The impact of direct oral anticoagulants on viscoelastic testing – A systematic review

Background: In case of bleeding patients and in acute care, the assessment of residual direct oral anticoagulant (DOAC) activity is essential for evaluating the potential impact on hemostasis, especially when a timely decision on urgent surgery or intervention is required. Viscoelastic tests are crucial in a modern goal-directed coagulation management to assess patients' coagulation status. However, the role of viscoelastic test to detect and quantify residual DOAC plasma levels is controversially discussed. The aim of this review was to systematically summarize the evidence of viscoelastic tests for the assessment of residual DOAC activity. Method: PubMed, Embase, Scopus, and the Cochrane Library were searched for original articles investigating the effect of rivaroxaban, apixaban, edoxaban, or dabigatran plasma levels on different viscoelastic tests of the adult population from database inception to December 31, 2021. Results: We included 53 studies from which 31 assessed rivaroxaban, 22 apixaban, six edoxaban, and 29 dabigatran. The performance of viscoelastic tests varied across DOACs and assays. DOAC specific assays are more sensitive than unspecific assays. The plasma concentration of rivaroxaban and dabigatran correlates strongly with the ROTEM EXTEM, ClotPro RVV-test or ECA-test clotting time (CT) and TEG 6s anti-factor Xa (AFXa) or direct thrombin inhibitor (DTI) channel reaction time (R). Results of clotting time (CT) and reaction time (R) within the normal range do not reliable exclude relevant residual DOAC plasma levels limiting the clinical utility of viscoelastic assays in this context. Conclusion: Viscoelastic test assays can provide fast and essential point-of-care information regarding DOAC activity, especially DOAC specific assays. The identification and quantification of residual DOAC plasma concentration with DOAC unspecific viscoelastic assays are not sensitive enough, compared to recommended anti-Xa activity laboratory measurements. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=320629], identifier [CRD42022320629]. Keywords: ClotPro; DOAC; FII inhibitor; FXa inhibitor; ROTEM; TEG; point-of-car

Faster Time to Treatment Decision of Viscoelastic Coagulation Test Results through Improved Perception with the Animated Visual Clot: A Multicenter Comparative Eye-Tracking Study

As the interpretation of viscoelastic coagulation test results remains challenging, we created Visual Clot, an animated blood clot aiming to facilitate raw rotational thromboelastometry (ROTEM) parameters. This study investigated anesthesia personnel's cognitive processing in managing simulated bleeding scenarios using eye-tracking technology. This multicenter, international, computer-based study across five large, central European hospitals included 35 participants with minimal to no prior experience interpreting viscoelastic test results. Using eye-tracking technology and an iPad tagged with quick response codes, we defined the time to treatment decision and the time on screen surface in seconds of correctly solved scenarios as our outcomes. The median time to treatment decision was 52 s for Visual Clot and 205 s for ROTEM (p < 0.0001). The probability of solving the scenario correctly was more than 8 times higher when using Visual Clot than when using ROTEM (Hazard ratio [HR] 8.54, 95% CI from 6.5 to 11.21; p < 0.0001). Out of 194 correctly answered scenarios of participants with the eye-tracker, 154 (79.4%) were solved with Visual Clot and 40 (20.6%) with ROTEM. Participants spent on average 30 s less looking at the screen surface with Visual Clot compared to ROTEM (Coefficient -30.74 s, 95% CI from -39.27 to -22.27; p < 0.0001). For a comparison of the two modalities in terms of information transfer, we calculated the percentage of time on the screen surface of the overall time to treatment decision, which with Visual Clot was 14 percentage points shorter than with ROTEM (Coefficient -14.55, 95% CI from -20.05 to -9.12; p < 0.0001). Visual Clot seems to improve perception and detection of coagulopathies and leads to earlier initiation of the appropriate treatment. In a high-pressure working environment such as the operating and the resuscitation room, correct and timely decisions regarding bleeding management may have a relevant impact on patients' outcomes. Keywords: Visual Clot; avatar; blood coagulation; eye-tracking; point-of-care; rotational thromboelastometry; viscoelastic test; visual perception

Improved Task Performance, Low Workload, and User-Centered Design in Medical Diagnostic Equipment Enhance Decision Confidence of Anesthesia Providers: A Meta-Analysis and a Multicenter Online Survey

