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Cardiogenic shock (CS) is a devastating and fatal complication of acute myocardial infarction (AMI). CS can affect the pharmacokinetics and pharmacodynamics of medications. The unique properties of cangrelor make it the optimal P2Y12 inhibitor for CS-AMI, in terms of both efficacy and safety. The DAPT-SHOCK-AMI trial (ClinicalTrials.gov: NCT03551964; EudraCT: 2018-002161-19) will assess the benefits of cangrelor in patients with an initial CS-AMI undergoing primary angioplasty. This randomised, multicentre, placebo-controlled trial of approximately 550 patients (with an allowed 10% increase) in 5 countries using a double-blind design will compare initial P2Y12 inhibitor treatment strategies in patients with CS-AMI of (A) intravenous cangrelor and (B) ticagrelor administered as crushed tablets at a loading dose of 180 mg. The primary clinical endpoint is a composite of all-cause death, myocardial infarction (MI), or stroke within 30 days. The main secondary endpoints are (1) the net clinical endpoint, defined as death, MI, urgent revascularisation of the infarct-related artery, stroke, or major bleeding as defined by the Bleeding Academic Research Consortium criteria; (2) cardiovascular-related death, MI, urgent revascularisation, or heart failure; (3) heart failure; and (4) cardiovascular-related death, all (1-4) within 1 year after study enrolment. A platelet reactivity study that tests the laboratory antiplatelet benefits of cangrelor, when given in addition to standard antiplatelet therapy, will be conducted using vasodilator-stimulated phosphoprotein phosphorylation. The primary laboratory endpoints are the periprocedural rate of onset and the proportion of patients who achieve effective P2Y12 inhibition. The DAPT-SHOCK-AMI study is the first randomised trial to evaluate the benefits of cangrelor in patients with CS-AMI.

Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The treatment of GBM consists of a combination of surgery and subsequent oncological therapy, i.e., radiotherapy, chemotherapy, or their combination. If postoperative oncological therapy involves irradiation, magnetic resonance imaging (MRI) is used for radiotherapy treatment planning. Unfortunately, in some cases, a very early worsening (progression) or return (recurrence) of the disease is observed several weeks after the surgery and is called rapid early progression (REP). Radiotherapy planning is currently based on MRI for target volumes definitions in many radiotherapy facilities. However, patients with REP may benefit from targeting radiotherapy with other imaging modalities. The purpose of the presented clinical trial is to evaluate the utility of 11 C-methionine in optimizing radiotherapy for glioblastoma patients with REP., Methods: This study is a nonrandomized, open-label, parallel-setting, prospective, monocentric clinical trial. The main aim of this study was to refine the diagnosis in patients with GBM with REP and to optimize subsequent radiotherapy planning. Glioblastoma patients who develop REP within approximately 6 weeks after surgery will undergo 11 C-methionine positron emission tomography (PET/CT) examinations. Target volumes for radiotherapy are defined using both standard planning T1-weighted contrast-enhanced MRI and PET/CT. The primary outcome is progression-free survival defined using RANO criteria and compared to a historical cohort with REP treated without PET/CT optimization of radiotherapy., Discussion: PET is one of the most modern methods of molecular imaging. 11 C-Methionine is an example of a radiolabelled (carbon 11) amino acid commonly used in the diagnosis of brain tumors and in the evaluation of response to treatment. Optimized radiotherapy may also have the potential to cover those regions with a high risk of subsequent progression, which would not be identified using standard-of-care MRI for radiotherapy planning. This is one of the first study focused on radiotherapy optimization for subgroup of patinets with REP., Trial Registration: NCT05608395, registered on 8.11.2022 in clinicaltrials.gov; EudraCT Number: 2020-000640-64, registered on 26.5.2020 in clinicaltrialsregister.eu. Protocol ID: MOU-2020-01, version 3.2, date 18.09.2020., (© 2024. The Author(s).)

The growing demand for polymer composites and their widespread use is inevitably accompanied by the need to know their degradation behavior over a sufficiently long period of time. This study focuses on commercial glass fiber rovings, which were stored in the indoor environment for up to 11 years. Fibers with different storage times, from fresh up to the oldest, were used to produce unidirectional fiber-reinforced polyester composites that were characterized to determine their shear and flexural properties dependent on fiber storage time. A significant decrease in shear strength was observed throughout the aging of the fibers, down to a decrease of 33% for the oldest fibers. An important finding, however, was that the significant decrease in shear strength was only partially reflected in the flexural strength, which corresponded to a decrease of 18% for the oldest fibers at consistent flexural modulus.

