Klinik und Poliklinik für Anästhesiologie (ab 2004)
Refine
Has Fulltext
- yes (195)
Is part of the Bibliography
- yes (195)
Year of publication
Document Type
- Journal article (187)
- Doctoral Thesis (8)
Language
- English (195) (remove)
Keywords
- COVID-19 (12)
- blood-brain barrier (11)
- inflammation (10)
- endothelial cells (8)
- molecular docking (8)
- blood–brain barrier (7)
- cytokines (7)
- sepsis (6)
- critical illness (5)
- microRNA (5)
- stroke (5)
- tight junctions (5)
- Medizin (4)
- SARS-CoV-2 (4)
- acute kidney injury (4)
- breast cancer (4)
- critical care (4)
- expression (4)
- in vitro (4)
- neuropathic pain (4)
- pain (4)
- Gibbs free energy of binding (3)
- acute respiratory distress syndrome (3)
- astrocytes (3)
- atrial fibrillation (3)
- blood brain barrier (3)
- central nervous system (3)
- gene expression (3)
- iron deficiency (3)
- ischemia (3)
- macrophages (3)
- molecular dynamics (3)
- oxidative stress (3)
- oxygen/glucose deprivation (3)
- patient blood management (3)
- skeletal muscle (3)
- systematic review (3)
- traumatic brain injury (3)
- ARDS (2)
- Alzheimer’s disease (2)
- Blut-Hirn-Schranke (2)
- CNS disorders (2)
- CRPS (2)
- Germany (2)
- Malignant hyperthermia (2)
- Schlaganfall (2)
- Schmerzforschung (2)
- Succinylcholine (2)
- age-related hearing loss (2)
- aging (2)
- airway management (2)
- anaemia (2)
- anaesthesiology (2)
- analysis of variance (2)
- anesthetics (2)
- animal model (2)
- anticoagulation (2)
- antimicrobial stewardship (2)
- barrier (2)
- blood (2)
- blood gas analysis (2)
- blood nerve barrier (2)
- blood-nerve barrier (2)
- blood–labyrinth barrier (2)
- brain (2)
- bridging (2)
- cEND (2)
- capsaicin (2)
- cardiac surgery (2)
- cerebEND (2)
- chemokines (2)
- chronic pain (2)
- claudin-1 (2)
- clinical trial (2)
- complex regional pain syndrome (2)
- critically ill (2)
- cytotoxicity (2)
- endotoxemia (2)
- evaluation (2)
- exosomes (2)
- glioma (2)
- glucocorticoid receptor (2)
- glucocorticoids (2)
- heart failure (2)
- intensive care (2)
- ischemia-reperfusion injury (2)
- lessons learned (2)
- malignant hyperthermia (2)
- mass casualties (2)
- medical nutrition therapy (2)
- meta-analysis (2)
- mice (2)
- multidrug resistance (2)
- neuropathy (2)
- neurotrophins (2)
- perioperative care (2)
- postoperative bleeding (2)
- postoperative nausea and vomiting (2)
- pregnancy (2)
- protein (2)
- randomized controlled trial (2)
- rat (2)
- rolipram (2)
- safety (2)
- selenium (2)
- simulation (2)
- spiral ganglion neuron (2)
- surgery (2)
- terror attack (2)
- thromboembolism (2)
- vitamin C (2)
- vitamin D (2)
- volatile anesthetics (2)
- zinc (2)
- (cardiac) surgery (1)
- 3D in vitro model (1)
- 4D (1)
- 6-percent hydroxyethyl starch (1)
- AD pathogenesis (1)
- APC (1)
- ARDS (acute respiratory distress syndrome) (1)
- ATP-binding cassette transporter (1)
- Accelerometry (1)
- Afferent nerve stimulation (1)
- Alzheimer's disease (1)
- Analgesia (1)
- Anästhesiologie (1)
- Apoptosis (1)
- Apple Watch 7 (1)
- Articular afferent (1)
- Aspartate Aminotransferases (1)
- Axl tyrosine kinase (1)
- Axonschaden (1)
- BDNF (1)
- BIRC7 (1)
- BK channel (1)
- BV-2 (1)
- Bland–Altman (1)
- Blood–brain barrier (1)
- C6 (1)
- CASP (1)
- CNS diseases (1)
- CNS injury (1)
- COVID 19 (1)
- COVID-19 pandemic (1)
- COVID‐19 (1)
- CT (1)
- CX3CL1 (1)
- CXCL13 (1)
- CXCR4-targeting (1)
- Ca2+ homeostasis (1)
- Ca2+ ion analysis (1)
- Ca2+ leak (1)
- Ca2+ oscillation (1)
- Capsaicin (1)
- Central venous-pressure (1)
- Claudin (1)
- ClearSight\(^®\) (1)
- Colloids (1)
- Complex regional pain syndrome (1)
- Computertomographie (1)
- Coronavirus Disease 2019 (1)
- Covid-19 (1)
- Creatine Kinase (1)
- Critically-ill patients (1)
- Crystalloids (1)
- Cutaneous hyperemia (1)
- DAMGO (1)
- DRG (1)
- Disaster response (1)
- Dorsal Root Ganglion (1)
- ECMO (1)
- ECMO indication (1)
- ER Ca2+ imaging (1)
- ER Ca2+ store (1)
- Einfluss (1)
- Elective cesarean-section (1)
- Electrical impedance tomography (1)
- Emery-Dreifuss muscular dystrophy (1)
- Endogenous opioids (1)
- Entzündung (1)
- Epidural Analgesia (1)
- Evaluation (1)
- Exercise testing (1)
- Expression (1)
- Extracorporeal Membrane Oxygenation (1)
- Fisher Z-score transformation (1)
- Fitbit Sense (1)
- Fresh Freeze Plasma (1)
- GABA\(_A\) (1)
- GBM (1)
- GDNF (1)
- GRO alpha (1)
- Garmin Fenix 6 Pro (1)
- Gene expression vectors (1)
- General anaesthesia (1)
- Glucosetransportproteine (1)
- HCW (1)
- HER2 conversion (1)
- HER2 targeted therapy (1)
- HER2-low (1)
- HES (1)
- HIV (1)
- HPβCD (1)
- Halothane (1)
- Hamman's syndrome (1)
- Healthcare Cost (1)
- Healthcare Economics (1)
- High-Frequency Ventilation (1)
- Horowitz Quotient (1)
- Hospital emergency plan (1)
- Hypertonic saline 7.5-percent (1)
- ICU staff (1)
- ICU treatment (1)
- IENFD (1)
- IL-6 (1)
- IL6 (1)
- IMA2.1 (1)
- INR rebound (1)
- ISS (1)
- IgG4 (1)
- In Situ Nick-End Labeling (1)
- In vitro contracture test (1)
- In vitro models (1)
- Inferior Vena Cava (1)
- Inflammation (1)
- Inflammatory Pain (1)
- Inflammatory pain (1)
- Interactive Ventilatory Support (1)
- Ionenkanal (1)
- Joint pain (1)
- Komplexes regionales Schmerzsyndrom (1)
- L-Lactate Dehydrogenase (1)
- Labour Analgesia (1)
- Labour Pain (1)
- Lactated ringers solution (1)
- Lamarckian genetic algorithms (1)
- Langerhans cells (1)
- Latrophilin (1)
- Lessons Learnt (1)
- Longitudinal analysis (1)
- Lung Injury (1)
- MK801 (1)
- MMP9 (1)
- Macrophage Migration Inhibitory Factor (MIF) (1)
- Major abdominal surgery (1)
- Mass critical care (1)
- Medical Managment (1)
- Metastatic breast cancer (1)
- Microcirculation (1)
- NF-kappa-B (1)
- NMDA-Antagonist (1)
- NMDA-Rezeptor (1)
- NMDAR (1)
- NS1608 (1)
- NSAIDs (1)
- NaV1.8 (1)
- Neuralgie (1)
- Neurogenie inflammation (1)
- Neuropathic Pain (1)
- Neuropathic pain (1)
- Neuropathischer Schmerz (1)
- Neuropathy (1)
- Neutrophils (1)
- New Zealand (1)
- Nicardipine (1)
- Nitric oxide (NO) (1)
- Nociceptor (1)
- North American (1)
- OSC (1)
- Oxidized Phospholipids (1)
- Oxygen uptake (1)
- P-glycoprotein (1)
- P-gp inhibitors (1)
- PBM (1)
- PCDHGC3 (1)
- PDE4-inhibitor roflumilast (1)
- PIK3R1 (1)
- POLO-chart (1)
- POLSCORE (1)
- Pain (1)
- Patient Blood Management (PBM) (1)
- Patient Controlled Analgesia (1)
- Patient Satisfaction (1)
- Pearson correlation coefficient (1)
- Phase II trials (1)
- Phospholipide (1)
- Polymerase chain reaction (1)
- Positive-Pressure Respiration (1)
- Postoperative complications (1)
- Predict fluid responsiveness (1)
- Prognose (1)
- Pulmonary Embolism (1)
- Pulmonary function tests (1)
- Puls-pressure variation (1)
- QST (1)
- Quantitative sensory testing (1)
- Questionnaire (1)
- RECK (1)
- Randomized controlled-trial (1)
- Remifentanil (1)
- RyR1 mutations (1)
- SARS-CoV2 (1)
- SERCA (1)
- SIRS (1)
- SOFA Score (1)
- SUSTAIN CSX (1)
- SWCNT CNTs (1)
- Sanger sequencing (1)
- Schmerztherapie (1)
- Sepsis (1)
- Serotonin (5-HT) (1)
- Severe Acute Respiratory Syndrome Coronavirus 2 (1)
- Shotgun method (1)
- Simulation (1)
- Spumaviren (1)
- Surgery (1)
- Swine (1)
- Synthetic biology (1)
- TNF-α (1)
- TRP channel (1)
- TRPA1 (1)
- TRPA1 channel (1)
- TTFields (1)
- TTS (1)
- Takotsubo cardiomyopathy (1)
- Takotsubo syndrome (1)
- Terror (1)
- Tight Junction Proteins (1)
- Tjap1 (1)
- Toll like receptors (1)
- Transwell® system (1)
