Summary
This study evaluates whether immature platelets (IPF) determined in the post anesthesia care unit (PACU) can predict major adverse cardiovascular events (MACE) or other thromboembolic events ...after intermediate and high-risk surgery. IPF are increased in patients with acute coronary syndrome and recently gained interest as novel biomarker for risk stratification. In this prospective observational trial 732 patients undergoing intermediate or high-risk non-cardiac surgery were enrolled (NCT02097602). IPF was measured preoperatively and postoperatively in the PACU. Primary outcome was a composite endpoint defined as MACE, deep vein thrombosis or pulmonary embolism during hospital stay (modMACE). A cut off for IPF identifying a threshold between a low and high risk for modMACE was calculated by logrank optimization. A multivariate Cox regression was calculated in a forward stepwise manner to assess the relation between this IPF cut off and modMACE as well as other established risk factors (inclusion if p<0.05). Preoperatively, there were no differences in IPF between patients with and without modMACE (3.1% 2.2% – 4.7%(median interquartile range) vs. 2.8% 1.9% – 4.3%. Patients with modMACE (28 of 730 patients; 3.8%) had higher IPF values in the PACU compared to patients without modMACE (3.6% 2.6–6% vs. 2.9% 2–4.4%; p=0.011). The optimal cut off of IPF > 5.4% was associated with an increased risk for modMACE after adjustment for covariates (hazard ratio: 2.528; 95% confidence interval: 1.156 to 5.528, p=0.02). In conclusion, IPF is an independent predictor of modMACE after surgery and might improve risk stratification of surgical patients.
Institution where the work was performed and funded: Klinikum rechts der Isar der Technischen Universität München, Ismaningerstr. 22, 81675 Munich, Germany.
Whole-Body Electromyostimulation (WB-EMS) is a training technology that enables simultaneous stimulation of all the main muscle groups with a specific impulse intensity for each electrode. The ...corresponding time-efficiency and joint-friendliness of WB-EMS may be particularly attractive for people unable or unmotivated to conduct (intense) conventional training protocols. However, due to the enormous metabolic and musculoskeletal impact of WB-EMS, particular attention must be paid to the application of this technology. In the past, several scientific and newspaper articles reported severe adverse effects of WB-EMS. To increase the safety of commercial non-medical WB-EMS application, recommendations "for safe and effective whole-body electromyostimulation" were launched in 2016. However, new developments and trends require an update of these recommendations to incorporate more international expertise with demonstrated experience in the application of WB-EMS. The new version of these consensus-based recommendations has been structured into 1) "general aspects of WB-EMS", 2) "preparation for training", recommendations for the 3) "WB-EMS application" itself and 4) "safety aspects during and after training". Key topics particularly addressed are 1) consistent and close supervision of WB-EMS application, 2) mandatory qualification of WB-EMS trainers, 3) anamnesis and corresponding consideration of contraindications prior to WB-EMS, 4) the participant's proper preparation for the session, 5) careful preparation of the WB-EMS novice, 6) appropriate regeneration periods between WB-EMS sessions and 7) continuous interaction between trainer and participant at a close physical distance. In summary, we are convinced that the present guideline will contribute to greater safety and effectiveness in the area of non-medical commercial WB-EMS application.
Purpose: To assess humoral responses longitudinally and cellular immunogenicity following SARS-CoV-2-vaccination in patients with hematologic and oncologic malignancies receiving ...checkpoint-inhibitors. Methods: This prospective multicenter trial of the East-German-Study-Group-for-Hematology-and-Oncology, enrolled 398 adults in a two (patients; n = 262) to one (controls; n = 136) ratio. Pre-vaccination, day 35 (d35), and day 120 (d120) blood samples were analyzed for anti-spike antibodies and d120 IL-2+IFNγ+TNFα+-CD4+- and CD8+-cells. Laboratories were blinded for patients and controls. Results: Patients belonged to the myeloid (n = 131), lymphoid (n = 104), and checkpoint-inhibitor (n = 17) cohorts. While d35 seroconversion was higher in controls (98%) compared to patients (68%) (p < 0.001), d120 seroconversion improved across all patient cohorts checkpoint-inhibitors (81% to 100%), myeloid (82% to 97%), lymphoid (48% to 66%). CD4+- and CovCD8+-cells in the lymphoid (71%/31%) and control (74%/42%) cohorts were comparable but fewer in the myeloid cohort (53%, p = 0.003 /24%, p = 0.03). In patients with hematologic malignancies, no correlation between d120 humoral and cellular responses was found. A sizeable fraction of lymphoid patients demonstrated T-cell responses without detectable spike-specific-IgGs. Conclusions: Evidence of vaccine-elicited humoral and/or cellular immunogenicity in most patients is provided. Both humoral and cellular responses are crucial to determine which patients will generate/maintain immunity. The findings have implications on public health policy regarding recommendations for SARS-CoV-2 booster doses.
