Attitude toward second opinions in Germany - a survey of the general population.

BACKGROUND: Second medical opinions (SOs) can assist patients in making informed treatment decisions and improve the understanding of their diagnosis. In Germany, there are different approaches to obtain a structured SO procedure: SO programs by health insurers and SOs according to the SO Directive. Through a direct survey of the population, we aimed to assess how structured SOs should be provided to fulfil patients' needs. METHODS: A stratified sample of 9990 adults (≥18 years) living in the federal states of Berlin and Brandenburg (Germany) were initially contacted by post in April and sent a reminder in May 2020. The survey results were analyzed descriptively. RESULTS: Among 1349 participants (response rate 14%), 56% were female and the median age was 58 years (interquartile range (IQR) 44-69). Participants wanted to be informed directly and personally about the possibility of obtaining an SO (89%; 1201/1349). They preferred to be informed by their physician (93%; 1249/1349). A majority of participants would consider it important to obtain an SO for oncological indications (78%; 1049/1349). Only a subset of the participants would seek an SO via their health insurer or via an online portal (43%; 577/1349 and 16%; 221/1349). A personally delivered SO was the preferred route of SO delivery, as 97% (1305/1349) would (tend to) consider this way of obtaining an SO. Participants were asked to imagine having moderate knee pain for years, resulting in a treatment recommendation for knee joint replacement. They were requested to rate potential qualification criteria for a physician providing the SO. The criteria rated to be most important were experience with the recommended diagnosis/treatment (criterion (very) important for 93%; 1257/1349) and knowledge of the current state of research (criterion (very) important for 86%; 1158/1349). Participants were willing to travel 60 min (median; IQR 60-120) and wait 4 weeks (median; IQR 2-4) for their SO in the hypothetical case of knee pain. CONCLUSION: In general, SOs were viewed positively. We found that participants have clear preferences regarding SOs. We propose that these preferences should be taken into account in the future design and development of SO programs.

Variants in FIX propeptide associated with vitamin K antagonist hypersensitivity: functional analysis and additional data confirming the common founder mutations.

One of the most common and unwanted side effects during oral anticoagulant therapy (OAT) is bleeding complications. In rare cases, vitamin K antagonist (VKA)-related bleeding events are associated with mutations affecting the F9 propeptide at amino acid position 37 due to a substitution of alanine to either valine or threonine. Based on our actual cohort of 18 patients, we update the knowledge on this rare phenotype and its origin. A founder mutation for both variants was reconfirmed by haplotype analysis of intronic and extragenic short tandem repeat (STR) polymorphisms with a higher prevalence in Switzerland than in other regions of Europe. Screening of healthy individuals for the presence of these F9 gene mutations did not identify any of these variants, thus proving the rare occurrence of this genotype. Furthermore, both variants were expressed in vitro and warfarin dose responses were studied. Our warfarin dose response analysis confirmed higher sensitivity of both variants to warfarin with the effect being more apparent for Ala37Thr. Thus, although F9 propeptide mutation-associated hypersensitivity to VKA is a rare phenomenon, awareness towards this bleeding phenotype is important to identify patients at risk.

[Viscoelasticity-based treatment of bleeding injuries]. / Viskoelastizitätsbasierte Therapie beim blutenden Schwerverletzten.

Uncontrolled bleeding is the leading preventable cause of death in patients with multiple injuries. Currently, trauma-induced coagulopathy is seen as an independent disease entity influencing survival. Severely bleeding trauma patients are often treated with classical blood products in predefined ratios (damage control resuscitation). Viscoelasticity-based and target-oriented approaches could possibly be given priority. Viscoelasticity-based diagnostics and therapy enable the qualitative investigation of whole blood and provide therapeutically usable information on initiation, dynamics and sustainability of thrombus formation. Due to the ease of handling and timely results this lends itself as a point-of-care procedure. This article presents the clinical issues with using viscoelastic procedures and current expert recommendations taking the literature into consideration.

Discovery, Structure Elucidation, and Biological Characterization of Nannocystin†A, a Macrocyclic Myxobacterial Metabolite with Potent Antiproliferative Properties.

Microbial natural products are a rich source of bioactive molecules to serve as drug leads and/or biological tools. We investigated a little-explored myxobacterial genus, Nannocystis sp., and discovered a novel 21-membered macrocyclic scaffold that is composed of a tripeptide and a polyketide part with an epoxyamide moiety. The relative and absolute configurations of the nine stereocenters was determined by NMR spectroscopy, molecular dynamics calculations, chemical degradation, and X-ray crystallography. The compound, named nannocystin A (1), was found to inhibit cell proliferation at low nanomolar concentrations through the early induction of apoptosis. The mode of action of 1 could not be matched to that of standard drugs by transcriptional profiling and biochemical experiments. An initial investigation of the structure-activity relationship based on seven analogues demonstrated the importance of the epoxide moiety for high activity.

