Budget impact analysis of apixaban to treat and prevent venous thromboembolism in Italy

BACKGROUND: Venous thromboembolism (VTE), a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious vascular condition associated to high economic and clinical burden. Apixaban, a Novel Oral Anticoagulant (NOAC) has shown non-inferiority efficacy versus the current standard of care (low molecular weight heparin [LMWH]/vitamin K antagonist [VKA]) in the acute treatment and prevention of VTE and a significant reduction in the risk of bleeding.AIM: Evaluate the economic impact of the use of apixaban for treatment and prevention of DVT and PE from the perspective of the Italian National Health System (NHS).METHODS: A budget impact model was adapted in order to compare clinical outcomes and economic consequences associated to apixaban vs. LMWH/VKA and others NOACs over a three-year time horizon in the Italian setting. In the analysis two scenario were compared: status quo scenario without apixaban and an alternative scenario with apixaban. Only direct healthcare costs have been considered.RESULTS: Assuming a population of patients receiving apixaban over the first 3 years equal to 20,957, the introduction of apixaban is associated to an incremental saving of € 821,748 in the first years, € 1,250,454 in the second year, and € 1,866,466 in the third year. The total net saving over the 3-year period is € 3,938,668, which is a 2.47% decrease from the total budget for the status quo scenario without apixaban. This saving is mainly due to reduced VTE events and bleeds by apixaban. Indeed apixaban is associated with less VTE events (both fatal and non-fatal), less major bleeding and less Clinical Relevant Non Major (CRNM) bleeding with a total of 52 fatal events avoided.CONCLUSIONS: The listing of apixaban for the treatment of VTE (both DVT and PE) and the prevention of recurrent VTE provides both significant clinical advantages, in terms of deaths and events avoided, and economical advantages, consisting in a reduction in the total expenditure on the Italian NHS

Experts bodies, experts minds: How physical and mental training shape the brain

Skill learning is the improvement in perceptual, cognitive, or motor performance following practice. Expert performance levels can be achieved with well-organized knowledge, using sophisticated and specific mental representations and cognitive processing, applying automatic sequences quickly and efficiently, being able to deal with large amounts of information, and many other challenging task demands and situations that otherwise paralyze the performance of novices. The neural reorganizations that occur with expertise reflect the optimization of the neurocognitive resources to deal with the complex computational load needed to achieve peak performance. As such, capitalizing on neuronal plasticity, brain modifications take place over time-practice and during the consolidation process. One major challenge is to investigate the neural substrates and cognitive mechanisms engaged in expertise, and to define “expertise” from its neural and cognitive underpinnings. Recent insights showed that many brain structures are recruited during task performance, but only activity in regions related to domain-specific knowledge distinguishes experts from novices. The present review focuses on three expertise domains placed across a motor to mental gradient of skill learning: sequential motor skill, mental simulation of the movement (motor imagery), and meditation as a paradigmatic example of “pure” mental training. We first describe results on each specific domain from the initial skill acquisition to expert performance, including recent results on the corresponding underlying neural mechanisms. We then discuss differences and similarities between these domains with the aim to identify the highlights of the neurocognitive processes underpinning expertise, and conclude with suggestions for future research

Heart Rate Variability from Wearable Photoplethysmography Systems: Implications in Sleep Studies at High Altitude

The interest in photoplethysmography (PPG) for sleep monitoring is increasing because PPG may allow assessing heart rate variability (HRV), which is particularly important in breathing disorders. Thus, we aimed to evaluate how PPG wearable systems measure HRV during sleep at high altitudes, where hypobaric hypoxia induces respiratory disturbances. We considered PPG and electrocardiographic recordings in 21 volunteers sleeping at 4554 m a.s.l. (as a model of sleep breathing disorder), and five alpine guides sleeping at sea level, 6000 m and 6800 m a.s.l. Power spectra, multiscale entropy, and self-similarity were calculated for PPG tachograms and electrocardiography R-R intervals (RRI). Results demonstrated that wearable PPG devices provide HRV measures even at extremely high altitudes. However, the comparison between PPG tachograms and RRI showed discrepancies in the faster spectral components and at the shorter scales of self-similarity and entropy. Furthermore, the changes in sleep HRV from sea level to extremely high altitudes quantified by RRI and PPG tachograms in the five alpine guides tended to be different at the faster frequencies and shorter scales. Discrepancies may be explained by modulations of pulse wave velocity and should be considered to interpret correctly autonomic alterations during sleep from HRV analysis

