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Background: The integration of computed tomography (CT)-derived left ventricular outflow tract area into the echocardiography-derived continuity equation results in the reclassification of a significant proportion of patients with severe aortic stenosis (AS) into moderate AS based on aortic valve area indexed to body surface area determined by fusion imaging (fusion AVAi). The aim of this study was to evaluate AS severity by a fusion imaging technique in patients with low-gradient AS and to compare the clinical impact of reclassified moderate AS versus severe AS. Methods: We included 359 consecutive patients who underwent transcatheter aortic valve implantation for low-gradient, severe AS at two academic institutions and created a joint database. The primary endpoint was a composite of all-cause mortality and rehospitalisations for heart failure at 1 year. Results: Overall, 35% of the population (n = 126) were reclassified to moderate AS [median fusion AVAi 0.70 (interquartile range, IQR 0.65–0.80) cm2/m2] and severe AS was retained as the classification in 65% [median fusion AVAi 0.49 (IQR 0.43–0.54) cm2/m2]. Lower body mass index, higher logistic EuroSCORE and larger aortic dimensions characterised patients reclassified to moderate AS. Overall, 57% of patients had a left ventricular ejection fraction (LVEF) <50%. Clinical outcome was similar in patients with reclassified moderate or severe AS. Among patients reclassified to moderate AS, non-cardiac mortality was higher in those with LVEF <50% than in those with LVEF ≥50% (log-rank p = 0.029). Conclusions: The integration of CT and transthoracic echocardiography to obtain fusion AVAi led to the reclassification of one third of patients with low-gradient AS to moderate AS. Reclassification did not affect clinical outcome, although patients reclassified to moderate AS with a LVEF <50% had worse outcomes owing to excess non-cardiac mortality. [ABSTRACT FROM AUTHOR]

Background: Functional mitral regurgitation (FMR) can be subclassified based on its proportionality relative to left ventricular function and end-diastolic volume. FMR proportionality could help identify responders to transcatheter edge-to-edge mitral valve repair (MitraClip) in terms of residual FMR and/or clinical improvement. Methods: This single-centre retrospective cohort study evaluated the feasibility of determining FMR proportionality in symptomatic heart failure patients with reduced left ventricular function who were treated with MitraClip for ≥ moderate-to-severe FMR. Baseline proportionate (pFMR) and disproportionate FMR (dFMR) were distinguished. Patient characteristics and MitraClip procedural outcomes were described. Results: From an overall cohort of 81 eligible FMR patients, 23/81 (28%) had to be excluded due to missing transthoracic echocardiogram parameters, 22/81 were excluded based on FMR severity. The remaining cohort, of 36/81 patients (44%), could be classified into dFMR (n = 26) or pFMR (n = 10). Conduction disorders were numerically increased in dFMR. All cases requiring > 2 clips were in the dFMR group and absence of FMR reduction occurred more frequently with dFMR. Point of view/Conclusion: Important limitations in terms of imaging acquisition affect the translation of the FMR proportionality concept to a real-world data set. We did observe different demographic and FMR response patterns in patients with proportionate and disproportionate FMR that warrant further investigation. [ABSTRACT FROM AUTHOR]

In the analysis of composite endpoints in a clinical trial, time to first event analysis techniques such as the logrank test and Cox proportional hazard test do not take into account the multiplicity, importance, and the severity of events in the composite endpoint. Several generalized pairwise comparison analysis methods have been described recently that do allow to take these aspects into account. These methods have the additional benefit that all types of outcomes can be included, such as longitudinal quantitative outcomes, to evaluate the full treatment effect. Four of the generalized pairwise comparison methods, ie, the Finkelstein-Schoenfeld, the Buyse, unmatched Pocock, and adapted O'Brien test, are summarized. They are compared to each other and to the logrank test by means of simulations while specifically evaluating the effect of correlation between components of the composite endpoint on the power to detect a treatment difference. These simulations show that prioritized generalized pairwise comparison methods perform very similarly, are sensitive to the priority rank of the components in the composite endpoint, and do not measure the true treatment effect from the second priority-ranked component onward. The nonprioritized pairwise comparison test does not suffer from these limitations and correlation affects only its variance. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Dense granule (DG) deficiency (DGD) is a feature of some platelet function disorders (PFD) with a prevalence similar to von Willebrand disease. Most laboratories assess for DGD using whole mount platelet preparations and electron microscopy (EM). We evaluated our experiences with this test and associations between DGD and bleeding. Methods: Dense granule EM records for 2006‐2017 were examined for patients and simultaneously tested controls, and for an overlapping PFD study cohort to evaluate findings and their relationship to bleeding. Results: More patient than control samples had reduced DG counts (6.5% vs 0.3%, P < .01). DG counts showed no relationship to age or mean platelet volume and had acceptable within‐subject variability that was higher for DGD than control participants (28% vs 12%). Repeat tests confirmed DGD in all persons with initial DG counts <4.0/platelet, but not in those with less severe reductions (4.0‐4.8 DG/platelet) or normal DG counts (≥4.9 DG/platelet). Aggregometry and adenosine triphosphate release tests, respectively, had only ~52% and 70% sensitivity for DGD. Confirmed DGD by EM was associated with higher bleeding scores and a bleeding disorder. Conclusion: Whole mount EM is useful for the evaluation of suspected PFD due to DGD and detects abnormalities associated with bleeding. [ABSTRACT FROM AUTHOR]