- Tumor-Treating Fields (TTFields) (1)
- Tyrian purple (1)
- University Hospital (1)
- VACV (1)
- Venous Thrombosis (1)
- Virtual sequencing (1)
- Volatile anesthetics (1)
- WNT signaling (1)
- Withings ScanWatch (1)
- Wnt signaling (1)
- ZO-1 (1)
- Zika virus (1)
- \(^1\)H-NMR spectroscopy (1)
- activated-receptor gamma (1)
- activity-dependent slowing (1)
- acupuncture (1)
- acute Respiratory Distress Syndrome (1)
- acute liver failure (1)
- acute lung injury (1)
- acute respiratory distress syndrome (ARDS) (1)
- adhesion molecules (1)
- adrenal tumor (1)
- adrenocortical cancer (1)
- adsorption (1)
- aged 80 and over (1)
- aggregation (1)
- agnoists (1)
- alveolar epithelium in vitro model, claudin-1, claudin-3, claudin-4, claudin-5 (1)
- alzheimer's disease (1)
- amyloid cardiomyopathy (1)
- anaemia walk‐in clinic (1)
- anaesthetics (1)
- analgesia (1)
- analgesics (1)
- anesthesia (1)
- anesthesiologists (1)
- anesthesiology (1)
- aneurysm repair (1)
- aneurysmal subarachnoid haemorrhage (1)
- angiogenesis (1)
- angioplasty (1)
- animals (1)
- anthocyanin derivatives (1)
- anti-cancer drug-like molecules (1)
- anti-hormonal therapy (1)
- antibacterial activity (1)
- antibiotic prescribing quality (1)
- anticoagulant therapy (1)
- antiemetics (1)
- antioxidant (1)
- antithrombotic therapy (1)
- anxiety (1)
- apolipoprotein J (1)
- apoptosis (1)
- approved drugs (1)
- arteriovenous extracorporeal hemadsorption technique (1)
- artificial intelligence (1)
- astrocytoma (1)
- autoimmune nodopathy (1)
- automated external defibrillators (1)
- autonomic nervous system (1)
- avoidable blood loss (1)
- awake prone positioning (1)
- axonal damage (1)
- barrier properties (1)
- bibliometrics (1)
- bioactive peptide (1)
- bioelectronics (1)
- bleeding (1)
- blockchain anchoring (1)
- blockchain in healthcare (1)
- blockchain in the pharmaceutical industry (1)
- blockchain interoperability (1)
- blood CSF barrier (1)
- blood loss (1)
- blood purification (1)
- blood transfusion (1)
- blood–brain barrier choline transporter (1)
- brain pathology (1)
- brain-metastasis (1)
- breast cancer metastases (1)
- c-fos (1)
- caffeine (1)
- calcitonin gene-related peptide (1)
- calcium level (1)
- calorimetry (1)
- cancer (1)
- carbon nanoparticles (1)
- carcinogen activation (1)
- cardiac arrest documentation (1)
- cardiac protection (1)
- cardio-pulmonary resuscitation (1)
- cardioprotection (1)
- cardiopulmonary resuscitation (1)
- caspase-3 (1)
- cell stretch (1)
- cell-adhesion (1)
- central autonomic network (1)
- central core disease (1)
- cerebEND cells (1)
- cerebral ischemia (1)
- cerebrospinal fluid (1)
- cerebrovascular disorders (1)
- chemical similarity (1)
- chest-compression rate (1)
- children (1)
- chronic constriction injury (1)
- chronic constriction nerve injury (1)
- chronic musculoskeletal pain (1)
- claudin-12 (1)
- claudin-5 (1)
- clinical decision support (1)
- clinical measurement in health technology (1)
- clinical studies (1)
- clinical trials (1)
- clusterin transporter (1)
- colloids (1)
- colorectal carcinoma (1)
- comparative molecular field analysis (1)
- comparative molecular similarity index analysis (1)
- comparison (1)
- complications (1)
- conference abstracts (1)
- connective tissue (1)
- contactin (1)
- core outcome set (1)
- coronary artery bypass (1)
- coronavirus disease 2019 (1)
- corticoid (1)
- corticosteroids (1)
- costs (1)
- creatinine (1)
- cut and sew technique (1)
- cyclodextrin (1)
- cyclodextrin formulations (1)
- cytochrome P450 3A4 (1)
- cytokine expression (1)
- data display (1)
- data harmonization (1)
- death (1)
- demography (1)
- density functional theory (1)
- depression (1)
- dermal B cells (1)
- dexamethasone (1)
- diabetes mellitus (1)
- diabetic nephropathy (1)
- diabetic retinopathy (1)
- diagnostic blood loss (1)
- diagnostic correctness (1)
- diazepam (1)
- differentially expressed genes (1)
- diffusion (1)
- digital phenotyping (1)
- disease (1)
- dorsal root ganglion (1)
- driving pressure (1)
- drug delivery (1)
- drug delivery vector (1)
- drug repurposing (1)
- drug transporter (1)
- drug-drug interactions (1)
- dual-room trauma suite (1)
- dual-room whole-body CT (1)
- dysfunction (1)
- ecological momentary assessment (1)
- electrical excitability (1)
- electrical impedance tomography (1)
- emergency (1)
- emergency information (1)
- emergency preparedness (1)
- encephalitis dementia (1)
- endocarditis (1)
- endothelial injury (1)
- endotoxin (1)
- enhanced recovery after surgery (1)
- enzyme-linkes immunoassays (1)
- epidural anaesthesia (1)
- epidural analgesia (1)
- epidural anesthesia (1)
- estrogens (1)
- ether (1)
- etomidate (1)
- eudaimonia (1)
- evidence synthesis (1)
- exercise (1)
- exposure (1)
- extracellular vesicles (1)
- extracorporeal hemadsorption (1)
- extracorporeal membrane oxygenation (ECMO) (1)
- extracorporeal techniques in hemadsorption therapy (1)
- extravascular lung water (1)
- failure (1)
- fascia (1)
- fears (1)
- fentanyl (1)
- fermentation (1)
- fetal lung (1)
- fibrosis (1)
- first responders (1)
- fish oil (1)
- fitness trackers (1)
- fluorescein isothiocyanate (1)
- fluorescence microscopy (1)
- formulations (1)
- frailty (1)
- free energy (1)
- free energy of solvation (1)
- free flap surgery (1)
- fullerenes (1)
- gastrointestinal tract (1)
- gene ontology (1)
- general anaesthesia (1)
- general anesthesia (1)
- genetic polymorphisms (1)
- genotoxicity (1)
- giant ventral hernia (1)
- glioblastoma multiforme (1)
- glut1 (1)
- glutathione peroxidase (1)
- good clinical practice (1)
- gradient optimisation (1)
- graft surgery (1)
- growth differentiation factor 15 (1)
- guanylyl cyclase (1)
- guideline adherence (1)
- guideline usage (1)
- haemoglobin concentration (1)
- haemostasis (1)
- halothane (1)
- health care (1)
- health care payers (1)
- health care workers (1)
- health sciences (1)
- health tracker (1)
- health-care workers (1)
- healthcare (1)
- heart (1)
- hedonia (1)
- hemadsorption (1)
- high-flow nasal cannula (1)
- histopathology (1)
- human (1)
- human brain microvascular endothelial cells (HBMVEC) (1)
- human cells (1)
- human factors (1)
- human immunodeficiency virus (1)
- humans (1)
- hydrochloride (1)
- hyperalgesia (1)
- hypertonic solution (1)
- hypoxia (1)
- iatrogenic anemia (1)
- immortalization (1)
- immune response (1)
- immunology (1)
- immunonutrition (1)
- immunosorbents (1)
- immunostaining (1)
- impedance aggregometry; WHOLE-BLOOD THROMBOELASTOMETRY; DEFINITION; DISEASE (1)
- implementation (1)
- in vitro cell culture models (1)
- in vitro contracture test (1)
- in vitro model (1)
- in-bed cycling (1)
- in-hospital cardiac arrest (1)
- indigo (1)
- induced impairment (1)
- infiltration (1)
- inflammatory bowel disease (1)
- inflammatory cytokines (1)
- inflammatory neuropathy (1)
- inflammatory pain (1)
- inflammatory response (1)
- infodemic (1)
- information strategies (1)
- inhalation anesthetics (1)
- inhibition (1)
- inner ear (1)
- innovative surgical methods (1)
- inos (1)
- insular cortex (1)
- intensive care medicine (1)
- intensive care unit (1)
- internalization (1)
- internet of things (1)
- intestinal absorption (1)
- intestinal microvascular perfusion (1)
- intracerebral haemorrhage (1)
- intubation (1)
- involvement (1)
- ion channel (1)
- ion channels in the nervous system (1)
- iron deficiency anemia (1)
