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Background: The extrafine single inhaler triple therapy (efSITT) containing beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg has proved to be efficacious in patients with chronic obstructive pulmonary disease (COPD) in randomized control trials., Objective: TRIWIN study evaluated the effectiveness of efSITT delivering beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg in COPD patients previously treated with multiple-inhaler triple therapy (MITT) in a real-world study in Greece., Design: Prospective, multicenter, observational, non-interventional study was conducted over 24 weeks., Methods: A total of 475 eligible patients had moderate-to-severe COPD, an indication for treatment with efSITT, and were symptomatic despite receiving MITT. COPD Assessment Test (CAT) score, pulmonary function parameters, use of rescue medication, and adherence to inhaler use were recorded at baseline (Visit 1), 3 (Visit 2), and 6 months (Visit 3) after treatment., Results: Mean CAT score decreased from 21.4 points at Visit 1, to 16.6 at Visit 2 and 15.1 at Visit 3 ( p  < 0.001 for all pair comparisons). At Visit 3, 79.8% of patients reached a CAT improvement exceeding minimal clinically important difference (⩾2), compared to baseline. Mean forced expiratory volume in 1 s (%pred.) increased from 55.4% at Visit 1 to 63.5% at the end of study period ( p  < 0.001), while mean forced vital capacity (%pred.) increased from 71.1% at Visit 1, to 76.7% at Visit 3 ( p  < 0.001). The mean Test of Adherence to Inhalers score increased from 42.5 to 45.3 and 46.3 points, for the three visits, respectively ( p  < 0.001 comparing Visits 1/2 and Visits 1/3; p  = 0.006 comparing Visits 2/3). The percentage of patients showing good adherence rose from 33.7% at baseline to 58.3% at Visit 3. The percentage of patients using rescue medication during the last month dropped from 16.2% to 7.4% at the end of study period ( p  < 0.001). Pulmonary function parameters also improved., Conclusion: The TRIWIN results suggest that extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium is effective in improving health status, pulmonary function, and adherence and in reducing rescue medication use in COPD patients previously treated with MITT, in a real-world setting in Greece.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments., (© 2023 The Authors. Molecular Informatics published by Wiley-VCH GmbH.)

Aim: To investigate the perspective of physicians treating chronic airway diseases on the importance of device and substance characteristics influencing the compliance of patients with chronic obstructive airways diseases., Objective: We surveyed physicians... perspective on the impact of device and substance characteristics on patients... compliance., Methods: This study was carried out by running a structured questionnaire, to a total of 144 physicians, conducting personal interviews and evaluating answers on a scale from 1 for most to 6 for least important influencing parameter., Results: Overall, the most important parameters influencing patients... compliance according to physicians... perspective were rapid onset of action, type of inhalation device and duration of action. Adverse events were considered as the least important parameter. When COPD and asthma were examined separately, the most important parameters influencing compliance were rapid onset of action, ease of use and duration of action. Rapid onset of action was significantly more important in asthma than COPD., Conclusion: Onset and duration of action and ease of use were classified higher as important parameters to increase patients... compliance, according to physicians..., (Copyright © 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Computational methods for virtual screening can dramatically accelerate early-stage drug discovery by identifying potential hits for a specified target. Docking algorithms traditionally use physics-based simulations to address this challenge by estimating the binding orientation of a query protein-ligand pair and a corresponding binding affinity score. Over the recent years, classical and modern machine learning architectures have shown potential for outperforming traditional docking algorithms. Nevertheless, most learning-based algorithms still rely on the availability of the protein-ligand complex binding pose, typically estimated via docking simulations, which leads to a severe slowdown of the overall virtual screening process. A family of algorithms processing target information at the amino acid sequence level avoid this requirement, however, at the cost of processing protein data at a higher representation level. We introduce deep neural virtual screening (DENVIS), an end-to-end pipeline for virtual screening using graph neural networks (GNNs). By performing experiments on two benchmark databases, we show that our method performs competitively to several docking-based, machine learning-based, and hybrid docking/machine learning-based algorithms. By avoiding the intermediate docking step, DENVIS exhibits several orders of magnitude faster screening times (i.e., higher throughput) than both docking-based and hybrid models. When compared to an amino acid sequence-based machine learning model with comparable screening times, DENVIS achieves dramatically better performance. Some key elements of our approach include protein pocket modeling using a combination of atomic and surface features, the use of model ensembles, and data augmentation via artificial negative sampling during model training. In summary, DENVIS achieves competitive to state-of-the-art virtual screening performance, while offering the potential to scale to billions of molecules using minimal computational resources.

