Parametrization of the dying brain: A case report from ICU bed-side EEG monitoring.

Background: Cortical high-frequency activation immediately before death has been reported, raising questions about an enhanced conscious state at this critical time. Here, we analyzed an electroencephalogram (EEG) from a comatose patient during the dying process with a standard bedside monitor and spectral parameterization techniques.

Methods: We report neurophysiologic features of a dying patient without major cortical injury.

Deprescribing of antidepressants: development of indicators of high-risk and overprescribing using the RAND/UCLA Appropriateness Method.

Background: Antidepressants are first-line medications for many psychiatric disorders. However, their widespread long-term use in some indications (e.g.

Digital Medication Management in Polypharmacy—Findings of a Cluster-Randomized, Controlled Trial With a Stepped-Wedge Design in Primary Care Practices (AdAM).

Background: Inappropriate drug prescriptions for patients with polypharmacy can have avoidable adverse consequences. We studied the effects of a clinical decision-support system (CDSS) for medication management on hospitalizations and mortality.

Methods: This stepped-wedge, cluster-randomized, controlled trial involved an open cohort of adult patients with polypharmacy in primary care practices (=clusters) in Westphalia-Lippe, Germany.

Amitriptyline's anticholinergic adverse drug reactions-A systematic multiple-indication review and meta-analysis.

Background: Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic.

Anticholinergic burden measures, symptoms, and fall-associated risk in older adults with polypharmacy: Development and validation of a prognostic model.

Background: Anticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls.

Evidence-Based Decision Support for a Structured Care Program on Polypharmacy in Multimorbidity: A Guideline Upgrade Based on a Realist Synthesis.

Evidence-based clinical guidelines generally consider single conditions, and rarely multimorbidity. We developed an evidence-based guideline for a structured care program to manage polypharmacy in multimorbidity by using a realist synthesis to update the German polypharmacy guideline including the following five methods: formal prioritization in focus groups; systematic guideline review of evidence-based multimorbidity/polypharmacy guidelines; evidence search/synthesis and recommendation development; multidisciplinary consent of recommendations; feasibility test of updated guideline. We identified the need for a better description of the target group, decision support, prioritization of medication, consideration of patient preferences and anticholinergic properties, and of healthcare interfaces.

Effectiveness of the application of an electronic medication management support system in patients with polypharmacy in general practice: a study protocol of cluster-randomised controlled trial (AdAM).

Introduction: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication.

Evaluation of Platelet Activation by HIV Protease Inhibitors - The HIV-PLA II Study.

Background: In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events (CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks.

Methods: The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naïve adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication.

Are Anticholinergic Symptoms a Risk Factor for Falls in Older General Practice Patients With Polypharmacy? Study Protocol for the Development and Validation of a Prognostic Model.

: Cumulative anticholinergic exposure, also known as anticholinergic burden, is associated with a variety of adverse outcomes. However, studies show that anticholinergic effects tend to be underestimated by prescribers, and anticholinergics are the most frequently prescribed potentially inappropriate medication in older patients. The grading systems and drugs included in existing scales to quantify anticholinergic burden differ considerably and do not adequately account for patients' susceptibility to medications.

Adverse drug reactions associated with amitriptyline - protocol for a systematic multiple-indication review and meta-analysis.

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-the-counter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs.

Differences in the quality of oral anticoagulation therapy with vitamin K antagonists in German GP practices - results of the cluster-randomized PICANT trial (Primary Care Management for Optimized Antithrombotic Treatment).

Background: In Germany, patients receiving oral anticoagulation (OAC) are often treated by general practitioners (GPs), and large proportions of patients receive vitamin K antagonists (VKAs). The quality of OAC in German GP practices, differences between various practices, and improvement potential through implementation of case management, have not yet been investigated satisfactorily. Based on results of a cluster-randomized controlled trial, we aimed to assess whether OAC quality can be improved, any variations between practices exist and determine practice- and patient-level factors.

Primary care management for patients receiving long-term antithrombotic treatment: A cluster-randomized controlled trial.

Purpose: To examine whether applying case management in general practices reduces thromboembolic events requiring hospitalization and major bleeding events (combined primary outcome). Secondary endpoints were mortality, frequency and duration of hospitalization, severe treatment interactions, adverse events, quality of anticoagulation, health-related quality of life and intervention costs, patients' assessment of chronic illness care, self-reported adherence to medication, GP and HCA knowledge, patient knowledge and satisfaction with shared decision-making.

Methods: Cluster-randomized controlled trial undertaken at 52 general practices in Germany with adult patients with a long-term indication for oral anticoagulation.

Surface Acoustic Wave-Based Microfluidic Coagulation Device for Monitoring Anticoagulant Therapy.

An universal coagulation test that reliably detects prolonged coagulation times in patients, regardless of which anticoagulant is administered, is not yet available. The authors developed a novel, miniaturized device utilizing surface acoustic waves (SAW) to detect clotting, and used it to develop a novel universal microfluidic coagulation test. Results from this assay were compared with results from standard coagulation assays to detect classical anticoagulants (unfractionated heparin, argatroban) and direct oral anticoagulants (dabigatran, rivaroxaban).

Direct oral anticoagulants for the treatment of venous thromboembolism in cancer patients: Potential for drug-drug interactions.

