HFrEF, LVEF < 40%) and preserved (HFpEF, LVEF ≥ 50%) left ventricular ejection fraction (LVEF) are well characterized, it is unknown whether patients with HF and mid-range LVEF (HFmrEF, LVEF 40-49%) have to be regarded as a separate clinical entity. The aim of this study was to characterize these three populations and to compare outcome and response to therapy.

Methods And Results: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising a population with established HF including the whole spectrum of LVEF.