We present an action that can be used to study variationally the collapse of Bose-Einstein condensates. This action is real, even though it includes dissipative terms. It adopts long-range interactions between the atoms, so that there is always a stable minimum of the energy, even if the remaining number of atoms is above the number that in the case of local interactions is the critical one. The proposed action incorporates the time needed for the abrupt and delayed onset of collapse, yielding in fact its dependence on the scattering length. We show that the evolution of the condensate is equivalent to the motion of a particle in an effective potential. The particle begins its motion far from the point of stable equilibrium and it then proceeds to oscillate about that point. We prove that the resulting large oscillations in the shape of the wave function after the collapse have frequencies equal to twice the frequencies of the traps. Our results agree with the experimental observations.

Colorectal cancer is a leading cause of cancer death in the USA. While locally advanced rectal cancer involving bone has been described extensively, colon cancer locally involving bone has only been described, to our knowledge, in a single case report. In this case report, we describe the presentation and treatment of locally advanced re-recurrent colon cancer involving the iliac bone. We also discuss the available literature on treatment for recurrent and re-recurrent colorectal cancer., (2014 BMJ Publishing Group Ltd.)

We examine the evolution of the ground state of a Bose-Einstein condensate in a two-dimensional circular box, the wall of which is initially at rest and then recedes with large and constant speed. The final state of the condensate depends on the rapidity of the expansion of the box. If the number of atoms in the condensate is small compared to the dimensionless speed of the wall, then the condensate becomes a mixture of excitations and follows the expansion of the box, leaving empty though an increasingly larger region between the condensate boundary and the wall. If, on the other hand, the number of atoms is large compared to the dimensionless speed of the wall, then the condensate is always in the ground state and spreads uniformly in all of the expanding box, the condensate boundary always coinciding with the receding wall. Approximate analytic expressions are found for the evolving wave function.

We use piecewise linear terms to emulate the polynomial nonlinear terms in a typical reaction-diffusion equation, replacing it thus with a set of simple linear inhomogeneous differential equations. The resulting analytic solution constitutes an excellent approximation to the exact propagating front, as is explicitly shown in the case of cubic and quintic nonlinearities, yielding also the correct value for the physically selected speed of the observable front. Such a piecewise linear emulation can be used for any nonlinearity, giving therefore a very reliable and accurate method for determining the selected speed of fronts invading unstable states, especially pushed fronts.

We emulate the cubic term Psi(3) in the nonlinear Schrödinger equation by a piecewise linear term, thus reducing the problem to a set of uncoupled linear inhomogeneous differential equations. The resulting analytic expressions constitute an excellent approximation to the exact solutions, as is explicitly shown in the case of the kink, the vortex, and a delta function trap. Such a piecewise linear emulation can be used for any differential equation where the only nonlinearity is a Psi(3) one. In particular, it can be used for the nonlinear Schrödinger equation in the presence of harmonic traps, giving analytic Bose-Einstein condensate solutions that reproduce very accurately the numerically calculated ones in one, two, and three dimensions.

We introduce a speed selection mechanism for front propagation in reaction-diffusion systems with multiple fields. This mechanism applies to pulled and pushed fronts alike, and operates by restricting the fields to large finite intervals in the comoving frames of reference. The unique velocity for which the center of a monotonic solution for a particular field is insensitive to the location of the ends of the finite interval is the velocity that is physically selected for that field, making thus the solution approximately translation invariant. The fronts for the various fields may propagate at different speeds, all of them being determined though through this mechanism. We present analytic results for the case of piecewise parabolic potentials, and numerical results for other cases.

We introduce a velocity selection criterion for fronts propagating into unstable and metastable states. We restrict these fronts to large finite intervals in the comoving frame of reference and require that their centers be insensitive to the locations of the ends of the finite intervals, thus exhibiting effectively an approximate translation invariance. Only one monotonic front has this behavior, and its velocity is the one that is physically selected. We present analytic results in the case of piecewise parabolic potentials and numerical results in other cases.

Although the role of prolactin in the initiation and promotion of mammary carcinoma has been proved in animal experiments, a similar effect of hormone in the development of human mammary tumor has not been clearly demonstrated. If hyperprolactinemia is a significant factor in the initiation and promotion of human breast carcinoma, the incidence of mammary carcinoma in patients with hyperprolactinemia, with or without prolactinomas, might be higher than in control populations, but this relationship has never been documented. We present this case to stimulate awareness of the possibility so the condition will be investigated further.