[Overdosing of direct oral anticoagulants]. / Überdosierung von direkten oralen Antikoagulanzien.

BACKGROUND: Direct oral anticoagulants (DOAC) are increasingly used for prophylaxis and treatment of thromboembolic events. Incorrectly dosed DOAC treatment is associated with excess mortality. PURPOSE: This article aims at raising awareness of DOAC overdosing and its causes as well as presenting a diagnostic and therapeutic work-up. MATERIAL AND METHODS: Based on a case presentation, a structured review of the current literature on DOAC overdosing was performed and treatment recommendations were extracted. RESULTS: In addition to wittingly or unwittingly increased DOAC intake, common causes of overdose are inadequate dose adjustment for concomitant medication or comorbidities. Global coagulation testing should be supplemented with DOAC-specific testing. Severe bleeding and the need for invasive diagnostics or urgent surgery represent indications for treating DOAC overdoses. Based on the cause of an DOAC overdose, active charcoal, endoscopic pill rescue, antagonization with idarucizumab or andexanet alfa and the targeted substitution of coagulation factors represent treatment options. CONCLUSION: The sensitization of clinicians is important to ensure a timely diagnosis and adequate treatment of DOAC overdosing. This report provides an overview of current knowledge on diagnostics and treatment; however, further studies are necessary to improve the existing algorithms.

Evaluation of Prehospital Undertriage in Relation to Trauma Team Activation-Results from a Prospective Study in 12 Level one German Trauma Centers.

Background/Objective: This prospective, multicenter observational cohort study was carried out in 12 trauma centers in Germany and Switzerland. Its purpose was to evaluate the rate of undertriage, as well as potential consequences, and relate these with different Trauma Team Activation Protocols (TTA-Protocols), as this has not been done before in Germany. Methods: Each trauma center collected the data during a three-month period between December 2019 and February 2021. All 12 participating hospitals are certified as supra-regional trauma centers. Here, we report a subgroup analysis of undertriaged patients. Those included in the study were all consecutive adult patients (age ≥ 18 years) with acute trauma admitted to the emergency department of one of the participating hospitals by the prehospital emergency medical service (EMS) within 6 h after trauma. The data contained information on age, sex, trauma mechanism, pre- and in-hospital physiology, emergency interventions, emergency surgical interventions, intensive care unit (ICU) stay, and death within 48 h. Trauma team activation (TTA) was initiated by the emergency medical services. This should follow the national guidelines for severe trauma using established field triage criteria. We used various denominators, such as ISS, and criteria for the appropriateness of TTA to evaluate the undertriage in four groups. Results: This study included a total of 3754 patients. The average injury severity score was 5.1 points, and 7.0% of cases (n = 261) presented with an injury severity score (ISS) of 16+. TTA was initiated for a total of 974 (26%) patients. In group 1, we evaluated how successful the actual practice in the EMS was in identifying patients with ISS 16+. The undertriage rate was 15.3%, but mortality was lower in the undertriage cohort compared to those with a TTA (5% vs. 10%). In group 2, we evaluated the actual practice of EMS in terms of identifying patients meeting the appropriateness of TTA criteria; this showed a higher undertriage rate of 35.9%, but as seen in group 1, the mortality was lower (5.9% vs. 3.3%). In group 3, we showed that, if the EMS were to strictly follow guideline criteria, the rate of undertriage would be even higher (26.2%) regarding ISS 16+. Using the appropriateness of TTA criteria to define the gold standard for TTA (group 4), 764 cases (20.4%) fulfilled at least one condition for retrospective definition of TTA requirement. Conclusions: Regarding ISS 16+, the rate of undertriage in actual practice was 15.3%, but those patients did not have a higher mortality.

Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening.

Kappa-opioid (KOP) receptor agonists exhibit analgesic effects without activating reward pathways. In the search for nonaddictive opioid therapeutics and novel chemical tools to study physiological functions regulated by the KOP receptor, we screened in silico its recently released inactive crystal structure. A selective novel KOP receptor agonist emerged as a notable result and is proposed as a new chemotype for the study of the KOP receptor in the etiology of drug addiction, depression, and/or pain.

Predicting tracheostomy in multiple injured patients with severe thoracic injury (AIS ≥ 3) with the new T3P-Score: a multivariable regression prediction analysis.

