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

Chronic exertional compartment syndrome of the forearm: a systematic review

The aim of this systematic review is to understand which surgical procedure provides better results in terms of pain relief and function in the treatment of chronic exertional compartment syndrome (CECS) of the forearm. We searched Medline (PubMed), Web of Science, Embase and Scopus databases on 8 July 2020. Twelve studies were included in this review. We assessed the quality of the studies using the Coleman Methodological Score. Data on demographic features, operative readings, diagnostic methods, follow-up periods, type and rates of complications, survivorship of the procedure, return to sport activity, and outcome measures were recorded. In conclusion, compared to the other techniques, endoscopic fasciotomy delivers similar success rates and lower incidence of complications

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

Venglustat, a novel glucosylceramide synthase inhibitor, in patients at risk of rapidly progressing ADPKD: primary results of a double-blind, placebo-controlled, phase 2/3 randomized clinical trial

RATIONALE AND OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STUDY DESIGN: STAGED-PKD was a two-stage, multicenter, double-blind, randomized, placebo-controlled Phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, selected based on Mayo Kidney Volume Class 1C-1E and an estimated glomerular filtration rate (eGFR) of 30-89.9 mL/min/1.73 m2. SETTING AND PARTICIPANTS: Enrollment included 236 and 242 patients in Stages 1 and 2, respectively. INTERVENTION(S): In Stage 1, patients were randomized 1:1:1 to venglustat 8 mg or 15 mg, or placebo. In Stage 2, patients were randomized 1:1 to venglustat 15 mg (highest dose identified as safe and well tolerated in Stage 1) or placebo. OUTCOMES: Primary endpoints were rate of change in TKV over 18 months in Stage 1 and eGFR slope over 24 months in Stage 2. Secondary endpoints were eGFR slope over 18 months (Stage 1), rate of change in TKV (Stage 2), and safety/tolerability, pain, and fatigue (Stages 1 and 2). RESULTS: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (Stage 1) and had a faster rate of decline in eGFR slope over 24 months (Stage 2). Due to this lack of efficacy, the study was terminated early. LIMITATIONS: The short follow-up after end-of-treatment and limited generalizability of findings. CONCLUSIONS: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8 mg or 15 mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in the STAGED-PKD trial despite a dose-dependent decrease in plasma glucosylceramide (GL-1) levels

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

Redifferentiation therapeutic strategies in cancer

The widely recognized problems of pharmacological strategies based on killing cancer cells demand a rethink of therapeutic approaches. Tumor reversion strategies that aim to shift cancer cells to a healthy differentiated state are a promising alternative. Although many studies have firmly demonstrated the possibility of reverting cancer to a normal differentiated state, we are still unable (with the exception of retinoic acid in a form of leukemia) to revert cancer cells to a stable differentiated healthy state. Here, we review the main biological bases of redifferentiation strategies and provide a description of the most promising research avenues

Acute scapholunate dissociation diagnosis and treatment

Scapholunate interosseous ligament (SLIL) is the most frequent injured carpal ligament among all the intrinsic wrist ones. The scapholunate (SL) joint kinetics appear to be handled by a more sophisticated complex of intrinsic and extrinsic ligaments: cadaveric studies investigated the role of the long radiolunate (LRL), short radiolunate (SRL), radioscaphoid (RS), and dorsal intercarpal ligament (DIC) in SL joint stability. The most common traumatic mechanism leading to SL lesions is the FOOSH (fall on outstretched hand), with the wrist in extension, ulnar deviation and carpal supination. Defining the clinical stage and the time elapsed since the injury is of utmost importance in planning an effective treatment: an injury is considered as “acute” when time lapse from the trauma to the presentation lies within 6 weeks. This paper will focus on the acute/subacute setting. Acute SL lesions can frequently be misdiagnosed as minor wrist sprains; since early recognition and prompt treatment can lead to better outcomes, a delay in the correct diagnosis is detrimental for clinical results. Furthermore, interrupting the natural progression from SLIL injury to SLAC is of utmost importance. Partial lesions can be treated conservatively with immobilization and proprioceptive reeducation, percutaneous K-wires pinning of SL and SC joints and thermal shrinkage. Complete lesions should be treated operatively; open repair with suture anchors and capsulodesis show good results, even if arthroscopic techniques are now gaining popularity, although further studies with long-term follow-up are needed to evaluate the durability of those procedures