- ischemia/reperfusion injury (1)
- isosteviol sodium (1)
- isosteviol sodium (STVNA) (1)
- kidney (1)
- kidney ischemia/reperfusion injury (1)
- kidneys (1)
- laparoscopic surgery (1)
- laparostomy (1)
- laryngoscopy (1)
- laterality (1)
- left atrial appendage occlusion (1)
- left-ventricular assist device (1)
- levosimendan (1)
- lidocaine (1)
- lipids (1)
- livin (1)
- lnterleukin-lβ (1)
- longitudinal studies (1)
- low molecular heparin (1)
- low-molecular heparin (1)
- low-risk intra-abdominal infections (1)
- lung injury (1)
- mRNA (1)
- machine learning (1)
- macrophage migration inhibitory factor (MIF) (1)
- major bleeding (1)
- management (1)
- mast cells (1)
- maternal critical care (1)
- mean force potential (1)
- meaning (1)
- mechanical power (1)
- mechanical ventilation (1)
- mechanical ventilator weaning (1)
- mechanisms (1)
- medical devices (1)
- medicine (1)
- metabolizing rate (1)
- metastasis (1)
- methylprednisolone (1)
- miRNS (1)
- mices (1)
- microanastomosis (1)
- microarray (1)
- microdialysis (1)
- microglia (1)
- micronutrients (1)
- microparticles (1)
- microvascular complications (1)
- microvascular endothelial cells (1)
- midazolam (1)
- milk proteins (1)
- mimetic peptide (1)
- minimally invasive surgery (1)
- mission strategies (1)
- mitochondria (1)
- mobile crowdsensing (1)
- mobile health (1)
- moderate sedation (1)
- molecular imaging (1)
- molecular liphophilicity potential (1)
- molecular medicine (1)
- molecular modeling (1)
- molecular modelling (1)
- monocytes (1)
- mortality (1)
- mouse models (1)
- movable sliding gantry (1)
- multidisciplinary (1)
- multimodal treatments (1)
- multiwalled carbon nanotube (1)
- muscle (1)
- muscle disease (1)
- myelin barrier (1)
- myeloperoxidase (1)
- myocardial infarction (1)
- myocardial-infarction (1)
- myofibroblasts (1)
- myotonia congenita (1)
- nanomedicine (1)
- necrosis factor alpha (1)
- need satisfaction (1)
- nerve (1)
- nerve injury (1)
- nervous system (1)
- netrin-1 (1)
- network meta-analysis (1)
- neurofascin (1)
- neurofilament light chain (1)
- neurological complications (1)
- neurology (1)
- neuronal tracing (1)
- neuroprotection (1)
- neuropsychiatric disorders (1)
- neuroscience (1)
- neurotrophic factor (1)
- neurovascular disorders (1)
- neurovasculature (1)
- neutrophil (1)
- nitric oxide (1)
- no-flow fraction (1)
- nociception (1)
- nociceptive Schwann cells (1)
- node of ranvier (1)
- non-invasive ventilation (1)
- nutrient supplementation (1)
- nutrition (1)
- nutrition support (1)
- nutrition therapy (1)
- obstetrics (1)
- off-chain data (1)
- omega-3 fatty acid (1)
- omega-6 fatty acid (1)
- one‐lung ventilation (1)
- open abdomen (1)
- opendsu (1)
- opioid peptides (1)
- opioid receptors (1)
- opioids (1)
- oral anticoagulants (1)
- oral nutrition supplements (1)
- orthopaedic patients (1)
- outcome reporting (1)
- oxidised lipids (1)
- oxidized phospholipids (1)
- oxygen-glucose deprivation (1)
- pain behavior (1)
- pain therapy (1)
- pandemia (1)
- parenteral nutrition (1)
- passive transfer (1)
- pathophysiology (1)
- patient (1)
- patient safety (1)
- patient serum (1)
- paxilline (1)
- peptide synthesis (1)
- performance (1)
- pericytes (1)
- perioperative antibiotic prophylaxis (1)
- perioperative setting (1)
- peripheral nerve (1)
- peripheral nerve injury (1)
- permeability (1)
- personalized antimicrobial therapy (1)
- personalized medicine (1)
- pharmaceutical applications (1)
- pharmacokinetic delivery (1)
- pharmacokinetics (1)
- pharmacology (1)
- pharmacotherapy (1)
- pharmaledger (1)
- phenprocoumon (1)
- phosphatidylinositol (1)
- phosphodiesterase (1)
- photoplethysmography (1)
- physical activity (1)
- pi-pi stacking (1)
- pigs (1)
- pioglitazone (1)
- piperacillin/tazobactam (1)
- point of care testing (1)
- point-of-care (1)
- point-of-care-testing (1)
- polarization (1)
- polymers (1)
- polyneuropathy (1)
- population characteristics (1)
- post-traumatic stress disorder (1)
- postoperative complications (1)
- preconditioning (1)
- prehabilitation (1)
- preoperative anaemia management (1)
- preoperative setting (1)
- presynaptic inhibition (1)
- preterm birth (1)
- prevalence (1)
- primary endpoint (1)
- primary microvascular endothelial cells (1)
- primary outcome (1)
- prognostic marker (1)
- proliferation (1)
- propofol (1)
- propranolol (1)
- prospective studies (1)
- protein corona (1)
- protein expression (1)
- protein hydrolysis (1)
- protein-protein interaction network (1)
- proteins (1)
- protocadherin gamma C3 (1)
- public health (1)
- public health preparedness (1)
- pulmonary edema (1)
- pulmonary function tests (1)
- pulmonary surgical procedures (1)
- pulse therapy (1)
- punctate mechanical allodynia (1)
- qualitative research (1)
- quality assurance (1)
- quality indicators (1)
- quality of life (1)
- quantum mechanics (1)
- questionnaire (1)
- randomized trial (1)
- rational drug design (1)
- reactive oxygen species (1)
- receptor antagonist (1)
- receptors (1)
- recombinant DNA (1)
- recurrence (1)
- red blood cell transfusion (1)
- red blood cells (1)
- registry trial (1)
- relapse (1)
- reperfusion injury (1)
- repetitive firing (1)
- rescue mission (1)
- research integrity (1)
- resolvin (1)
- respiratory distress syndrome (1)
- respiratory failure (1)
- resuscitation time (1)
- reticulocyte haemoglobin (1)
- risk prediction (1)
- robotic surgery (1)
- ryanodine receptor gene (1)
- salvage therapy (1)
- sarcoplasmic reticulum (1)
- scaffold search (1)
- scanning electron microscopy (1)
- sciatic nerve (1)
- scurvy (1)
- selective outcome reporting (1)
- selen (1)
- self-sovereign identities (1)
- senescence (1)
- sensory neurons (1)
- septic shock (1)
- severe multiple trauma (1)
- sevoflurane (1)
- sex hormone (1)
- sglt1 (1)
- shape-based approach (1)
- sheep (1)
- side-effects (1)
- single-electron transistor (1)
- single-walled carbon nanotubes (1)
- situation awareness (1)
- situational awareness (1)
- skin punch biopsy (1)
- smartwatch (1)
- smooth muscle cells (1)
- solnatide (1)
- spinal dorsal horn (1)
- spontaneous pneumomediastinum (1)
- spontaneous pneumopericardium (1)
- sport medicine (1)
- stent (1)
- store-operated Ca2+ entry (1)
- stress (1)
- stress resilience (1)
- structure-activity relationship (1)
- subarachnoid hemorrhage (1)
- succinylcholine (1)
- supine hypotensive syndrome (1)
- survey (1)
- susceptibility (1)
- suxamethonium (1)
- synthetic mesh (1)
- systematic review, (1)
- systemic inflammatory response syndrome (1)
- systemic reviews (1)
- targeting (1)
- team-training (1)
- technology (1)
- terror attacks (1)
- theranostics (1)
- therapeutic antibody (1)
- therapeutic drug monitoring (1)
- therapy (1)
- three-dimensional quantitative structure–activity relationship (1)
- thromboelastometry (1)
- thrombosis (1)
- tight junction (1)
- tight junction protein (1)
- tight junction proteins (1)
- tissue resident T cells (1)
- torsional energy (1)
- trace elements (1)
- transfusion (1)
- transgenic mouse (1)
- transient receptor potential channels (1)
- transition state (1)
- transport inhibition assay (1)
- transporter (1)
- trastuzumab (1)
- trastuzumab deruxtecan (1)
- trauma centre (1)
- trauma management (1)
- trial protocol (1)
- trial registration (1)
- trimethyl-β-cyclodextrin (1)
- tumor (1)
- tumor microenvironment (1)
- tumor necrosis factor-α (1)