Background: Vagal nerve stimulation (VNS) can be indicated in patients with drug-resistant epilepsy, who are not eligible for resective epilepsy surgery. In VNS therapy, the responder rate (i.e., percentage of subjects experiencing ≥50% seizure reduction) is ~50%. At the moment, there is no widely-accepted possibility to predict VNS efficacy in a particular patient based on pre-implantation data, which can lead to unnecessary surgery and improper allocation of financial resources. The principal aim of PRediction of vagal nerve stimulation EfficaCy In drug-reSistant Epilepsy (PRECISE) study is to verify the predictability of VNS efficacy by analysis of pre-implantation routine electroencephalogram (EEG)., Methods: PRECISE is designed as a prospective multicentric study in which patients indicated to VNS therapy will be recruited. Patients will be classified as predicted responders vs. predicted non-responders using pre-implantation EEG analyses. After the first and second year of the study, the real-life outcome (responder vs. non-responder) will be determined. The real-life outcome and predicted outcome will be compared in terms of accuracy, specificity, and sensitivity. In the meantime, the patients will be managed according to the best clinical practice to obtain the best therapeutic response. The primary endpoint will be the accuracy of the statistical model for prediction of response to VNS therapy in terms of responders and non-responders. The secondary endpoint will be the quantification of differences in EEG power spectra (Relative Mean Power, %) between real-life responders and real-life non-responders to VNS therapy in drug-resistant epilepsy and the sensitivity and specificity of the model., Discussion: PRECISE relies on the results of our previous work, through which we developed a statistical classifier for VNS response (responders vs. non-responders) based on differences in EEG power spectra dynamics (Pre-X-Stim)., Trial Registration: www.ClinicalTrials.gov, identifier: NCT04935567., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dolezalova, Koritakova, Souckova, Chrastina, Chladek, Stepanova and Brazdil.)

Background: Enteral nutrition is part of the treatment of critically ill patients. Administration of enteral nutrition may be associated with signs of intolerance, such as high gastric residual volumes, diarrhea, and vomiting. Clinical trials regarding the effects of the mode of administration of enteral nutrition on the occurrence of these complications have yielded conflicting results. This trial aims to investigate whether the mode of administration of enteral nutrition affects the time to reach nutritional targets, intolerance, and complications., Methods: COINN is a randomized, monocentric study for critically ill adult patients receiving enteral nutrition. Patients will be randomly assigned to two groups receiving (1) continuous or (2) intermittent administration of enteral nutrition. Enhancement of enteral nutrition will depend on signs of tolerance, mainly the gastric residual volume. The primary outcome will be the time to reach the energetic target. Secondary outcomes will be the time to reach the protein target, tolerance, complications, hospital and ICU lengths of stay, and 28-day mortality., Discussion: This trial aims to evaluate whether the mode of application of enteral nutrition affects the time to reach nutritional targets, signs of intolerance, and complications., Trial Registration: ClinicalTrials.gov NCT03573453. Registered on 29 June 2018.

Despite efforts to develop novel treatment strategies, refractory and relapsing sarcoma, and high-risk neuroblastoma continue to have poor prognoses and limited overall survival. Monocyte-derived dendritic cell (DC)-based anti-cancer immunotherapy represents a promising treatment modality in these neoplasias. A DC-based anti-cancer vaccine was evaluated for safety in an academic phase-I/II clinical trial for children, adolescents, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors, mainly sarcomas and neuroblastomas. The DC vaccine was loaded with self-tumor antigens obtained from patient tumor tissue. DC vaccine quality was assessed in terms of DC yield, viability, immunophenotype, production of IL-12 and IL-10, and stimulation of allogenic donor T-cells and autologous T-cells in allo-MLR and auto-MLR, respectively. Here, we show that the outcome of the manufacture of DC-based vaccine is highly variable in terms of both DC yield and DC immunostimulatory properties. In 30% of cases, manufacturing resulted in a product that failed to meet medicinal product specifications and therefore was not released for administration to a patient. Focusing on the isolation of monocytes and the pharmacotherapy preceding monocyte harvest, we show that isolation of monocytes by elutriation is not superior to adherence on plastic in terms of DC yield, viability, or immunostimulatory capacity. Trial patients having undergone monocyte-interfering pharmacotherapy prior to monocyte harvest was associated with an impaired DC-based immunotherapy product outcome. Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters. Searching for a surrogate marker predicting an adverse outcome of DC manufacture in the peripheral blood complete blood count prior to monocyte harvest, we observed an association between an increased number of immature granulocytes in peripheral blood and decreased potency of the DC-based product as quantified by allo-MLR. We conclude that the DC-manufacturing yield and the immunostimulatory quality of anti-cancer DC-based vaccines generated from the monocytes of patients were not influenced by the monocyte isolation modality but were detrimentally affected by the specific combination of anti-cancer agents used prior to monocyte harvest., (Copyright © 2019 Hlavackova, Pilatova, Cerna, Selingerova, Mudry, Mazanek, Fedorova, Merhautova, Jureckova, Semerad, Pacasova, Flajsarova, Souckova, Demlova, Sterba, Valik and Zdrazilova-Dubska.)

