Potential efficiency gains and expenditure savings in the Italian Regional Healthcare Systems

The paper aims to analyse the extent to which the adoption of best practice policies could improve the efficiency of Italian Regional Healthcare Systems (RHSs) and reduce public healthcare expenditures. By means of a stochastic frontier model we estimate the RHSs’ technical inefficiency and its determinants using a panel data of 16 regions over the period 2010-2016. We use the Essential Levels of Care (LEA) scores computed by the Ministry of Health as a proxy for the RHSs’ output and public healthcare expenditure as the main input. The level of inefficiency is a function of a set of variables summarising the organisational arrangements implemented by RHS policymakers. The results allow us to identify the best-practice policy, defined as the set of observable organisational arrangements that maximises aggregate efficiency. Adoption of the best-practice policy by all RHSs leads to potential efficiency gains of 1.5 per cent on average (from 93.4 per cent to 94.9 per cent) and to potential healthcare expenditure savings of 1.8 billion euro in 2016 (1.77 per cent of current expenditures)

Water regulates the residence time of Benzamidine in Trypsin

We simulate with state-of-the-art enhanced sampling techniques the binding of Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein system. We use machine learning methods and in particular Time-lagged Independent Component Analysis to determine efficient collective coordinates. These coordinates are used to perform On-the-fly Probability Enhanced Sampling simulations, which we adapt to calculate also the ligand residence time. Our results, both static and dynamic, are in good agreement with experiments. We underline the role of water in the unbinding process and find that the presence of a water molecule located at the bottom of the binding pocket allows via a network of hydrogen bonds the ligand to be released into the solution. On a finer scale, even when unbinding is allowed, another water molecule further modulates the exit time

Multimap targeted free energy estimation

We present a new method to compute free energies at a quantum mechanical (QM) level of theory from molecular simulations using cheap reference potential energy functions, such as force fields. To overcome the poor overlap between the reference and target distributions, we generalize targeted free energy perturbation (TFEP) to employ multiple configuration maps. While TFEP maps have been obtained before from an expensive training of a normalizing flow neural network (NN), our multimap estimator allows us to use the same set of QM calculations to both optimize the maps and estimate the free energy, thus removing almost completely the overhead due to training. A multimap extension of the multistate Bennett acceptance ratio estimator is also derived for cases where samples from two or more states are available. Furthermore, we propose a one-epoch learning policy that can be used to efficiently avoid overfitting when computing the loss function is expensive compared to generating data. Finally, we show how our multimap approach can be combined with enhanced sampling strategies to overcome the pervasive problem of poor convergence due to slow degrees of freedom. We test our method on the HiPen dataset of drug-like molecules and fragments, and we show that it can accelerate the calculation of the free energy difference of switching from a force field to a DFTB3 potential by about 3 orders of magnitude compared to standard FEP and by a factor of about 8 compared to previously published nonequilibrium calculations.Comment: Added Algorithm 1, wall-clock timings, additional uncertainty estimates, and other minor edits. Main Text: 12 pages, 5 figures, 7 equations. Supplemental Material: 17 pages, 5 figures, 22 equation

Rare Event Kinetics from Adaptive Bias Enhanced Sampling

We introduce a novel enhanced sampling approach named OPES flooding for calculating the kinetics of rare events from atomistic molecular dynamics simulation. This method is derived from the On-the-fly-Probability-Enhanced-Sampling (OPES) approach [Invernizzi and Parrinello, JPC Lett. 2020], which has been recently developed for calculating converged free energy surfaces for complex systems. In this paper, we describe the theoretical details of the OPES flooding technique and demonstrate the application on three systems of increasing complexity: barrier crossing in a two-dimensional double well potential, conformational transition in the alanine dipeptide in gas phase, and the folding and unfolding of the chignolin polypeptide in aqueous environment. From extensive tests, we show that the calculation of accurate kinetics not only requires the transition state to be bias-free, but the amount of bias deposited should also not exceed the effective barrier height measured along the chosen collective variables. In this vein, the possibility of computing rates from biasing suboptimal order parameters has also been explored. Furthermore, we describe the choice of optimum parameter combinations for obtaining accurate results from limited computational effort

Carbon dioxide adsorption and hydrogenation on nickel-based surfaces: a first principles study

2009/2010The chemistry of carbon dioxide has recently become of great interest both for technological and environmental issues. Indeed, carbon dioxide is one of the most problematic greenhouse gases and is also a fundamental ingredient for the industrial catalytic organic synthesis of many compounds like, for example, methanol. Recent investigations have shown that, while the common industrial process for methanol synthesis is carried out on Cu catalysts, Ni-Cu model catalysts show a particularly high e ciency. In order to understand the origin of such increase in the catalyst activity, a thorough characterization of the CO2-Ni interaction and the atomic-scale description of the hydrogenation process are mandatory. This thesis is focused on the study of the adsorption and activation of carbon dioxide mainly on pure Ni(110) surface and of its reactions with atomic and molecular hydrogen by means of accurate quantum mechanical rst principles numerical simulations. The interaction of the CO2 molecule with the surface is characterized in terms of adsorption geometries, energetics, vibrational and electronic properties, including charge transfer, core-level shifts and scanning tunneling microscopy images, obtained from electronic structure calculations and compared with original experimental results achieved mainly by the Surface Structure and Reactivity Group active at the TASC laboratory. A consistent picture of CO2 chemisorption on Ni(110) is provided on the basis of the newly available information, yielding a deeper insight into the previously existing spectroscopic and theoretical data. We nd that CO2 molecule can be chemisorbed in diff erent, almost energetically equivalent adsorption confi gurations on a Ni(110) surface,with high charge transfer from the substrate. The molecule, that in gas phase is linear and unreactive, is chemisorbed in a bent and activated state on the nickel surface and can react with the hydrogen. The atomic-scale investigation sheds light also on the long-standing debate on the actual reaction path followed by the reactants. Di fferent hydrogenation channels have been explored to determine the reaction network: using molecular hydrogen, only a Langmuir-Hinshelwood process (both reactants are adsorbed) is possible, resulting in the production of formate which is just a 'dead-end' molecule; with atomic hydrogen, instead, the reaction proceeds also through parallel Eley-Rideal channels (only one of the molecules adsorbs and the other one reacts with it directly from the gas phase, without adsorbing), where hydrogen-assisted C-O bond cleavage in CO2 yields CO already at low temperature.XXIII Ciclo197