- ulfobutylether-\(\beta\)-cyclodextrin (1)
- ultrasound strain elastography (1)
- ultrastructure (1)
- urgent surgery (1)
- urine (1)
- user experience (1)
- user-centred design (1)
- vaccination (1)
- vaccination campaign (1)
- vaccination hesitancy (1)
- vaccine (1)
- vaccine hesitancy (1)
- vaccine refusal (1)
- vacuum conditioning (1)
- ventilation (1)
- video laryngoscopy (1)
- video-assisted laryngoscopy (1)
- viral load (1)
- virtual reality (1)
- virtual screening (1)
- viruses (1)
- vitamins (1)
- vitro contracture test (1)
- volume clamp (1)
- vomiting (1)
- warfarin interruption (1)
- water (1)
- wearable (1)
- white blood cells (1)
- wistar rats (1)
- µ-Opioid receptor (1)
Institute
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (195)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (15)
- Medizinische Klinik und Poliklinik I (11)
- Neurochirurgische Klinik und Poliklinik (11)
- Theodor-Boveri-Institut für Biowissenschaften (9)
- Neurologische Klinik und Poliklinik (8)
- Frauenklinik und Poliklinik (7)
- Institut für Anatomie und Zellbiologie (6)
- Institut für Klinische Neurobiologie (6)
- Kinderklinik und Poliklinik (6)
Sonstige beteiligte Institutionen
- Zentrallabor, Universitätsklinikum Würzburg (2)
- Apotheke, Universitätsklinikum Würzburg (1)
- Department of Medicinal Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria (1)
- Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria (1)
- EMBL Mouse Biology Unit, Monterotondo, Italien (1)
- Interdisziplinäres Zentrum für Klinische Forschung (ZIKF), Würzburg (1)
- Klinik und Poliklinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie des Universitätsklinikums Würzburg (1)
- Krankenhaushygiene und Antimicrobial Stewardship (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
Visual Blood, a 3D animated computer model to optimize the interpretation of blood gas analysis
(2023)
Acid–base homeostasis is crucial for all physiological processes in the body and is evaluated using arterial blood gas (ABG) analysis. Screens or printouts of ABG results require the interpretation of many textual elements and numbers, which may delay intuitive comprehension. To optimise the presentation of the results for the specific strengths of human perception, we developed Visual Blood, an animated virtual model of ABG results. In this study, we compared its performance with a conventional result printout. Seventy physicians from three European university hospitals participated in a computer-based simulation study. Initially, after an educational video, we tested the participants’ ability to assign individual Visual Blood visualisations to their corresponding ABG parameters. As the primary outcome, we tested caregivers’ ability to correctly diagnose simulated clinical ABG scenarios with Visual Blood or conventional ABG printouts. For user feedback, participants rated their agreement with statements at the end of the study. Physicians correctly assigned 90% of the individual Visual Blood visualisations. Regarding the primary outcome, the participants made the correct diagnosis 86% of the time when using Visual Blood, compared to 68% when using the conventional ABG printout. A mixed logistic regression model showed an odds ratio for correct diagnosis of 3.4 (95%CI 2.00–5.79, p < 0.001) and an odds ratio for perceived diagnostic confidence of 1.88 (95%CI 1.67–2.11, p < 0.001) in favour of Visual Blood. A linear mixed model showed a coefficient for perceived workload of −3.2 (95%CI −3.77 to −2.64) in favour of Visual Blood. Fifty-one of seventy (73%) participants agreed or strongly agreed that Visual Blood was easy to use, and fifty-five of seventy (79%) agreed that it was fun to use. In conclusion, Visual Blood improved physicians’ ability to diagnose ABG results. It also increased perceived diagnostic confidence and reduced perceived workload. This study adds to the growing body of research showing that decision-support tools developed around human cognitive abilities can streamline caregivers’ decision-making and may improve patient care.
The relevance of user experience in safety–critical domains has been questioned and lacks empirical investigation. Based on previous studies examining user experience in consumer technology, we conducted an online survey on positive experiences with interactive technology in acute care. The participants of the study consisted of anaesthesiologists, nurses, and paramedics (N = 55) from three German cities. We report qualitative and quantitative data examining (1) the relevance and notion of user experience, (2) motivational orientations and psychological need satisfaction, and (3) potential correlates of hedonic, eudaimonic, and extrinsic motivations such as affect or meaning. Our findings reveal that eudaimonia was the most salient aspect in these experiences and that the relevance of psychological needs is differently ranked than in experiences with interactive consumer technology. We conclude that user experience should be considered in safety–critical domains, but research needs to develop further tools and methods to address the domain-specific requirements.
Artificial intelligence (AI) is predicted to play an increasingly important role in perioperative medicine in the very near future. However, little is known about what anesthesiologists know and think about AI in this context. This is important because the successful introduction of new technologies depends on the understanding and cooperation of end users. We sought to investigate how much anesthesiologists know about AI and what they think about the introduction of AI-based technologies into the clinical setting. In order to better understand what anesthesiologists think of AI, we recruited 21 anesthesiologists from 2 university hospitals for face-to-face structured interviews. The interview transcripts were subdivided sentence-by-sentence into discrete statements, and statements were then grouped into key themes. Subsequently, a survey of closed questions based on these themes was sent to 70 anesthesiologists from 3 university hospitals for rating. In the interviews, the base level of knowledge of AI was good at 86 of 90 statements (96%), although awareness of the potential applications of AI in anesthesia was poor at only 7 of 42 statements (17%). Regarding the implementation of AI in anesthesia, statements were split roughly evenly between pros (46 of 105, 44%) and cons (59 of 105, 56%). Interviewees considered that AI could usefully be used in diverse tasks such as risk stratification, the prediction of vital sign changes, or as a treatment guide. The validity of these themes was probed in a follow-up survey of 70 anesthesiologists with a response rate of 70%, which confirmed an overall positive view of AI in this group. Anesthesiologists hold a range of opinions, both positive and negative, regarding the application of AI in their field of work. Survey-based studies do not always uncover the full breadth of nuance of opinion amongst clinicians. Engagement with specific concerns, both technical and ethical, will prove important as this technology moves from research to the clinic.
Purpose
Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease.
Methods
This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated.
Results
In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion.