Purpose: The acute effect of radiofrequency (RF) ablation includes local necrosis and oedema. We investigated the spatiotemporal change of atrial electrograms in the area surrounding the site of single standardized pulse of RF energy. Methods: The study enrolled 12 patients (45-67 years, 10 males) with paroxysmal atrial fibrillation (AF) undergoing ablation procedure with irrigated-tip ablation catheter and 3D navigation. The high-density mapping/remapping (129 ± 63 points) within the circular area with radius of ~10 mm, centered at the pre-specified posterior left pulmonary vein antrum ablation site was performed at baseline, immediately after single RF energy delivery (25 W, 30 s, 20 ml/min) and after 30 min waiting period. Bipolar voltages of atrial electrograms (A-EGM-biV) were averaged within the central and 12 adjacent left atrium segments and their relative change was studied. Results: After the ablation, overall A-EGM-biV within the mapping zone (3.51 ± 1.89 mV at baseline) reduced to 2.83 ± 1.77 mV (immediately) and to 2.68 ± 1.58 mV (after 30 min waiting period). In per-segment pair-wise comparison, we observed highly significant change in A-EGM-biV that extended up to the distance of 8.8 mm from the lesion core. The maximum early A-EGM-biV attenuation by 39-49% ( P < 0.001) was registered in segments adjacent to pulmonary vein ostia. The subsequent (delayed) A-EGM-biV reduction by 17-24% ( P < 0.05) was observed in opposite direction from the lesion center. Conclusions: Significant alteration of atrial electrograms was detectable rather distant from the central lesion. Spatiotemporal development of ablation lesion was eccentric/asymmetric. While acute A-EGM-biV reduction can be attributed predominantly to direct thermal injury, delayed effects are probably due to oedema progression.

Background: Left atrial (LA) enlargement is a predictor of worse outcome after catheter ablation for atrial fibrillation (AF). Widely used two-dimensional (2D)-echocardiography is inaccurate and underestimates real LA volume (LAV). We hypothesized that baseline clinical characteristics of patients can be used to adjust 2D-ECHO indices of LAV in order to minimize this disagreement., Methods: The study enrolled 535 patients (59 ± 9 years; 67% males; 43% paroxysmal AF) who underwent catheter ablation for AF in three specialized centers. We investigated multivariately the relationship between 2D-echocardiographic indices of LA size, specifically LA diameter in M-mode in the parasternal long-axis view (LAD), LAV assessed by the prolate-ellipsoid method (LAVEllipsoid), LAV by the planimetric method (LAVPlanimetry), and LAV derived from 3D-electroanatomic mapping (LAVCARTO)., Results: Cubed LAD of 106 ± 45 ml, LAVEllipsoid of 72 ± 24 ml and LAVPlanimetry of 88 ± 30 ml correlated only modestly (r = 0.60, 0.69, and 0.53, respectively) with LAVCARTO of 137 ± 46 ml, which was significantly underestimated with a bias (±1.96 standard deviation) of -31 (-111; +49) ml, -64 (-132; +2) ml, and -49 (-125; +27) ml, respectively; p < 0.0001 for their mutual difference. LA enlargement itself, age, gender, type of AF, and the presence of structural heart disease were independent confounders of measurement error of 2D-echocardiographic LAV., Conclusion: Accuracy and precision of all 2D-echocardiographic LAV indices are poor. Their agreement with true LAV can be significantly improved by multivariate adjustment to clinical characteristics of patients.

Purpose: Atrioventricular (AV) conduction turbulence, biphasic dromotropic response of AV node to single ventricular premature contraction (VPC), consists of early shortening and later prolongation of AV conduction intervals due to the direct electrophysiological mechanisms and perturbation in autonomic modulation. We investigated the acute effect of radiofrequency catheter ablation of slow pathway on AV turbulence., Methods: The electrophysiological study was performed in 18 patients (7 men, mean age 49 ± 15 years) undergoing catheter ablation for AV nodal reentrant tachycardia. The stimulation protocol consisting of series of isolated VPC (coupling interval of 273 ± 23 ms) delivered from right ventricle apex during constant atrial pacing at 100 bpm was performed immediately prior to and 8 ± 4 min after successful slow-pathway ablation. Averaged post-VPCs profiles of AV conduction intervals were analyzed by purpose-written software. The descriptors of AV turbulence, turbulence onset (TOAV), turbulence slope (TSAV), and AV recovery (R AV) were assessed., Results: Slow-pathway ablation suppressed the AV nodal responsiveness to VPC as evidenced by significant reduction of AV turbulence indices: TOAV: -6.4 ± 7.5 % vs. -4.3 ± 6.1 % (p < 0.05); TSAV: 2.0 ± 2.6 ms/RRi vs. 1.0 ± 0.7 ms/RRi (p < 0.05); and R AV: -13.8 ± 7.3 % vs. -6.5 ± 12.7 % (p < 0.05)., Conclusions: Slow-pathway ablation significantly attenuated both vagal and non-autonomic modulation of AV nodal conduction. This effect is likely due to direct thermal injury of AV node associated with the change of properties of AV nodal fast-pathway although specific alteration of peri-AV nodal ganglionated plexi or their neural inputs into the AV node cannot be excluded.