Tuning functional properties of thin caloric films by mechanical stress is currently of high interest. In particular, a controllable magnetisation or transition temperature is desired for improved ...usability in magnetocaloric devices. Here, we present results of epitaxial magnetocaloric Ni-Mn-Ga-Co thin films on ferroelectric Pb(Mg
Nb
)
Ti
O
(PMN-PT) substrates. Utilizing X-ray diffraction measurements, we demonstrate that the strain induced in the substrate by application of an electric field can be transferred to the thin film, resulting in a change of the lattice parameters. We examined the consequences of this strain on the magnetic properties of the thin film by temperature- and electric field-dependent measurements. We did not observe a change of martensitic transformation temperature but a reversible change of magnetisation within the austenitic state, which we attribute to the intrinsic magnetic instability of this metamagnetic Heusler alloy. We demonstrate an electric field-controlled entropy change of about 31 % of the magnetocaloric effect - without any hysteresis.
The Nrf2 signaling pathway prevents cancer initiation, but genetic mutations that activate this pathway are found in various types of cancer. The molecular mechanisms underlying this Janus-headed ...character are still not understood. Here, we show that sustained Nrf2 activation induces proliferation and dedifferentiation of a Wnt-responsive perivenular hepatic progenitor cell population, transforming them into metastatic cancer cells. The neoplastic lesions display many histological features known from human hepatoblastoma. We describe an Nrf2-induced upregulation of β-catenin expression and its activation as the underlying mechanism for the observed malignant transformation. Thus, we have identified the Nrf2–β-catenin axis promoting proliferation of hepatic stem cells and triggering tumorigenesis. These findings support the concept that different functional levels of Nrf2 control both the protection against various toxins as well as liver regeneration by activating hepatic stem cells. Activation of the hepatic stem cell compartment confers the observation that unbridled Nrf2 activation may trigger tumorigenesis.
Abstract Background The association between coronary atherosclerosis progression or regression and long-term prognosis remains poorly defined. We assessed the association of atherosclerosis ...progression or regression with long-term mortality and factors that promote angiographic progression or regression of coronary atherosclerosis in patients with angiographically-proven coronary artery disease. Methods The study included 605 patients with coronary artery disease who underwent coronary angiography at baseline and at 2 years later. Pan-coronary artery tree quantitative coronary angiography was performed. Of 6259 coronary segments (10.3 lesions per patient) analyzed, 1790 non-stented segments with ≥25% diameter stenosis at baseline were included. Atherosclerosis progression or regression was defined as a decrease or increase in the mean minimal lumen diameter (MLD) of the non-stented segments of ≥0.2 mm in the 2-year angiography compared to baseline angiography. The primary outcome was all-cause mortality. Results Based on the change in mean MLD between baseline and 2-year angiography, patients were divided into 3 groups: the group with progression of atherosclerosis (n=53; 8.8%), group with no progression or regression of atherosclerosis (n=472; 78.0%) and the group with regression of atherosclerosis (n=80; 13.2%). There were 126 deaths over 8-year follow-up: 17 deaths among patients with progression, 103 deaths occurred among patients with no progression/regression and 6 deaths among patients with regression (Kaplan-Meier estimates of mortality, 37.5%, 25.2% and 8.9%, respectively; adjusted hazard ratio=1.16, 95% confidence interval 1.05 to 1.29, P=0.004 for 0.1 mm reduction in mean MLD). Conclusions Progression or regression of coronary atherosclerosis in non-treated coronary segments was significantly associated with 8-year mortality.
Hate speech has become a widespread phenomenon, however, it remains largely unclear why adolescents engage in it and which factors are associated with their motivations for perpetrating hate speech. ...To this end, we developed the multidimensional “Motivations for Hate Speech Perpetration Scale” (MHATE) and evaluated the psychometric properties. We also explored the associations between social norms and adolescents’ motivations for hate speech perpetration. The sample consisted of 346 adolescents from Switzerland (54.6% boys; Mage=14; SD=0.96) who reported engagement in hate speech as perpetrators. The analyses revealed good psychometric properties for the MHATE, including good internal consistency. The most frequently endorsed subscale was revenge, followed by ideology, group conformity, status enhancement, exhilaration, and power. The results also showed that descriptive norms and peer pressure were related to a wide range of different motivations for perpetrating hate speech. Injunctive norms, however, were only associated with power. In conclusion, findings indicate that hate speech fulfills various functions. We argue that knowing the specific motivations that underlie hate speech could help us derive individually tailored prevention strategies (e.g., anger management, promoting an inclusive classroom climate). Furthermore, we suggest that practitioners working in the field of hate speech prevention give special attention to social norms surrounding adolescents.