Conclusion
HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important.
Purpose
Anaemia is common in patients presenting with aneurysmal subarachnoid (aSAH) and intracerebral haemorrhage (ICH). In surgical patients, anaemia was identified as an idenpendent risk factor for postoperative mortality, prolonged hospital length of stay (LOS) and increased risk of red blood cell (RBC) transfusion. This multicentre cohort observation study describes the incidence and effects of preoperative anaemia in this critical patient collective for a 10-year period.
Methods
This multicentre observational study included adult in-hospital surgical patients diagnosed with aSAH or ICH of 21 German hospitals (discharged from 1 January 2010 to 30 September 2020). Descriptive, univariate and multivariate analyses were performed to investigate the incidence and association of preoperative anaemia with RBC transfusion, in-hospital mortality and postoperative complications in patients with aSAH and ICH.
Results
A total of n = 9081 patients were analysed (aSAH n = 5008; ICH n = 4073). Preoperative anaemia was present at 28.3% in aSAH and 40.9% in ICH. RBC transfusion rates were 29.9% in aSAH and 29.3% in ICH. Multivariate analysis revealed that preoperative anaemia is associated with a higher risk for RBC transfusion (OR = 3.25 in aSAH, OR = 4.16 in ICH, p < 0.001), for in-hospital mortality (OR = 1.48 in aSAH, OR = 1.53 in ICH, p < 0.001) and for several postoperative complications.
Conclusions
Preoperative anaemia is associated with increased RBC transfusion rates, in-hospital mortality and postoperative complications in patients with aSAH and ICH.
PURPOSE
The threat of national and international terrorism remains high. Preparation is the key requirement for the resilience of hospitals and out-of-hospital rescue forces. The scientific evidence for defining medical and tactical strategies often feeds on the analysis of real incidents and the lessons learned derived from them. This systematic review of the literature aims to identify and systematically report lessons learned from terrorist attacks since 2001.
METHODS
PubMed was used as a database using predefined search strategies and eligibility criteria. All countries that are part of the Organization for Economic Cooperation and Development (OECD) were included. The time frame was set between 2001 and 2018.
RESULTS
Finally 68 articles were included in the review. From these, 616 lessons learned were extracted and summarized into 15 categories. The data shows that despite the difference in attacks, countries, and casualties involved, many of the lessons learned are similar. We also found that the pattern of lessons learned is repeated continuously over the time period studied.
CONCLUSIONS
The lessons from terrorist attacks since 2001 follow a certain pattern and remained constant over time. Therefore, it seems to be more accurate to talk about lessons identified rather than lessons learned. To save as many victims as possible, protect rescue forces from harm, and to prepare hospitals at the best possible level it is important to implement the lessons identified in training and preparation.
Effect of Tjap1 knock-down on blood-brain barrier properties under normal and hypoxic conditions
(2023)
Stroke is one of the leading causes of mortality and disability worldwide. The blood-brain barrier (BBB) plays an important role in maintaining brain homeostasis by tightly regulating the exchange of substances between circulating blood and brain parenchyma. BBB disruption is a common pathologic feature of stroke and traumatic brain injury. Understanding the cellular and molecular events that affect the BBB after ischaemic brain injury is important to improve patient prognosis.
We have previously shown that microRNA-212/132 is elevated in hypoxic brain microvascular endothelial cells and acts through suppressing the expression of direct microRNA-212/132 target genes with function at the BBB: claudin-1, junctional adhesion molecule 3 (Jam3) and tight-junction associated protein 1 (Tjap1). While the role of claudin-1 and Jam3 at the BBB is well known, the role of Tjap1 is still unclear. The aim of this work was therefore to characterize the role of Tjap1 in brain endothelial cells using a knock-down (KD) approach in established murine in vitro BBB models cEND and cerebEND. Tjap1 KD was established by stable transfection of a plasmid expressing shRNA against Tjap1. The successful downregulation of Tjap1 mRNA and protein was demonstrated by qPCR and Western blot. Tjap1 KD resulted in impaired barrier properties of endothelial cells as shown by lower TEER values and higher paracellular permeability. Interestingly, the Tjap1 KD cells showed lower cell viability and proliferation but migrated faster in a wound healing assay. In the tube formation assay, Tjap1 KD cell lines showed a lower angiogenic potential due to a significantly lower tube length and number as well as a lower amount of branching points in formed capillaries. Tjap1 KD cells showed changes in gene and protein expression. The TJ proteins claudin-5, Jam3 and ZO-1 were significantly increased in Tjap1 KD cell lines, while occludin was strongly decreased. In addition, efflux pump P-glycoprotein was downregulated in Tjap1 KD cells. Oxygen-glucose deprivation (OGD) is a method to mimic stroke in vitro. Brain endothelial cell lines treated with OGD showed lower barrier properties compared to cells cultured under normal condition. These effects were more severe in Tjap1 KD cells, indicating active Tjap1 involvement in the OGD response in brain microvascular endothelial cells.
We thus have shown that Tjap1 contributes to a tight barrier of the BBB, regulates cell viability and proliferation of endothelial cells, suppresses their migration and promotes new vessel formation. This means that Tjap1 function is important for mature BBB structure in health and disease.
Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days.
Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb\(^®\) and four Oxiris\(^®\) hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45–85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb\(^®\) blood flow [mL/min] = 4.226 × MAP [mmHg] − 3.496 (R-square 0.8133) and Oxiris\(^®\) blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb\(^®\) and Oxiris\(^®\) devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes.
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid β peptide (Aβ) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aβ deposits and NFT formation are the central pathological hallmarks in AD brains, and the majority of AD cases have been shown to exhibit a complex combination of systemic comorbidities. While AD is the foremost common cause of dementia in the elderly, age-related hearing loss (ARHL) is the most predominant sensory deficit in the elderly. During aging, chronic inflammation and resulting endothelial dysfunction have been described and might be key contributors to AD; we discuss an intriguing possible link between inner ear strial microvascular pathology and blood–brain barrier pathology and present ARHL as a potentially modifiable and treatable risk factor for AD development. We present compelling evidence that ARHL might well be seen as an important risk factor in AD development: progressive hearing impairment, leading to social isolation, and its comorbidities, such as frailty, falls, and late-onset depression, link ARHL with cognitive decline and increased risk of dementia, rendering it tempting to speculate that ARHL might be a potential common molecular and pathological trigger for AD. Additionally, one could speculate that amyloid-beta might damage the blood–labyrinth barrier as it does to the blood–brain barrier, leading to ARHL pathology. Finally, there are options for the treatment of ARHL by targeted neurotrophic factor supplementation to the cochlea to improve cognitive outcomes; they can also prevent AD development and AD-related comorbidity in the future.
Alzheimer’s disease (AD) is considered a chronic and debilitating neurological illness that is increasingly impacting older-age populations. Some proteins, including clusterin (CLU or apolipoprotein J) transporter, can be linked to AD, causing oxidative stress. Therefore, its activity can affect various functions involving complement system inactivation, lipid transport, chaperone activity, neuronal transmission, and cellular survival pathways. This transporter is known to bind to the amyloid beta (Aβ) peptide, which is the major pathogenic factor of AD. On the other hand, this transporter is also active at the blood–brain barrier (BBB), a barrier that prevents harmful substances from entering and exiting the brain. Therefore, in this review, we discuss and emphasize the role of the CLU transporter and CLU-linked molecular mechanisms at the BBB interface in the pathogenesis of AD.
Cyclodextrins (CDs) are cyclic oligosaccharide structures that could be used for theranostic applications in personalized medicine. These compounds have been widely utilized not only for enhancing drug solubility, stability, and bioavailability but also for controlled and targeted delivery of small molecules. These compounds can be complexed with various biomolecules, such as peptides or proteins, via host-guest interactions. CDs are amphiphilic compounds with water-hating holes and water-absorbing surfaces. Architectures of CDs allow the drawing and preparation of CD-based polymers (CDbPs) with optimal pharmacokinetic and pharmacodynamic properties. These polymers can be cloaked with protein corona consisting of adsorbed plasma or extracellular proteins to improve nanoparticle biodistribution and half-life. Besides, CDs have become famous in applications ranging from biomedicine to environmental sciences. In this review, we emphasize ongoing research in biomedical fields using CD-based centered, pendant, and terminated polymers and their interactions with protein corona for theranostic applications. Overall, a perusal of information concerning this novel approach in biomedicine will help to implement this methodology based on host-guest interaction to improve therapeutic and diagnostic strategies.