Closed-Loop Cardiovascular Interactions and the Baroreflex Cardiac Arm: Modulations Over the 24 h and the Effect of Hypertension

Closed-loop models of the interactions between blood pressure (BP) and heart rate variations allow for estimation of baroreflex sensitivity (feedback effects of BP changes on heart rate) while also considering the feedforward effects of heart rate on BP. Our study is aimed at comparing modulations of feedback and feedforward couplings over 24 h in normotensive and hypertensive subjects, by assessing closed-loop baroreflex models in ambulatory conditions. Continuous intra-arterial BP recordings were performed for 24 h in eight normotensive and eight hypertensive subjects. Systolic BP (SBP) and pulse interval (PI) beat-by-beat series were analyzed by an autoregressive moving average model over consecutive 6-min running windows, estimating closedloop feedback and feedforward gains in each window. The open-loop feedback gain was estimated for comparison. Normotensive and hypertensive patients were compared during wake (18:00–22:00) and sleep (23:00–5:00) periods by a mixed-effect linear model at p \u3c 0.05. In both groups feedback (feedforward) gain averaged values were higher (lower) in sleep than in wake. Moreover, the closed-loop feedback gain was higher in normotensive subjects both in wake and sleep, whereas the closedloop feedforward gain was higher in hypertensive subjects during sleep. By contrast, no significant differences were found between the normotensive and hypertensive groups for the open-loop feedback gain. Therefore, the closed-loop SBP-PI model can detect circadian alterations in the feedforward gain of PI on SBP and derangements of spontaneous baroreflex sensitivity in hypertension not detectable with the open-loop approach. These findings may help to obtain a more comprehensive assessment of the autonomic dysfunction underlying hypertension and for the in-depth evaluation of the benefits of rehabilitation procedures on autonomic cardiovascular modulation

Hydrogeological and hydrogeochemical monitoring in the Cumae archaeological site (Phlegraean Fields, southern Italy)

Phlegraean Fields, hydrogeological model, hydrochemical facie

Elderly hypertensive patients: Silent white matter lesions, blood pressure variability, baroreflex impairment and cognitive deterioration