El discurso de odio se ha convertido en un fenómeno generalizado. Sin embargo, todavía no está claro por qué los adolescentes se involucran en el discurso de odio y qué factores están asociados con las motivaciones para perpetrarlo. Con esta finalidad, desarrollamos una medida multidimensional, la «Escala de Motivaciones para Perpetrar Discurso de Odio» (MHATE), y evaluamos sus propiedades psicométricas. Asimismo, investigamos las asociaciones entre las normas sociales y las motivaciones para participar en el discurso de odio. La muestra estuvo compuesta por 346 adolescentes suizos (54,6% chicos; Medad=14; DT=0,96) que informaron haber perpetrado discurso de odio. Los análisis revelaron buenas propiedades psicométricas de MHATE, incluyendo adecuada consistencia interna. La subescala con mayor frecuencia fue venganza, seguida de las de ideología, conformidad con el grupo, mejora del estatus, regocijo y poder. Las normas descriptivas y la presión de iguales estuvieron relacionadas con varias motivaciones para perpetrar discurso de odio. Las normas prescriptivas, sin embargo, solo se asociaron con el poder. En conclusión, los hallazgos indican que el discurso de odio cumple varias funciones. Conocer las motivaciones específicas para el discurso de odio ayuda a derivar estrategias de intervención individualmente adaptadas (ej., manejo de la ira, promover un clima escolar inclusivo). Además, sugerimos que los profesionales que trabajan en la prevención del discurso de odio presten especial atención a las normas sociales que rodean a los adolescentes.
The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve ...metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy.
Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival.
CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33–0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29–0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41–0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20–0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012)
In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri.
Trial registration ID (clinicaltrials.gov) NCT01249638.
•Consensus molecular subtypes (CMS) are novel biomarkers in colorectal cancer (CRC).•CMS were predicted in the randomised phase III XELAVIRI trial using gene expression.•No prognostic benefit of CMS in a collective with elderly patients with colorectal cancer.•CMS and RAS status might act as biomarkers of treatment intensification in XELAVIRI.•RAS WT CMS2 tumours most likely to benefit from initial combination treatment.
The hematopoietic granulocyte-colony stimulating growth factor (G-CSF, filgrastim) is an approved drug in hematology and oncology. Filgrastim’s potential in neurodegenerative disorders is gaining ...increasingly more attention, as preclinical and early clinical studies suggest it could be a promising treatment option. G-CSF has had a tremendous record as a safe drug for more than three decades; however, its effects upon the central nervous system (CNS) are still not fully understood. In contrast to conceptual long-term clinical application with lower dosing, our present pilot study intends to give a first insight into the molecular effects of a single subcutaneous (s.c.) high-dose G-CSF application upon different regions of the rodent brain. We analyzed mRNA—and in some instances—protein data of neurogenic and non-neurogenic differentiation markers in different regions of rat brains five days after G-CSF (1.3 mg/kg) or physiological saline. We found a continuous downregulation of several markers in most brain regions. Remarkably, cerebellum and hypothalamus showed an upregulation of different markers. In conclusion, our study reveals minor suppressive or stimulatory effects of a single exceptional high G-CSF dose upon neurogenic and non-neurogenic differentiation markers in relevant brain regions, excluding unregulated responses or unexpected patterns of marker expression.
Myasthenia gravis is an autoimmune disorder defined by muscle weakness and fatigability associated with antibodies against proteins of the neuromuscular junction (NMJ). The most common autoantibody ...target is the acetylcholine receptor (AChR). Three mechanisms have been postulated by which autoantibodies might interfere with neurotransmission: direct antagonism of the receptor, complement-mediated destruction of the postsynaptic membrane, and enhanced internalization of the receptor. It is very likely that more than one of these mechanisms act in parallel. Dissecting the mechanisms of autoantibody-mediated pathology requires patient-derived, monoclonal antibodies. Using membrane antigen capture activated cell sorting (MACACS), we isolated AChR-specific B cells from patients with myasthenia gravis, and produced six recombinant antibodies. All AChR-specific antibodies were hypermutated, including isotypes IgG
1
, IgG
3
, and IgG
4
, and recognized different subunits of the AChR. Despite clear binding, none of the individual antibodies showed significant antagonism of the AChR measured in an in vitro neuromuscular synapse model, or AChR-dependent complement activation, and they did not induce myasthenic signs in vivo. However, combinations of antibodies induced strong complement activation in vitro, and severe weakness in a passive transfer myasthenia gravis rat model, associated with NMJ destruction and complement activation in muscle. The strongest complement activation was mediated by combinations of antibodies targeting disparate subunits of the AChR, and such combinations also induced the formation of large clusters of AChR on the surface of live cells in vitro. We propose that synergy between antibodies of different epitope specificities is a fundamental feature of this disease, and possibly a general feature of complement-mediated autoimmune diseases. The importance of synergistic interaction between antibodies targeting different subunits of the receptor can explain the well-known discrepancy between serum anti-AChR titers and clinical severity, and has implications for therapeutic strategies currently under investigation.
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