Right ventricular function in AL amyloidosis: characteristics and prognostic implication

AIM: The importance of right ventricle (RV) dysfunction in AL amyloidosis has been underestimated. This study was designed to comprehensively evaluate RV function and its prognostic role in patients with AL amyloidosis with and without echocardiographic evidence of cardiac involvement. METHOD AND RESULTS: Fifty-two biopsy-proven AL amyloidosis patients underwent a thorough echocardiographic evaluation. Twenty-seven patients (CA) met the international echocardiographic criteria for cardiac involvement [left ventricular (LV) wall thickness >/= 12 mm] and 25 patients had no cardiac amyloidosis features (NCA). Patients were compared with a sex- age-matched control group. Patients and controls underwent traditional, tissue Doppler (TDI), speckle-tracking left and RV echocardiographic evaluation. No difference was observed between groups in RV diastolic diameter, whereas CA patients showed increased RV free wall thickness (P< 0.0001). Compared with controls and NCA patients, traditional echocardiography, TDI, and speckle-tracking evaluation detected significantly (P< 0.0001) depressed RV longitudinal systolic function in CA patients. No difference was observed between groups at Doppler diastolic evaluation, whereas at tricuspidal annulus TDI analysis, CA subject showed significantly lower E' and A' values with increased E/E' ratio (P< 0.0001). Over a 19 months median follow-up period, 18 patients died. Cox multivariate analysis showed that N-terminal pro-Brain natriuretic peptide and RV longitudinal strain were the strongest death predictor. CONCLUSION: Our data show that in patients with AL amyloidosis, RV involvement develops later than LV amyloid deposition but when it occurs, prognosis dramatically worsens. Moreover RV longitudinal strain was the only echocardiographic predictor of prognosis. We suggest that RV function analysis should be performed routinely as a part of echocardiographic evaluation in these patients

Molecular Mechanism of Inhibition of DNA Methylation by Zebularine

In this work, we have analyzed the molecular mechanism of inhibition of a C5-DNA methyltransferase by zebularine using classical and QM/MM simulations. We found that the reaction proceeds with the addition of an unprotonated cysteine to the C6 position of the ring followed by methyl transfer to the C5 position. However, while the first step is reversible and presents a moderate free-energy barrier, the second step presents a large free-energy barrier, preventing the formation of the methylated complex. This mechanistic proposal agrees with recent experimental observations that point to the formation of a reversible covalent complex between DNA containing zebularine and methyltransferases. The absence of the exocyclic amino group in zebularine, as compared to the natural substrate cytosine, makes it more difficult to reach an optimal orientation of the substrate both for cysteine addition and methyl transfer and decreases the nucleophilicity of the carbon atom to be methylated, making this step unaffordable at physiological conditions

Lactate improves SAPS 3 prognostication

Introduction: Lactate concentration is known to be a strong predictor of mortality, but is not included in any of the major intensive care scorings systems such as the Simplified Acute Physiology Score (SAPS 3). The objective of this study was to investigate the prognostic value of lactate concentration when combined with SAPS 3. Materials and methods: In the period of 2008 to June 2017 the general intensive care unit at Skåne University Hospital in Lund, Sweden had 5141 first-time admissions. Of these, 3039 patients had lactate concentrations analysed within 1 h of admission. Results: As expected, lactate concentration was found to be strongly related to 30-day mortality. Lactate concentration was found to be a SAPS 3 independent predictor of mortality (odds ratio 1.08, 95% confidence interval 1.05-1.11, P < 0.001), but did not improve the area under the receiver operating characteristic curve (AUC) (AUC 78.9% vs. 78.7%, P = 0.053). However, we found that lactate added prognostic value to SAPS 3 for patients with cardiac arrest (AUC 79.6% vs. 76.4%, P = 0.0082) and sepsis (AUC 75.1% vs. 72.7%, P = 0.033). Conclusion: Even compared to our current prognostication model, SAPS 3, lactate concentration was found to be an independent predictor for all diagnoses, cardiac arrest and sepsis. The addition of lactate concentration level improved the AUC for cardiac arrest and sepsis, but not for all diagnoses

Enabling adaptive analytics at the edge with the Bi-Rex Big Data platform

Zero Defect Manufacturing (ZDM) is an emergent and disruptive paradigm that aims to optimize industrial process efficiency and sustainability by leveraging innovative and sophisticated data-driven approaches. It is a technology intensive concept that has the ambition of achieving and maintaining ``first-time-right'' quality goals in spite of varying processes and input material. As a result, developing ZDM applications might become overwhelming for small enterprises due to the multitude of diverse platform, the lack of know-how, and the need to adapt general purpose solutions to meet their needs. The Big Data Innovation and Research Excellence (Bi-Rex) is an Italian consortium that aims to accelerate the industrial innovation process of small enterprises. Within this consortium we developed a Big Data platform that enables adaptive analytics at the IT/OT boundary by leveraging innovative solutions for the safe and automatic deployment of data-driven apps, using MLOps and DevOps techniques and technologies, and evaluated it in real use cases provided by the world leading industrial partners involved in the project