Decision confidence-the subjective belief to have made the right decision-is central in planning actions in a complex environment such as the medical field. It is unclear by which factors it is influenced. We analyzed a pooled data set of eight studies and performed a multicenter online survey assessing anesthesiologists' opinions on decision confidence. By applying mixed models and using multiple imputation to determine the effect of missing values from the dataset on the results, we investigated how task performance, perceived workload, the utilization of user-centered medical diagnostic devices, job, work experience, and gender affected decision confidence. The odds of being confident increased with better task performance (OR: 1.27, 95% CI: 0.94 to 1.7; p = 0.12; after multiple imputation OR: 3.19, 95% CI: 2.29 to 4.45; p < 0.001) and when user-centered medical devices were used (OR: 5.01, 95% CI: 3.67 to 6.85; p < 0.001; after multiple imputation OR: 3.58, 95% CI: 2.65 to 4.85; p < 0.001). The odds of being confident decreased with higher perceived workload (OR: 0.94, 95% CI: 0.93 to 0.95; p < 0.001; after multiple imputation, OR: 0.94, 95% CI: 0.93 to 0.95; p < 0.001). Other factors, such as gender, job, or professional experience, did not affect decision confidence. Most anesthesiologists who participated in the online survey agreed that task performance (25 of 30; 83%), perceived workload (24 of 30; 80%), work experience (28 of 30; 93%), and job (21 of 30; 70%) influence decision confidence. Improved task performance, lower perceived workload, and user-centered design in medical equipment enhanced the decision confidence of anesthesia providers. Keywords: diagnostic; diagnostic confidence; gender; online survey; over-confidence; self-assessment; under-confidence; user-centered design; workloa

Improved Task Performance, Low Workload, and User-Centered Design in Medical Diagnostic Equipment Enhance Decision Confidence of Anesthesia Providers: A Meta-Analysis and a Multicenter Online Survey

Decision confidence-the subjective belief to have made the right decision-is central in planning actions in a complex environment such as the medical field. It is unclear by which factors it is influenced. We analyzed a pooled data set of eight studies and performed a multicenter online survey assessing anesthesiologists' opinions on decision confidence. By applying mixed models and using multiple imputation to determine the effect of missing values from the dataset on the results, we investigated how task performance, perceived workload, the utilization of user-centered medical diagnostic devices, job, work experience, and gender affected decision confidence. The odds of being confident increased with better task performance (OR: 1.27, 95% CI: 0.94 to 1.7; p = 0.12; after multiple imputation OR: 3.19, 95% CI: 2.29 to 4.45; p < 0.001) and when user-centered medical devices were used (OR: 5.01, 95% CI: 3.67 to 6.85; p < 0.001; after multiple imputation OR: 3.58, 95% CI: 2.65 to 4.85; p < 0.001). The odds of being confident decreased with higher perceived workload (OR: 0.94, 95% CI: 0.93 to 0.95; p < 0.001; after multiple imputation, OR: 0.94, 95% CI: 0.93 to 0.95; p < 0.001). Other factors, such as gender, job, or professional experience, did not affect decision confidence. Most anesthesiologists who participated in the online survey agreed that task performance (25 of 30; 83%), perceived workload (24 of 30; 80%), work experience (28 of 30; 93%), and job (21 of 30; 70%) influence decision confidence. Improved task performance, lower perceived workload, and user-centered design in medical equipment enhanced the decision confidence of anesthesia providers. Keywords: diagnostic; diagnostic confidence; gender; online survey; over-confidence; self-assessment; under-confidence; user-centered design; workloa

Diagnóstico de reabsorção radicular: influência da resolução espacial de captura de imagens digitais periapicais