Multiple trauma patients with severe chest trauma are at increased risk for tracheostomy. While the risk factors associated with the need for tracheostomy are well established in the general critical care population, they have not yet been validated in a cohort of patients suffering severe thoracic trauma. This retrospective cohort study analysed data on patients aged 18 years or older who were admitted to one of the six participating academic level I trauma centres with multiple injuries, including severe thoracic trauma (AISThorax ≥ 3) between 2010 and 2014. A multivariable binary regression was used to identify predictor variables for tracheostomy and to develop the Tracheostomy in Thoracic Trauma Prediction Score (T3P-Score). The study included 1019 adult thoracic trauma patients, of whom 165 underwent tracheostomy during their intensive care unit (ICU) stay. Prehospital endotracheal intubation (adjusted OR [AOR]: 2.494, 95% CI [1.412; 4.405]), diagnosis of pneumonia during the ICU stay (AOR: 4.374, 95% CI [2.503; 7.642]), duration of mechanical ventilation (AOR: 1.008/hours of intubation, 95% CI [1.006; 1.009]), and an AISHead ≥ 3 (AOR 1.840, 95% CI [1.039; 3.261]) were independent risk factors for tracheostomy. Patients with sepsis had a lower risk of tracheostomy than patients without sepsis (AOR 0.486, 95% CI [0.253; 0.935]). The T3P-Score had high predictive validity for tracheostomy (ROCAUC = 0.938, 95% CI [0.920, 0.956]; Nagelkerke's R2 was 0.601). The T3P-Score's specificity was 0.68, and the sensitivity was 0.96. The severity of thoracic trauma did not predict the need for tracheostomy. Follow-up studies should validate the T3P-Score in external data sets and study the reasons for the reluctant use of tracheostomy in patients with severe thoracic trauma and subsequent sepsis.Trial registration: The study was applied for and registered a priori with the respective ethics committees.

Behavioral effects and central nervous system levels of the broadly available κ-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo.

Active blood-brain barrier mechanisms, such as the major efflux transporter P-glycoprotein (mdr1), modulate the in vivo/central nervous system (CNS) effects of many pharmacological agents, whether they are used for nonmedical reasons or in pharmacotherapy. The powerful, widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy, selective κ-opioid agonist and displays fast-onset behavioral effects (e.g., within 1 min of administration) and relatively short duration of action. In vitro studies suggest that salvinorin A may be a P-glycoprotein substrate; thus, the functional status of P-glycoprotein may influence the behavioral effects of salvinorin A or its residence in CNS after parenteral administration. We therefore studied whether a competing P-glycoprotein substrate (the clinically available agent loperamide; 0.032-0.32 mg/kg) or a selective P-glycoprotein blocker, tariquidar (0.32-3.2 mg/kg) could enhance unconditioned behavioral effects (ptosis and facial relaxation, known to be caused by κ-agonists in nonhuman primates) of salvinorin A, as well as its entry and residence in the CNS, as measured by cerebrospinal fluid sampling. Pretreatment with either loperamide or tariquidar dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation. In a control study, loperamide and tariquidar were inactive when given as a pretreatment to ((+)-(5α,7α,8ß)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593), a κ-agonist known to be a very poor P-glycoprotein substrate. Furthermore, pretreatment with tariquidar (3.2 mg/kg) also enhanced peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier.

Global Coagulation Testing in Acute Care Medicine: Back to Bedside?

OBJECTIVES: Detailed and decisive information about the patients' coagulation status is important in various emergency situations. Conventional global coagulation testing strategies are often used to provide a quick overview, but several limitations particularly in the trauma setting are well described. With the introduction of direct oral anticoagulations (DOACs), a milestone for several disease entities resulting in overall improved outcomes could be reached, but at the same time providing new diagnostic challenges for the emergency situation. DESIGN: As an alternative to conventional coagulation tests, there is increasing clinical and scientific interest in the use of early whole blood strategies to provide goal-directed coagulation therapies (GDCT) and hemostatic control in critically ill patients. Viscoelastic hemostatic assays (VHAs) were therefore introduced to several clinical applications and may provide as a bedside point-of-care method for faster information on the underlying hemostatic deficiency. CONCLUSION: The use of VHA-based algorithms to guide hemostatic control in emergency situations now found its way to several international guidelines for patients at risk of bleeding. With this qualitative review, we would like to focus on VHA-based GDCT and review the current evidence for its use, advantages, and challenges in the two different clinical scenarios of trauma and intracerebral bleeding/stroke management.