Chronic stress, even stress of a moderate intensity related to daily life, is widely acknowledged to be a predisposing or precipitating factor in neuropsychiatric diseases. There is a clear relationship between disturbances induced by stressful stimuli, especially long-lasting stimuli, and cognitive deficits in rodent models of affective disorders. Regular physical activity has a positive effect on the central nervous system (CNS) functions, contributes to an improvement in mood and of cognitive abilities (including memory and learning), and is correlated with an increase in the expression of the neurotrophic factors and markers of synaptic plasticity as well as a reduction in the inflammatory factors. Studies published so far show that the energy challenge caused by physical exercise can affect the CNS by improving cellular bioenergetics, stimulating the processes responsible for the removal of damaged organelles and molecules, and attenuating inflammation processes. Regular physical activity brings another important benefit: increased stress robustness. The evidence from animal studies is that a sedentary lifestyle is associated with stress vulnerability, whereas a physically active lifestyle is associated with stress resilience. Here, we have performed a comprehensive PubMed Search Strategy for accomplishing an exhaustive literature review. In this review, we discuss the findings from experimental studies on the molecular and neurobiological mechanisms underlying the impact of exercise on brain resilience. A thorough understanding of the mechanisms underlying the neuroprotective potential of preconditioning exercise and of the role of exercise in stress resilience, among other things, may open further options for prevention and therapy in the treatment of CNS diseases.
Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted.
Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction.
Intracranial hemorrhage results in devastating forms of cerebral damage. Frequently, these results also present with cardiac dysfunction ranging from ECG changes to Takotsubo syndrome (TTS). This suggests that intracranial bleeding due to subarachnoid hemorrhage (SAH) disrupts the neuro–cardiac axis leading to neurogenic stress cardiomyopathy (NSC) of different degrees. Following this notion, SAH and secondary TTS could be directly linked, thus contributing to poor outcomes. We set out to test if blood circulation is the driver of the brain–heart axis by investigating serum samples of TTS patients. We present a novel in vitro model combining SAH and secondary TTS to mimic the effects of blood or serum, respectively, on blood–brain barrier (BBB) integrity using in vitro monolayers of an established murine model. We consistently demonstrated decreased monolayer integrity and confirmed reduced Claudin-5 and Occludin levels by RT-qPCR and Western blot and morphological reorganization of actin filaments in endothelial cells. Both tight junction proteins show a time-dependent reduction. Our findings highlight a faster and more prominent disintegration of BBB in the presence of TTS and support the importance of the bloodstream as a causal link between intracerebral bleeding and cardiac dysfunction. This may represent potential targets for future therapeutic inventions in SAH and TTS.
The biomedical consequences of allogeneic blood transfusions and the possible pathomechanisms of transfusion-related morbidity and mortality are still not entirely understood. In retrospective studies, allogeneic transfusion was associated with increased rates of cancer recurrence, metastasis and death in patients with colorectal cancer. However, correlation does not imply causation. The purpose of this study was to elucidate this empirical observation further in order to address insecurity among patients and clinicians. We focused on the in vitro effect of microparticles derived from red blood cell units (RMPs). We incubated different colon carcinoma cells with RMPs and analyzed their effects on growth, invasion, migration and tumor marker expression. Furthermore, effects on Wnt, Akt and ERK signaling were explored. Our results show RMPs do not seem to affect functional and phenotypic characteristics of different colon carcinoma cells and did not induce or inhibit Wnt, Akt or ERK signaling, albeit in cell culture models lacking tumor microenvironment. Allogeneic blood transfusions are associated with poor prognosis, but RMPs do not seem to convey tumor-enhancing effects. Most likely, the circumstances that necessitate the transfusion, such as preoperative anemia, tumor stage, perioperative blood loss and extension of surgery, take center stage.
Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted.
Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy.
Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABA\(_A\) in NaV1.8-positive sensory neurons (Scn10a\(^{Cre}\);Gabrb3\(^{fl/fl}\)) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABA\(_A\). Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABA\(_A\) and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8\(^+\) afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABA\(_A\) in NaV1.8\(^+\) nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.
Background: The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring. Methods: In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight\(^®\) (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight\(^®\) through questioning. Results: 139 measurements from 11 patients were included in the final analysis. Employing Bland–Altman analyses, we identified a bias of −10.8 mmHg for systolic, of −0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements. Discussion: Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight\(^®\) to oscillometric blood pressure measurement in regard of comfort and handling.
Advances in breast cancer management and extracellular vesicle research, a bibliometric analysis
(2021)
Extracellular vesicles transport variable content and have crucial functions in cell–cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers.
Anaemia is a risk factor for several adverse postoperative outcomes. Detailed data about the prevalence of anaemia are not available over a long time-period in Germany. In this retrospective, observational, multicentre study, patients undergoing surgery in March in 2007, 2012, 2015, 2017 and 2019 were studied. The primary objective was the prevalence of anaemia at hospital admission. The secondary objectives were the association between anaemia and the number of units of red blood cells transfused, length of hospital stay and in-hospital mortality. A total of 23,836 patients were included from eight centres. The prevalence of pre-operative anaemia in patients aged ≥ 18 years decreased slightly from 37% in 2007 to 32.5% in 2019 (p = 0.01) and increased in patients aged ≤ 18 years from 18.8% in 2007 to 26.4% in 2019 (p > 0.001). The total amount of blood administered per 1000 patients decreased from 671.2 units in 2007 to 289.0 units in 2019. Transfusion rates in anaemic patients declined from 33.8% in 2007 to 19.1% in 2019 (p < 0.001) and in non-anaemic patients from 8.4% in 2007 to 3.4% in 2019 (p < 0.001). Overall, the mortality rate remained constant over the years: 2.9% in 2007, 2.1% in 2012, 2.5% in 2015, 1.9% in 2017 and 2.5% in 2019. In the presence of anaemia, mortality was significantly increased compared with patients without anaemia (OR 5.27 (95%CI 4.13–6.77); p < 0.001). Red blood cell transfusion was associated with an increased risk of mortality (OR 14.98 (95%CI 11.83–19.03); p < 0.001). Using multivariable linear regression analysis with fixed effects, we found that pre-operative anaemia (OR 2.08 (95%CI 1.42–3.05); p < 0.001) and red blood cell transfusion (OR 4.29 (95%CI 3.09–5.94); p < 0.001) were predictors of mortality but not length of stay (0.99 (95%CI 0.98–1.00) days; p = 0.12) and analysed years (2007 vs. 2019: OR 1.49 (95%CI 0.86–2.69); p = 0.07). Pre-operative anaemia affects more than 30% of surgical patients in Germany and multidisciplinary action is urgently required to reduce adverse outcomes.
Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing “Risk of Bias” aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.
In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness—a condition also resulting in death of thousands in the 21st century—has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019.
Inflammation and oxidative stress represent physiological response mechanisms to different types of stimuli and injury during critical illness. Its proper regulation is fundamental to cellular and organismal survival and are paramount to outcomes and recovery from critical illness. A proper maintenance of the delicate balance between inflammation, oxidative stress, and immune response is crucial for resolution from critical illness with important implications for patient outcome. The extent of inflammation and oxidative stress under normal conditions is limited by the antioxidant defense system of the human body, whereas the antioxidant capacity is commonly significantly compromised, and serum levels of micronutrients and vitamins significantly depleted in patients who are critically ill. Hence, the provision of antioxidants and anti-inflammatory nutrients may help to reduce the extent of oxidative stress and therefore improve clinical outcomes in patients who are critically ill. As existing evidence of the beneficial effects of antioxidant supplementation in patients who are critically ill is still unclear, actual findings about the most promising anti-inflammatory and antioxidative candidates selenium, vitamin C, zinc, and vitamin D will be discussed in this narrative review. The existing evidence provided so far demonstrates that several factors need to be considered to determine the efficacy of an antioxidant supplementation strategy in patients who are critically ill and indicates the need for adequately designed multicenter prospective randomized control trials to evaluate the clinical significance of different types and doses of micronutrients and vitamins in selected groups of patients with different types of critical illness.
Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.
Background
Complex regional pain syndrome (CRPS) is an orphan disease occurring as a complication after trauma. Due to its acute onset and the typical clinical presentation of the inflammatory and autonomous signs, it is an eye-catching chronic pain disease affecting also young and working people. In social media and the internet, high pain severity and the unfavourable prognosis are often empathized.