Introduction: Hypertension may increase the risk for stroke and is frequently associated with subcortical and periventricular white matter lesions (WML). This is considered a prognostic factor for the development of stroke and cognitive impairment, particularly in attention processes. Additionally, in elderly subjects, it is known the implications of alterations in the neural cardiovascular regulation and the cardiovascular risk. Aims: To evaluate, in asymptomatic elderly hypertensives, the association of ambulatory blood pressure values and autonomic activity with neurocognitive impairment and WML. In addition, we also evaluated the role of the autonomic nervous system particularly the vagal component, in the pathogenesis of white matter lesions. Methods: We studied 22 elderly essential hypertensive patients (69±1.1y) and as control group, 16 normotensive elderly subjects (age 67±3.2y) were also enrolled. To each one of them, a cerebral MRI was performed to classify them, by a neuro-radiologist blinded of the subject clinical status, using a 0 to 9 scale where 0 denoted no WML and 9 the most severe lesions. Twenty four hours arterial blood pressure monitoring was performed to each one of the subjects under study. Office blood pressure was measured 3 times and the mean value reported. Beat to beat finger arterial pressure monitoring (Finapres) was performed for a 2h period. During the first hour the patient remained lying supine in a quiet darkened room and during the second hour four manoeuvres: stand-up, cold pressor test, handgrip and quiet activity were randomly performed. Mean blood pressure and pulse interval values, from the two periods, and their respective variabilities, baroreflex sensitivity and power spectral analysis were calculated. Regarding neuropsychological assessment: Minimental test, attention evaluation, RAVLT, visual memory, language and executive function, geriatric depression scale, cognitive deficit rate tests were performed in all subject. Results: We found a closer correlation of WML with 24hs ABPM than with office BP readings being more evident with systolic blood pressure during the night time period. WML failed to show any correlation with SBP average values derived from the Finapres recordings in either the supine or the upright position, while it was positively and significantly related to PP in both conditions. However, beat to beat SBP variability, either in the supine or in the upright position, showed a positive and significant correlation with WML. During the resting period, BRS calculated through the sequence method (Time Domain) was similar in HT and NT subjects. However when BRS was assessed in the frequency domain a significant reduction was observed in HT compared with NT. In addition, At the time of laboratory manoeuvres implying sympathetic activation, BRS was significantly reduced as compared to the resting values being particularly evident for the HF values. In hypertensive subjects, only semantic fluency showed a significant difference (p=0.01), when compared to normotensives. When the patients were divided in older and younger than 75 years, a significant difference was observed in the delayed analysis of words, and in the phonological fluency showing a significant higher rate of pathological results in the group of patients older than 75 years. Conclusions: As previously shown, incidental WML, suggestive of silent cerebrovascular disease, is a frequent finding in elderly hypertensives. Night-time BP mean values and SBP variability in upright position seems to be the best predictor on silent cerebral WML. The vagal component of the autonomic nervous system seems to be involved in the pathogenesis of these lesions. Finally, the neurocognitive alterations are multifactorial in origin where the aging process seems to be the principal component.Fil: Ramírez, Agustín José. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Parati, Gianfranco. San Gerardo Hospital; Italia. University of Milan-Bicocca; ItaliaFil: Castiglioni, Paolo. Fondazione Don Gnocchi; ItaliaFil: Consalvo, Damian. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Solis, Patricia Cristina Lourdes. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Risk, Marcelo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Computación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Waissman, Paola. Fundación Favaloro; ArgentinaFil: di Rienzo, Marco. Fondazione Don Gnocchi; ItaliaFil: Mancia, Giusepe. San Gerardo Hospital; Italia. University of Milan-Bicocca; ItaliaFil: Sanchez, Ramiro A.. Fundación Favaloro; Argentin

Exploiting Reaction-Diffusion Conditions to Trigger Pathway Complexity in the Growth of a MOF

Coordination polymers (CPs), including metal-organic frameworks (MOFs), are crystalline materials with promising applications in electronics, magnetism, catalysis, and gas storage/separation. However, the mechanisms and pathways underlying their formation remain largely undisclosed. Herein, we demonstrate that diffusion-controlled mixing of reagents at the very early stages of the crystallization process (i.e., within ≈40 ms), achieved by using continuous-flow microfluidic devices, can be used to enable novel crystallization pathways of a prototypical spin-crossover MOF towards its thermodynamic product. In particular, two distinct and unprecedented nucleation-growth pathways were experimentally observed when crystallization was triggered under microfluidic mixing. Full-atom molecular dynamics simulations also confirm the occurrence of these two distinct pathways during crystal growth. In sharp contrast, a crystallization by particle attachment was observed under bulk (turbulent) mixing. These unprecedented results provide a sound basis for understanding the growth of CPs and open up new avenues for the engineering of porous materials by using out-of-equilibrium conditions

A meta-learning algorithm for respiratory flow prediction from FBG-based wearables in unrestrained conditions