Patients with cancer are at high risk of developing venous thromboembolism (VTE). Although the recommended low molecular weight heparins (LMWHs) are more effective than vitamin K antagonists in treating VTE in patients with cancer, they have limitations and contraindications. Direct oral anticoagulants (DOACs) circumvent some of these limitations.

Comparative risks of bleeding, ischemic stroke and mortality with direct oral anticoagulants versus phenprocoumon in patients with atrial fibrillation.

Purpose: The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce.

Methods: Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database.

Effectiveness of a complex intervention on Prioritising Multimedication in Multimorbidity (PRIMUM) in primary care: results of a pragmatic cluster randomised controlled trial.

Objectives: Investigate the effectiveness of a complex intervention aimed at improving the appropriateness of medication in older patients with multimorbidity in general practice.

Design: Pragmatic, cluster randomised controlled trial with general practice as unit of randomisation.

Setting: 72 general practices in Hesse, Germany.

[Piperacillin/Tazobactam Shortage: Central Restriction and Alternative Recommendations as Effective Antibiotic-Stewardship Intervention at a Maximal Care Hospital].

Background:  Drug supply bottleneck is a worldwide challenge, e. g. the antibiotics Piperacillin/Tazobactam shortage in 2016/2017.

The 10-D assessment and evidence-based medicine tool for authors and peer reviewers in clinical pharmacology .

Background: Peer reviewers and authors of clinical pharmacology manuscripts need to meet the standards for Evidence-Based Medicine (EBM) and Good Publication Practices (GPP), and editors of clinical pharmacology journals have to maintain an overview of the peer review process.

Methods And Results: The peer review process can be monitored and facilitated using the 10-D assessment, which comprises peer review criteria to determine if: 1. design of the study, 2.

CXCL16/CXCR6-mediated adhesion of human peripheral blood mononuclear cells to inflamed endothelium.

The endothelial chemokine CXC motif ligand 16 (CXCL16) is involved in the recruitment and firm adhesion of CXCR6 cells to the atherosclerosis-prone aortic vessel wall. Recently we showed that CXCR6 platelets from flowing blood attach to CXCL16 expressed by activated endothelium on the luminal side of the blood vessel. With this study we supplement these findings with the observation that platelets bound to the inflamed endothelium are presenting CXCR6 to CXCL16-positive peripheral blood mononuclear cells (PBMCs) and, thus, are mediating an increased adhesion of PBMCs to the arterial wall.

Activated Platelets Induce an Anti-Inflammatory Response of Monocytes/Macrophages through Cross-Regulation of PGE and Cytokines.

Platelets are well known for their role in hemostasis and are also increasingly recognized for their roles in the innate immune system during inflammation and their regulation of macrophage activation. Here, we aimed to study the influence of platelets on the production of inflammatory mediators by monocytes and macrophages. Analyzing cocultures of platelets and murine bone marrow-derived macrophages or human monocytes, we found that collagen-activated platelets release high amounts of prostaglandin E (PGE) that leads to an increased interleukin- (IL-) 10 release and a decreased tumor necrosis factor (TNF) secretion out of the monocytes or macrophages.

Anti-GPVI Fab SAR264565 effectively blocks GPVI function in ex vivo human platelets under arterial shear in a perfusion chamber.

Introduction: Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro.

Methods: The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen's ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow.

Microfluidic coagulation assay for monitoring anticoagulant therapy in acute stroke patients.

Reliable detection of anticoagulation status in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) is challenging but of importance especially in the emergency setting. This study evaluated the potential of a whole-blood clotting time assay based on Surface Acoustic Waves (SAW-CT) in stroke-patients. The SAW-technology was used for quick and homogenous recalcification of whole blood inducing a surface-activated clotting reaction quantified and visualised by real-time fluorescence microscopy with automatic imaging processing.

Pilot study to test the feasibility of a trial design and complex intervention on PRIoritising MUltimedication in Multimorbidity in general practices (PRIMUMpilot).

Objective: To improve medication appropriateness and adherence in elderly patients with multimorbidity, we developed a complex intervention involving general practitioners (GPs) and their healthcare assistants (HCA). In accordance with the Medical Research Council guidance on developing and evaluating complex interventions, we prepared for the main study by testing the feasibility of the intervention and study design in a cluster randomised pilot study.

Setting: 20 general practices in Hesse, Germany.

Micro-optical prototyping of a surface acoustic wave-based point-of-care coagulation assay and first application in anticoagulated patients.

Objective: Clinicians demand for methods to monitor effects of direct anticoagulants in the emergency setting. We recently described a coagulation assay based on surface acoustic waves (SAW) technology, which quantifies anticoagulant effects by image processing. Here we describe the first step in miniaturizing this laboratory method and provide a portable prototype that contains the optical illumination and automatic on-board image processing.

Pharmacokinetic and pharmacodynamic evaluation of rivaroxaban: considerations for the treatment of venous thromboembolism.

Patients with deep vein thrombosis or pulmonary embolism are recommended to receive anticoagulation for acute treatment and secondary prevention of venous thromboembolism (VTE). Fast-acting direct oral anticoagulants, with or without parenteral heparin, have the potential to replace vitamin K antagonists in this setting. Rivaroxaban, a direct Factor Xa inhibitor, is approved in the European Union and the United States for the single-drug treatment of deep vein thrombosis and pulmonary embolism and the secondary prevention of recurrent VTE in adults.