Methods
Here, we compared epidemiological, pain and lifestyle factors of 223 CPRS patients from the “ncRNAPain” cohort with 255 patients with chronic musculoskeletal pain (MSK). MSK patients were recruited at the beginning of a multimodal pain therapy programme. We searched for factors predicting pain intensity.
Results
Both chronic pain diseases affected women in middle age. Patients with MSK were more obese, drank more alcohol, and were less educated (Pearson chi-square Test or Mann–Whitney/U-Test). Both groups smoked more than healthy people in the OECD (Organization for Economic Cooperation and Development). Mann–Whitney/U-Test confirmed that CRPS patients did not have more severe pain and did not suffer more from pain-related disability than patients with MSK. CRPS patients also had less psychiatric comorbidities. Multiple linear regression analysis revealed that group assignment, depressive characteristics, body mass index, average alcohol consumption and smoking predicted higher pain ratings, while disease duration, anxiety symptoms or gender had no influence on pain intensity.
Conclusion
In summary, our study supports a more optimistic view on pain in CRPS patients in comparison to MSK and identifies lifestyle factors that might contribute to the pathophysiology like smoking and drinking. Important next steps are the identification of CRPS patients at risk for chronification or—vice versa—with protective factors for pain resolution.
Significance
This study compares complex regional pain syndrome (CRPS) and chronic musculoskeletal pain and questions previously reported pain, disability and lifestyle factors associated with CRPS.
Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.
The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68\(^+\) macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy.
Microvascular endothelial cells are an essential part of many biological barriers, such as the blood–brain barrier (BBB) and the endothelium of the arteries and veins. A reversible opening strategy to increase the permeability of drugs across the BBB could lead to improved therapies due to enhanced drug bioavailability. Vanilloids, such as capsaicin, are known to reversibly open tight junctions of epithelial and endothelial cells. In this study, we used several in vitro assays with the murine endothelial capillary brain cells (line cEND) as a BBB model to characterize the interaction between capsaicin and endothelial tight junctions.
(1) Background: Health care workers (HCWs) play a key role in increasing anti-COVID vaccination rates. Fear of potential side effects is one of the main reasons for vaccine hesitancy. We investigated which side effects are of concern to HCWs and how these are associated with vaccine hesitancy. (2) Methods: Data were collected in an online survey in February 2021 among HCWs from across Germany with 4500 included participants. Free-text comments on previously experienced vaccination side effects, and fear of short- and long-term side effects of the COVID-19 vaccination were categorized and analyzed. (3) Results: Most feared short-term side effects were vaccination reactions, allergic reactions, and limitations in daily life. Most feared long-term side effects were (auto-) immune reactions, neurological side effects, and currently unknown long-term consequences. Concerns about serious vaccination side effects were associated with vaccination refusal. There was a clear association between refusal of COVID-19 vaccination in one's personal environment and fear of side effects. (4) Conclusions: Transparent information about vaccine side effects is needed, especially for HCW. Especially when the participants' acquaintances advised against vaccination, they were significantly more likely to fear side effects. Thus, further education of HCW is necessary to achieve good information transfer in clusters as well.
Backround: In February 2021, the first formal evidence and consensus-based (S3) guidelines for the inpatient treatment of patients with COVID-19 were published in Germany and have been updated twice during 2021. The aim of the present study is to re-evaluate the dissemination pathways and strategies for ICU staff (first evaluation in December 2020 when previous versions of consensus-based guidelines (S2k) were published) and question selected aspects of guideline adherence of standard care for patients with COVID-19 in the ICU. Methods: We conducted an anonymous online survey among German intensive care staff from 11 October 2021 to 11 November 2021. We distributed the survey via e-mail in intensive care facilities and requested redirection to additional intensive care staff (snowball sampling). Results: There was a difference between the professional groups in the number, selection and qualitative assessment of information sources about COVID-19. Standard operating procedures were most frequently used by all occupational groups and received a high quality rating. Physicians preferred sources for active information search (e.g., medical journals), while nurses predominantly used passive consumable sources (e.g., every-day media). Despite differences in usage behaviour, the sources were rated similarly in terms of the quality of the information on COVID-19. The trusted organizations have not changed over time. The use of guidelines was frequently stated and highly recommended. The majority of the participants reported guideline-compliant treatment. Nevertheless, there were certain variations in the use of medication as well as the criteria chosen for discontinuing non-invasive ventilation (NIV) compared to guideline recommendations. Conclusions: An adequate external source of information for nursing staff is lacking, the usual sources of physicians are only appropriate for the minority of nursing staff. The self-reported use of guidelines is high.
Background: The adequate choice of perioperative antibiotic prophylaxis (PAP) could influence the risk of surgical site infections (SSIs) in general surgery. A new local PAP guideline was implemented in May 2017 and set the first-generation cefazolin (CFZ) instead the second-generation cefuroxime (CXM) as the new standard prophylactic antibiotic. The aim of this study was to compare the risk of SSIs after this implementation in intra-abdominal infections (IAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Germany analyzing patients after emergency surgery during 2016 to 2019 (n = 985), of which patients receiving CXM or CFZ were selected (n = 587). Propensity score matching was performed to ensure a comparable risk of SSIs in both groups. None-inferiority margin for SSIs was defined as 8% vs. 4%. Results: Two matched cohorts with respectively 196 patients were compared. The rate of SSIs was higher in the CFZ group (7.1% vs. 3.6%, p = 0.117) below the non-inferiority margin. The rate of other postoperative infections was significantly higher in the CFZ group (2.0% vs. 8.7%, p = 0.004). No other differences including postoperative morbidity, mortality or length-of-stay were observed. Conclusion: Perioperative antibiotic prophylaxis might be safely maintained by CFZ even in the treatment of intra-abdominal infections.
In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies.
Simple Summary
Anti-hormonal therapie regimes are well established in oncological treatments in breast cancer. In contrast there is limited knowledge of their effects on metastatic brain metastases in advanced breast cancer and their ability to cross the blood brain-barrier. In this review, we point out the usual antihormonal therapy options in the primary disease, but also in metastatic breast cancer. In addition, we explain the epidemiological facts of brain metastases, as well as the basics of the blood-brain barrier and how this is overcome by metastase. Last but not least, we deal with the known anti-hormonal therapy options and present clinical studies on their intracerebral effect, as well as the known basics of their blood-brain barrier penetration. Not all common anti-hormonal therapeutics are able to penetrate the CNS. It is therefore important for the treating oncologists to use substances that have been proven to cross the BBB, despite the limited data available. Aromataseinhibitors, especially letrozole, probably also tamoxifen, everolimus and CDK4/6 inhibitors, especially abemaciclib, appear to act intracerebrally by overcoming the blood-brain barrier. Nevertheless, further data must be obtained in basic research, but also health care research in relation to patients with brain metastases.
Abstract
The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer.
The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases.
Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects.
At any moment in time, cells coordinate and balance their calcium ion (Ca\(^{2+}\)) fluxes. The term ‘Ca\(^{2+}\) homeostasis’ suggests that balancing resting Ca2+ levels is a rather static process. However, direct ER Ca\(^{2+}\) imaging shows that resting Ca\(^{2+}\) levels are maintained by surprisingly dynamic Ca\(^{2+}\) fluxes between the ER Ca\(^{2+}\) store, the cytosol, and the extracellular space. The data show that the ER Ca\(^{2+}\) leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca\(^{2+}\) dynamics. Based on simplistic Ca\(^{2+}\) toolkit models, we discuss how the ER Ca\(^{2+}\) leak could contribute to evolutionarily conserved Ca\(^{2+}\) phenomena such as Ca\(^{2+}\) entry, ER Ca\(^{2+}\) release, and Ca\(^{2+}\) oscillations.
Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use.
Background
Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients.
Methods
A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed.
Results
1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] − 6.88; 95% CI − 11.27, − 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD − 3.53; 95% CI − 6.16, − 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care.
Conclusion
Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact.
Background
The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration.
Methods
Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials.
Results
Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95% confidence interval 0.62–0.97, p = 0.03; I2 = 30%), reduced intensive care unit length of stay (12 studies: mean difference − 3.13 days, 95% CI − 5.36 to − 0.89, n = 1250, p = 0.006; I2 = 70%), and shorter duration of mechanical ventilation (9 studies: mean difference − 5.07 days, 95% CI − 7.42 to − 2.73, n = 572, p < 0.0001; I2 = 54%). Parenteral administration was associated with a greater effect on overall mortality than enteral administration (test of subgroup differences, p = 0.04), whereas studies of parenteral subgroups had lower quality. There were no subgroup differences based on baseline vitamin D levels.