The continuous monitoring of an individual's breathing can be an instrument for the assessment and enhancement of human wellness. Specific respiratory features are unique markers of the deterioration of a health condition, the onset of a disease, fatigue and stressful circumstances. The early and reliable prediction of high-risk situations can result in the implementation of appropriate intervention strategies that might be lifesaving. Hence, smart wearables for the monitoring of continuous breathing have recently been attracting the interest of many researchers and companies. However, most of the existing approaches do not provide comprehensive respiratory information. For this reason, a meta-learning algorithm based on LSTM neural networks for inferring the respiratory flow from a wearable system embedding FBG sensors and inertial units is herein proposed. Different conventional machine learning approaches were implemented as well to ultimately compare the results. The meta-learning algorithm turned out to be the most accurate in predicting respiratory flow when new subjects are considered. Furthermore, the LSTM model memory capability has been proven to be advantageous for capturing relevant aspects of the breathing pattern. The algorithms were tested under different conditions, both static and dynamic, and with more unobtrusive device configurations. The meta-learning results demonstrated that a short one-time calibration may provide subject-specific models which predict the respiratory flow with high accuracy, even when the number of sensors is reduced. Flow RMS errors on the test set ranged from 22.03 L/min, when the minimum number of sensors was considered, to 9.97 L/min for the complete setting (target flow range: 69.231 ± 21.477 L/min). The correlation coefficient r between the target and the predicted flow changed accordingly, being higher (r = 0.9) for the most comprehensive and heterogeneous wearable device configuration. Similar results were achieved even with simpler settings which included the thoracic sensors (r ranging from 0.84 to 0.88; test flow RMSE = 10.99 L/min, when exclusively using the thoracic FBGs). The further estimation of respiratory parameters, i.e., rate and volume, with low errors across different breathing behaviors and postures proved the potential of such approach. These findings lay the foundation for the implementation of reliable custom solutions and more sophisticated artificial intelligence-based algorithms for daily life health-related applications

Closed-Loop Cardiovascular Interactions and the Baroreflex Cardiac Arm: Modulations Over the 24 h and the Effect of Hypertension

Closed-loop models of the interactions between blood pressure (BP) and heart rate variations allow for estimation of baroreflex sensitivity (feedback effects of BP changes on heart rate) while also considering the feedforward effects of heart rate on BP. Our study is aimed at comparing modulations of feedback and feedforward couplings over 24 h in normotensive and hypertensive subjects, by assessing closed-loop baroreflex models in ambulatory conditions. Continuous intra-arterial BP recordings were performed for 24 h in eight normotensive and eight hypertensive subjects. Systolic BP (SBP) and pulse interval (PI) beat-by-beat series were analyzed by an autoregressive moving average model over consecutive 6-min running windows, estimating closed-loop feedback and feedforward gains in each window. The open-loop feedback gain was estimated for comparison. Normotensive and hypertensive patients were compared during wake (18:00–22:00) and sleep (23:00–5:00) periods by a mixed-effect linear model at p < 0.05. In both groups feedback (feedforward) gain averaged values were higher (lower) in sleep than in wake. Moreover, the closed-loop feedback gain was higher in normotensive subjects both in wake and sleep, whereas the closed-loop feedforward gain was higher in hypertensive subjects during sleep. By contrast, no significant differences were found between the normotensive and hypertensive groups for the open-loop feedback gain. Therefore, the closed-loop SBP-PI model can detect circadian alterations in the feedforward gain of PI on SBP and derangements of spontaneous baroreflex sensitivity in hypertension not detectable with the open-loop approach. These findings may help to obtain a more comprehensive assessment of the autonomic dysfunction underlying hypertension and for the in-depth evaluation of the benefits of rehabilitation procedures on autonomic cardiovascular modulation

Insights into the Interaction Mechanism of DTP3 with MKK7 by Using STD-NMR and Computational Approaches

GADD45β/MKK7 complex is a non-redundant, cancer cell-restricted survival module downstream of the NF-kB survival pathway, and it has a pathogenically critical role in multiple myeloma, an incurable malignancy of plasma cells. The first-in-class GADD45β/MKK7 inhibitor DTP3 effectively kills MM cells expressing its molecular target, both in vitro and in vivo, by inducing MKK7/JNK-dependent apoptosis with no apparent toxicity to normal cells. DTP3 combines favorable drug-like properties, with on-target-specific pharmacology, resulting in a safe and cancer-selective therapeutic effect; however, its mode of action is only partially understood. In this work, we have investigated the molecular determinants underlying the MKK7 interaction with DTP3 by combining computational, NMR, and spectroscopic methods. Data gathered by fluorescence quenching and computational approaches consistently indicate that the N-terminal region of MKK7 is the optimal binding site explored by DTP3. These findings further the understanding of the selective mode of action of GADD45β/MKK7 inhibitors and inform potential mechanisms of drug resistance. Notably, upon validation of the safety and efficacy of DTP3 in human trials, our results could also facilitate the development of novel DTP3-like therapeutics with improved bioavailability or the capacity to bypass drug resistance