Objectives: To prospectively evaluate image quality (IQ) and radiation dose of dual-source cardiac computed tomography (CCTA) using different imaging protocols.Methods: CCTA was performed in 150 patients using the retrospective ECG-gated spiral technique (rECG) the prospective ECG-gated technique (pECG), or the prospective ECG-gated technique with systolic imaging and automated tube voltage selection (pECGsys). IQ was rated using a 16-segment coronary artery model. Techniques were compared for overall IQ, IQ of the large and the small coronary artery segments. Effective dose was used for comparison of radiation dose.Results: Overall IQ and IQ of the large segments showed no differences between the groups. IQ analysis of the small segments showed lowered IQ in pECGsys compared to rECG (p = 0.02), but not to pECG (p = 0.6). Effective dose did not differ significantly between rECG and pECG (p = 0.13), but was significantly lower for pECGsys (p < 0.001 vs. rECG and pECG).Conclusion: Radiation dose of dual-source CCTA in heart transplant recipients is significantly reduced by using prospective systolic scanning and automated tube voltage selection, while overall IQ and IQ of the large coronary segments are maintained. IQ appears to be lower compared to retrospective techniques with regard to small coronary segments.Key Points: • Cardiac computed tomography angiography is useful for cardiac allograft vasculopathy assessment. • Despite elevated heart rate, dose reduction in cardiac computed tomography is possible. • Prospective systolic gating and automated tube voltage selection enable 50 % dose reduction. [ABSTRACT FROM AUTHOR]

We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 μg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-γ, and TNF-α of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy. [ABSTRACT FROM AUTHOR]

Expression of proliferating cell nuclear antigen (PCNA) and c- erbB-2 oncoprotein has been assessed in 471 women with breast cancer to evaluate their prognostic value as compared to conventional histopathological factors. In univariate analysis, high PCNA expression (≥20%) predicted a significantly worse survival in lymph-node-negative tumors (univariate P=0.031). However, the effect disappeared in multivariate analysis and the histological grade remained the only independent factor for this group. Despite its close correlation to histological grade ( P<0.001), PCNA expression discriminated subsets with different survival within the heterogeneous group of moderately differentiated tumors (univariate P=0.073, multivariate P=0.075). PCNA expression was not found to be a significant prognostic factor in lymph-node-positive tumors, thus it was of limited value for breast cancer patients as a whole. c-erbB-2 protein overexpression was associated with a worse survival (univariate P=0.019, multivariate P=0.057) for the entire group of patients. The effect was mainly attributed to the significance of c-erbB-2 as an independent factor in lymph-node-positive (up to three nodes, multivariate P=0.04; four or more nodes: multivariate P=0.017) and large tumors (>2 cm: multivariate P=0.002). c- erbB-2 was without significance in lymph-node-negative patients. Though both factors might amplify the prognostic information for distinct patient subsets they do not achieve the strong prognostic value of conventional histopathological features in breast cancer. [ABSTRACT FROM AUTHOR]

A method for the cultivation of organ explants from abdominal mammary glands of virgin mice has been established. In a serum-free medium containing aldosterone, prolactin, insulin, and cortisol (APIH medium) mammary gland development was documented by lobuloalveolar morphogenesis. The hormonal requirements for in vitro expression of beta-casein and of the mammary-derived growth inhibitor (MDGI) were tested. To this end, a full length cDNA coding for mouse MDGI was prepared displaying strong homologies to a mouse heart fatty acid binding protein, which is also expressed in the mammary gland. MDGI and beta-casein transcripts were found to be absent in the mammary tissue from primed virgin mice, and were induced upon culture of mammary explants in the APIH medium. An immunohistochemical analysis with specific antibodies against MDGI and casein revealed a different pattern of expression for the two proteins. In the APIH medium, MDGI was expressed mainly in differentiating alveolar cells of the lobuloalveolar structures, whereas beta-casein was present in both ductules and alveoli. The relationship between functional differentiation and MDGI expression was further studied in explants from glands of late-pregnant mice. At this stage of development, MDGI is found both in ducts and in alveoli. If explants were cultured with epidermal growth factor (EGF) and insulin, the lobuloalveolar structure was still present, whereas MDGI disappeared. Reinduction of MDGI expression was achieved by subsequent PIH treatment. Independent on developmental stage, EGF strongly inhibits MDGI mRNA expression. It is concluded that MDGI-expression is associated with functional differentiation in the normal gland. [ABSTRACT FROM AUTHOR]

LY121019 and amphotericin B were equally active in vitro against most clinical isolates of Candida albicans and Candida tropicalis. Higher concentrations of LY121019 were required for inhibition of Candida glabrata. Other Candida species were inhibited by amphotericin B but not by LY121019. [ABSTRACT FROM AUTHOR]