Conclusions
Vitamin D supplementation in critically ill patients may reduce mortality. Parenteral administration might be associated with a greater impact on mortality. Heterogeneity and assessed certainty among the studies limits the generalizability of the results.
The trauma center of the University Hospital Wuerzburg has developed an advanced trauma pathway based on a dual-room trauma suite with an integrated movable sliding gantry CT-system. This enables simultaneous CT-diagnostics and treatment of two trauma patients. The focus of this study was to investigate the quality of the concept based on defined outcome criteria in this specific setting (time from arrival to initiation of CT scan: tCT; time from arrival to initiation of emergency surgery: tES). We analyzed all trauma patients admitted to the hospital’s trauma suite from 1st May 2019 through 29th April 2020. Two subgroups were defined: trauma patients, who were treated without a second trauma patient present (group 1) and patients, who were treated simultaneously with another trauma patient (group 2). Simultaneous treatment was defined as parallel arrival within a period of 20 min. Of 423 included trauma patients, 46 patients (10.9%) were treated simultaneously. Car accidents were the predominant trauma mechanism in this group (19.6% vs. 47.8%, p < 0.05). Prehospital life-saving procedures were performed with comparable frequency in both groups (intubation 43.5% vs. 39%, p = 0.572); pleural drainage 3.2% vs. 2.2%, p = 0.708; cardiopulmonary resuscitation 5% vs. 2.2%, p = 0.387). At hospital admission, patients in group 2 suffered significantly more pain (E-problem according to Advanced Trauma Life Support principles©; 29.2% vs. 45.7%, p < 0.05). There were no significant differences in the clinical treatment (emergency procedures, vasopressor and coagulant therapy, and transfusion of red blood cells). tCT was 6 (4–10) minutes (median and IQR) in group 1 and 8 (5–15.5) minutes in group 2 (p = 0.280). tES was 90 (78–106) minutes in group 1 and 99 (97–108) minutes in group 2 (p = 0.081). The simultaneous treatment of two trauma patients in a dual-room trauma suite with an integrated movable sliding gantry CT-system requires a medical, organizational, and technical concept adapted to this special setting. Despite the oftentimes serious and life-threatening injuries, optimal diagnostic and therapeutic procedures can be guaranteed for two simultaneous trauma patients at an individual medical level in consistent quality.
Background
Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients.
Methods
673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival.
Results
Most patients were between 50 and 70 years of age. PaO\(_{2}\)/FiO\(_{2}\) ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events.
Conclusions
Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival.
Background: Over the recent years, technological advances of wrist-worn fitness trackers heralded a new era in the continuous monitoring of vital signs. So far, these devices have primarily been used for sports.
Objective: However, for using these technologies in health care, further validations of the measurement accuracy in hospitalized patients are essential but lacking to date.
Methods: We conducted a prospective validation study with 201 patients after moderate to major surgery in a controlled setting to benchmark the accuracy of heart rate measurements in 4 consumer-grade fitness trackers (Apple Watch 7, Garmin Fenix 6 Pro, Withings ScanWatch, and Fitbit Sense) against the clinical gold standard (electrocardiography).
Results: All devices exhibited high correlation (r≥0.95; P<.001) and concordance (rc≥0.94) coefficients, with a relative error as low as mean absolute percentage error <5% based on 1630 valid measurements. We identified confounders significantly biasing the measurement accuracy, although not at clinically relevant levels (mean absolute error<5 beats per minute).
Conclusions: Consumer-grade fitness trackers appear promising in hospitalized patients for monitoring heart rate.
Background
Systematic reviews attempt to gather all available evidence. Controversy exists regarding effort and benefit of including study results presented at conferences only. We recently published a Cochrane network meta-analysis (NMA) including 585 randomized controlled trials comparing drugs for prevention of postoperative nausea and vomiting (PONV). Studies published as conference abstracts only were excluded. This study aimed to include all eligible studies published as abstracts only, assessing their added value regarding reporting quality and effect on the review’s interpretation.
Methods
Conference abstracts were searched in the review’s excluded studies and conference proceedings of anaesthesiologic societies. We assessed their reporting quality regarding review’s eligibility criteria, Cochrane ‘risk of bias’ assessment tool 1.0, and adherence to CONSORT (Consolidated Standards of Reporting Trials) for abstracts. Abstracts were included in sensitivity NMA, and impact on the NMA structure was investigated.
Results
We identified 90 abstracts. A total of 14% (13/90) were eligible. A total of 86% (77/90) are awaiting classification due to insufficient reporting of review’s eligibility criteria. In abstracts awaiting classification, sufficient information was missing on standardization of anaesthesia in 71% (55/77), age of participants in 56% (43/77), and outcome details in 46% (36/77). A total of 73% (66/90) of abstracts lacked sufficient information on 15/25 data extraction items. Reported study characteristics of abstracts were comparable to included studies of the review. A total of 62% (56/90) of abstract trials were assessed as overall high risk of bias due to poor reporting. Median adherence to CONSORT for abstracts was 24% (IQR, 18 to 29%). Six of the 13 eligible abstracts reported relevant outcome data in sufficient detail for NMA on seven outcomes of the Cochrane review. Inclusion of abstracts did not substantially change the network structure, network effect estimates, ranking of treatments, or the conclusion. Certainty of evidence for headache on palonosetron use was upgraded from very low to low.
Conclusions
Most conference abstracts on PONV were insufficiently reported regarding review’s narrow inclusion criteria and could not be included in NMA. The resource-intensive search and evaluation of abstracts did not substantially extent the full-text evidence base of the review, given the few adequately reported abstracts. Conferences should oblige authors to adhere to CONSORT for abstracts.
Background:
Studies have reported on the incidence of sedation-related adverse events (AEs), but little is known about their impact on health care costs and resource use.
Methods: Health care providers and payers in five countries were recruited for an online survey by independent administrators to ensure that investigators and respondents were blinded to each other. Surveys were conducted in the local language and began with a "screener" to ensure that respondents had relevant expertise and experience. Responses were analyzed using Excel and R, with the Dixon's Q statistic used to identify and remove outliers. Global and country-specific average treatment patterns were calculated via bootstrapping; costs were mean values. The sum product of costs and intervention probability gave a cost per AE.
Results: Responses were received from 101 providers and 26 payers, the majority having. 5 years of experience. At a minimum, the respondents performed a total of 3,430 procedural sedations per month. All AEs detailed occurred in clinical practice in the last year and were reported to cause procedural delays and cancellations in some patients. Standard procedural sedation costs ranged from (sic)74 (Germany) to $2,300 (US). Respondents estimated that AEs would increase costs by between 16% (Italy) and 179% (US). Hypotension was reported as the most commonly observed AE with an associated global mean cost (interquartile range) of $43 ($27-$68). Other frequent AEs, including mild hypotension, bradycardia, tachycardia, mild oxygen desaturation, hypertension, and brief apnea, were estimated to increase health care spending on procedural sedation by $2.2 billion annually in the US.
Conclusion: All sedation-related AEs can increase health care costs and result in substantial delays or cancellations of subsequent procedures. The prevention of even minor AEs during procedural sedation may be crucial to ensuring its value as a health care service.
Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians' alertness.
Takotsubo syndrome (TTS), also known as the transient left ventricular apical ballooning syndrome, is in contemporary times known as novel acute cardiac syndrome. It is characterized by transient left ventricular apical akinesis and hyperkinesis of the basal left ventricular portions. Although the precise etiology of TTS is unknown, events like the sudden release of stress hormones, such as the catecholamines and the increased inflammatory status might be plausible causes leading to the cardiovascular pathologies. Recent studies have highlighted that an imbalance in lipid accumulation might promote a deviant immune response as observed in TTS. However, there is no information on comprehensive profiling of serum lipids of TTS patients. Therefore, we investigated a detailed quantitative lipid analysis of TTS patients using ES-MSI. Our results showed significant differences in the majority of lipid species composition in the TTS patients compared to the control group. Furthermore, the computational analyses presented was able to link the altered lipids to the pro-inflammatory cytokines and disseminate possible mechanistic pathways involving TNFα and IL-6. Taken together, our study provides an extensive quantitative lipidome of TTS patients, which may provide a valuable Pre-diagnostic tool. This would facilitate the elucidation of the underlying mechanisms of the disease and to prevent the development of TTS in the future.
Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.