Introdução: a detecção da reabsorção da raiz dentária é realizada por meio de exames de imagens, pois frequentemente não apresenta sinal e sintoma clínicos. Dentre os exames de imagem disponíveis, o exame radiográfico periapical, é indicado para diagnóstico, prognóstico e acompanhamento da reabsorção radicular. Objetivo: o estudo tem como objetivo investigar a relação de diferentes resoluções espaciais com o diagnóstico de reabsorção radicular. Metodologia: foram realizados desgastes simulando reabsorção externa no terço apical e vestibular de 15 (quinze) incisivos inferiores, radiografados em crânio seco, antes e depois do desgaste. A técnica radiográfica foi realizada utilizando o sistema VistaScan (Durr Dental, Bietigheim-Bissingen, Germany), aparelho CS 2200 (Carestream Dental LLC, Atlanta-GA, USA) usando tempo de exposição de 0,15 segundos e escaneadas sob diferentes protocolos de resolução espacial, a saber, 20 pares de linhas por milímetro (pl/mm) e 40 pl/mm. Posteriormente dois avaliadores experientes fizeram análises das referidas imagens sem conhecimento prévio da resolução de escaneamento. Resultados: 75% das radiografias realizadas com 20 pl/mm foram classificadas como excelentes pelos avaliadores, contra 33% com 40 pl/mm, estatisticamente significativa. Discussão: ao avaliar a reabsorção radicular, obteve-se uma acurácia diagnóstica igual para os dois protocolos sem distinção, estatisticamente significativa, entre localização ou profundidade. Conclusão: tendo em vista que para os examinadores imagens com 20 pl/mm foram satisfatórias, com percentual de qualidade maior quando comparado a imagens obtidas com 40 pl/mm, este estudo indica o emprego de imagens com 20 pl/mm para avaliação inicial de suspeita de reabsorções nas raízes dentárias

Faster Time to Treatment Decision of Viscoelastic Coagulation Test Results through Improved Perception with the Animated Visual Clot: A Multicenter Comparative Eye-Tracking Study

As the interpretation of viscoelastic coagulation test results remains challenging, we created Visual Clot, an animated blood clot aiming to facilitate raw rotational thromboelastometry (ROTEM) parameters. This study investigated anesthesia personnel’s cognitive processing in managing simulated bleeding scenarios using eye-tracking technology. This multicenter, international, computer-based study across five large, central European hospitals included 35 participants with minimal to no prior experience interpreting viscoelastic test results. Using eye-tracking technology and an iPad tagged with quick response codes, we defined the time to treatment decision and the time on screen surface in seconds of correctly solved scenarios as our outcomes. The median time to treatment decision was 52 s for Visual Clot and 205 s for ROTEM (p < 0.0001). The probability of solving the scenario correctly was more than 8 times higher when using Visual Clot than when using ROTEM (Hazard ratio [HR] 8.54, 95% CI from 6.5 to 11.21; p < 0.0001). Out of 194 correctly answered scenarios of participants with the eye-tracker, 154 (79.4%) were solved with Visual Clot and 40 (20.6%) with ROTEM. Participants spent on average 30 s less looking at the screen surface with Visual Clot compared to ROTEM (Coefficient −30.74 s, 95% CI from −39.27 to −22.27; p < 0.0001). For a comparison of the two modalities in terms of information transfer, we calculated the percentage of time on the screen surface of the overall time to treatment decision, which with Visual Clot was 14 percentage points shorter than with ROTEM (Coefficient −14.55, 95% CI from −20.05 to −9.12; p < 0.0001). Visual Clot seems to improve perception and detection of coagulopathies and leads to earlier initiation of the appropriate treatment. In a high-pressure working environment such as the operating and the resuscitation room, correct and timely decisions regarding bleeding management may have a relevant impact on patients’ outcomes

Ability of omega-3 fatty acids to modulate uterine fibrotic cell structure and gene expression

