Understanding Sample Generation Strategies for Learning Heuristic Functions in Classical Planning

We study the problem of learning good heuristic functions for classical planning tasks with neural networks based on samples that are states with their cost-to-goal estimates. It is well known that the learned model quality depends on the training data quality. Our main goal is to understand better the influence of sample generation strategies on the performance of a greedy best-first heuristic search guided by a learned heuristic function. In a set of controlled experiments, we find that two main factors determine the quality of the learned heuristic: the regions of the state space included in the samples and the quality of the cost-to-goal estimates. Also, these two factors are interdependent: having perfect estimates of cost-to-goal is insufficient if an unrepresentative part of the state space is included in the sample set. Additionally, we study the effects of restricting samples to only include states that could be evaluated when solving a given task and the effects of adding samples with high-value estimates. Based on our findings, we propose practical strategies to improve the quality of learned heuristics: three strategies that aim to generate more representative states and two strategies that improve the cost-to-goal estimates. Our resulting neural network heuristic has higher coverage than a basic satisficing heuristic. Also, compared to a baseline learned heuristic, our best neural network heuristic almost doubles the mean coverage and can increase it for some domains by more than six times.Comment: 27 page

Normal and five-fingered hand: comparative X-ray morphometry in the post-natal age

Background: Five-fingered hand (5-FH) with completely developed phalanges is a rare phenotype observed so far only in humans and characterised by three phalanges of the 1st ray. A long-lasting, debated question is if the missing element of the normal hand 1st ray is the metacarpal or the phalanx. In this study, comparative X-rays morphometry of long bones in normal and 5-FH is carried out with the aim to face this question through homology analysis of long bone segments in the transverse and longitudinal line of normal hand and 5-FH. Materials and methods: In the normal hand X-rays (n =20) and in a 5-FH X-rays series (n = 9) the relative length of each segment on the ray total length and the index of growth rate (IGR) were assessed. The calculation of the first parameter in normal hand bi-phalangeal thumb was carried out on the 3rd ray total length in the same hand. Results: The parameters of relative length and the proximal/distal growth rate asymmetry in the post-natal period (assessed through the IGR) confirmed in 5-FH the homology of all the five segment on the transverse line. In the normal control hand, the relative length assessment methodology was biased by the missing segment of the thumb, therefore, the reference to the 3rd ray total length in the same hand (instead of the 1st), allowed the homology analysis of the thumb metacarpal and 1st phalanx with the lateral segments (2nd–5th ray) of the same hand. The 5-FH analysis was used to choose the more appropriate reference ray for the normal hand group. Conclusions: The comparative analysis of relative lengths and IGRs in the two groups suggested homology of the (anatomical) 1st metacarpal with the 2nd–5th proximal phalanges in the same hand and that of the (anatomical) 1st proximal phalanx with the 2nd–5th mid phalanges. These data suggest that the missing segment of the normal hand thumb is the metacarpal

Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program)

Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a)

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Sensibilizzazione ai metalli delle protesi ortopediche: uno studio su 50 pazienti

Background: currently, about 5% of operations of prosthesis implantation fail, but only a small part of these failures can be attributed to allergic reactions that result in dermatosis such as eczemas, eritrodermia, urticaria and prurigo. Objective: to understand the relevance of the sensitization to the materials used in orthopedic prostheses and the kind of allergic reactions that they can cause. Materials and Methods: the study group consisted of 50 patients (20 women and 30 men), whose ages ranged from 12 to 76 (the average age was 52.26 and the median 59) and who were attending at hospital specialized in orthopedics. All the patients underwent patch tests for metals and orthopedic metals. Ten of them were tested also for SIDAPA (Italian Society of Allergological, Occupational and Environmental Dermatology) integrated standard series and nine for polylactic acid 10% in vaseline. Thirty patients were patch tested before the orthopedic operation and 20 patients were tested after. Results and discussion: fourteen patients tested positive to one or more substances: nickel (14), potassium dichromate (2), palladium (2), cobalt chloride (1) and tin (1). It is difficult to determine if the patients who tested positive after the operation were also positive before, or if they became positive after contact with the metals in the prosthesis. Their case histories did not indicate if they underwent patch-tests for these substances prior to their operations. Moreover, we can not predict if a patient who had a negative patch-test before the operation can develop sensitivity to some metals after the implantation of a prosthesis. Allergy to metals is rather frequent in the general population, and for this reason a patient who must receive a prosthesis can be sensitive before the intervention or they can develop an allergy over time. As a matter of fact the implanted alloy can cause sensitization in a time window ranging from a few days to some years. More and more patients should undergo these tests before being operated for the implantation of a prosthesis and not only when potential sensitization to metals is suspected or when dermatological or orthopedic complications occur

Sharing historical geodata through a WebGIS. A Web application for History researchers

GIS have become a very powerful instrument supporting a wide range of applications based on geo-referenced data, i.e. data which are connected with specific positions on the Earth surface. However, in Italy GIS have not yet been widely exploited in the field of Humanistic disciplines, although there are to-date many examples of applications in other Countries. Following the GIS technology, WebGIS applications are very useful means of sharing data through the Web. In the course of a project aiming at the development of specific GIS tools supporting the digital archiving and analysis of historical Medieval data (Southern Italy, XIII-XV century) a WebGIS has been designed and implemented in order that History researchers can share and query data via the Internet. All software components are FOSS. The system is hosted on a server at Politecnico di Milano and is undergoing assessment tests