I leiomiomi uterini, anche conosciuti come fibromi, rappresentano la forma tumorale benigna più comune nelle donne fertili. Spesso si ricorre all’asportazione chirurgica dell’utero, isteroctomia, con conseguente morbilità e onere socioeconomico. La patogenesi non è del tutto conosciuta, pertanto è auspicabile una migliore comprensione della malattia per definire nuovi bersagli terapeutici. In questo studio, abbiamo analizzato gli effetti degli acidi grassi omega-3 sul profilo lipidico, sull'architettura della membrana cellulare e sull'espressione di specifici geni nelle cellule isolate da miometrio e da leiomioma. Le cellule primarie di miometrio e di leiomioma sono state trattate con gli acidi grassi omega-3, l’acido eicosapentaenoico (EPA) e l’acido docosaesaenoico (DHA) (50 μM) per 48 ore. Il contenuto degli acidi grassi è stato misurato mediante gas-cromatografia con rivelatore a ionizzazione di fiamma (GC-FID). Lo stato di fluidità o rigidità delle membrane è stato individuato utilizzando la fluorescenza del Laurdan. I livelli di espressione genica dei component della matrice extracellulare (Collagene1A1, fibronectina, versican), dei fattori pro-fibrotici (activina A), delle molecole di mechanical signaling (integrina β1, FAK and AKAP13) e di regolazione degli steroli (ABCG1, ABCA1, CAV1 and SREBF2), nonché degli enzimi mitocondriali (CYP11A1) sono stati valutati mediante PCR real-time. I risultati che abbiamo ottenuto mostrano che l’EPA e il DHA riducono il contenuto degli acidi grassi monoinsaturi e fanno incrementare gli acidi grassi polinsaturi in vitro nelle cellule isolate da entrambi i tipi di tessuto, miometrio e leiomioma. Le membrane cellulari miometriali e di leiomioma non trattate erano nella fase liquido-cristallina. Quando trattati con EPA e DHA, entrambi i tipi di cellule hanno riportato valori di polarizzazione generalizzata di eccitazione del Laurdan più elevati, indice di una maggiore rigidità. Sebbene non siano stati rilevati cambiamenti nell'espressione di mRNA dei componenti della matrice extracellulare, l’EPA e il DHA hanno ridotto i livelli di ABCG1, ABCA1 e AKAP13 in entrambi i tipi di cellule e hanno anche diminuito la produzione di FAK e CYP11A1 nelle cellule del miometrio. In conclusione, gli acidi grassi omega-3 sono in grado di modificare il profilo degli acidi grassi, di modificare l'architettura della membrana cellulare, di ridurre l'espressione dei geni necessari per il mechanical signaling e per l'accumulo intracellulare di lipidi nelle cellule di miometrio e di leiomioma.Uterine leiomyomas, also known as fibroids, represent the most common form of benign tumors in premenopausal women. Treatment often results in hysterectomy, which correlates with a high morbidity and socio-economic burden. Also, as knowledge on the pathogenesis is limited, it is important to gain a better understanding of the disease and define new therapeutic targets. In this study, we analyzed the effects of omega-3 fatty acids on the lipid profile, membrane architecture and specific gene expression in myometrial and leiomyoma cells. Primary myometrial and leiomyoma cells were treated with omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (50 μM) for 48 hours. Gaschromatography with flame ionization detector (GC-FID) was used to measure fatty acid content and by applying the method of Laurdan fluorescence we assessed membrane fluidity or rigidity. Real-time PCR was used for measurement of gene expression of extracellular matrix components (Collagen1A1, fibronectin, versican), pro-fibrotic factor (activin A), mechanical signaling (integrin β1, FAK and AKAP13) and sterol regulatory molecules (ABCG1, ABCA1, CAV1 and SREBF2) as well as mitochondrial enzyme (CYP11A1). Our results show that EPA and DHA reduce the monounsaturated fatty acid content and lead to an increase of polyunsaturated fatty acids in both, myometrial and leiomyoma cells in vitro. Untreated myometrial and leiomyoma cell membranes were in the liquid-crystalline phase. When treated with EPA and DHA, both cell types had higher Laurdan excitation generalized polarization values indicating an increased rigidity. Though there was no change in the mRNA expression of EMC components detectable, EPA and DHA lead to reduced levels of ABCG1, ABCA1 and AKAP13 in both cell types and also decreased FAK and CYP11A1 production in myometrial cells. In conclusion, omega-3 fatty acids are able to modify the fatty acid profile, restructuring the cell membrane architecture and downregulating the expression of genes required for mechanical signaling and cellular lipid accumulation in myometrial and leiomyoma cells

CADASIL: ultrastructural insights into the morphology of granular osmiophilic material

Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder. Granular osmiophilic material (GOM) is its ultrastructural marker. We reviewed tissue biopsies from CADASIL patients to establish whether ultrastructural observations help clarify the pathogenic mechanism of CADASIL. Given the resemblance of the GOM deposits to the immunoglobulin deposits seen in glomerulonephritis and focal segmental glomerulosclerosis (FSGS), their morphologies were investigated and compared. Methods Skin, skeletal muscle, kidney, and pericardium tissue biopsies from 13 patients with a clinical and molecular diagnosis of CADASIL, and kidney biopsies from five patients with IgA nephropathy and five patients with primary FSGS were subjected to ultrastructural examination. Results In CADASIL patients, several GOM deposits from all sites were partially or totally surrounded by an electron-lucent halo. The deposits frequently had a more electron-dense portion with a regular outline on the inner side and a less osmiophilic, looser outer side displaying a less regular profile. The uniformly dense deposits tended to be more osmiophilic if located close to the cell membrane and less osmiophilic if laid farther away from it. The immunoglobulin deposits from the glomerulonephritis and FSGS patients lacked both the granular pattern and the halo. Conclusions This study demonstrates that GOM deposits may have a nonuniform morphology and describes in detail an electron-lucent halo surrounding several of them. It is conceivable that the halo is the morphological evidence and possibly the cause of an aberrant NOTCH3 processing, already suspected to be involved in CADASIL

Präklinische Schmerztherapie: Übersicht und Verbesserungsmöglichkeiten

Zusammenfassung. Schmerzen sind ein Problem, mit dem das Rettungsdienstpersonal in der Präklinik häufig konfrontiert ist. Eine schnelle und effektive Analgesie wirkt sich positiv auf den physiologischen und psychologischen Zustand der Patientinnen und Patienten aus. Doch nach wie vor werden präklinisch bis zu 43 % der Betroffenen unzureichend analgetisch therapiert. Mehrere Studien identifizierten Faktoren, die ursächlich für diese Problematik sind. Die drei wesentlichen sind das behandelnde Personal sowie patienten- und einsatzspezifische Besonderheiten. Damit die präklinische Analgesie künftig weiter verbessert werden kann, braucht es neben strukturellen und organisatorischen Veränderungen auch die Implementierung neuer Methoden und Therapien. = Prehospital Pain Management: Overview and Potential Improvements Abstract. Pain is a frequent issue in the prehospital setting. Rapid and adequate analgesia has a positive effect on the physiological and psychological condition of patients. However, up to 43 % of patients still suffer insufficient analgesia. Several studies have identified some factors that contribute to this problem; these factors can be patient- and intervention-specific or dependent on the staff on duty. In order to improve prehospital analgesia in the future, structural and organizational changes as well as the implementation of new methods and therapies are essential. Keywords: Analgésie préhospitalière; Notarztdienst; Oligoanalgesie; Prehospital analgesia; Präklinische Analgesie; Rettungsdienst; Schmerz; douleur; emergency physician; médecin urgentiste; oligoanalgesia; oligoanalgésie; pain; rescue service; service de secours

Locostatin, a disrupter of Raf kinase inhibitor protein, inhibits extracellular matrix production, proliferation, and migration in human uterine leiomyoma and myometrial cells

Objective To investigate the presence of Raf kinase inhibitor protein (RKIP) in human myometrium and leiomyoma as well as to determine the effect of locostatin (RKIP inhibitor) on extracellular matrix (ECM) production, proliferation, and migration in human myometrial and leiomyoma cells. Design Laboratory study. Setting Human myometrium and leiomyoma. Patient(s) Thirty premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Intervention(s) Myometrial and leiomyoma tissues were used to investigate the localization and the expression level of RKIP through immunohistochemistry and Western blotting. Myometrial and leiomyoma cells were treated with locostatin (10 μM) to measure ECM expression by real-time polymerase chain reaction, GSK3β expression by Western blotting, cell migration by wound-healing assay, and cell proliferation by MTT assay and immunocytochemistry. Main Outcome Measure(s) The expression of RKIP in human myometrial and leiomyoma tissue; ECM components and GSK3β expression, migration, and proliferation in myometrial and leiomyoma cells. Result(s) RKIP is expressed in human myometrial and leiomyoma tissue. Locostatin treatment resulted in the activation of the mitogen-activated protein kinase (MAPK) signal pathway (ERK phosphorylation), providing a powerful validation of our targeting protocol. Further, RKIP inhibition by locostatin reduces ECM components. Moreover, the inhibition of RKIP by locostatin impaired cell proliferation and migration in both leiomyoma and myometrial cells. Finally, locostatin treatment reduced GSK3β expression. Therefore, even if the activation of MAPK pathway should increase proliferation and migration, the destabilization of GSK3β leads to the reduction of proliferation and migration of myometrial and leiomyoma cells. Conclusion(s) Our results indicate that RKIP may be involved in leiomyoma pathophysiology