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

Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control

Background: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non–high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin. Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses. Results: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%–52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63–0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57–0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non–high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions. Conclusions: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513

Functional Characterization of Two Mutations Located in the Ligand Binding Domain in the SF1

Purpose: Since SF1 gene mutations located in the ligand binding domain are associated with a wide phenotypic spectrum in 46,XY subjects, the functional and structural characterization of these variations is of great interest. The aim of this study is to evaluate the clinical phenotype, hormonal pattern and molecular studies (genetic, functional data and protein structural analysis) in two non-related 46,XY disorder of sex development (DSD) index patients. Methods: Clinical characteristics, genomic DNA sequencing analysis, protein prediction software study and protein structure analysis, and functional characterization of the mutations was carried out. Results: Both index DSD patients showed a similar phenotype, however several affected members of Family 1 showed variable phenotypes. While in Family 1 a previously reported heterozygous missense point mutation (p.Arg313His) was found, in Family 2 a novel heterozygous missense point mutation (p.Ser303Arg) was detected. Both mutations were predicted to be as “probably damaging”. The transcriptional activity of SF1 mutants p.Arg313His and p.Ser303Arg, studied using two different promoters in two cell lines, exhibited significant reductions of transactivation activity. Structural analysis showed differences between both mutants, such as changes in the flexibility of the receptor backbone and in the tertiary structure around the ligand and in the AF-2 domain. Conclusions: One of these ligand binding domain mutations in SF1 showed phenotypic heterogeneity among family members, while both variations showed similarities in prepubertal phenotype, as well as in damage prediction and experimental decreases in transcriptional activity, but marked differences in structural consequence predictions. Finally the present study reinforces the concept of the wide variability in the clinical phenotype in affected 46,XY DSD patients.Fil: Perez Garrido, Natalia Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marino, R.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ramirez, P.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ciaccio, Marta Graciela Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Costanzo, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Guercio, Gabriela Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Warman, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Minini, L.. Universidad de la República. Facultad de Ciencias; UruguayFil: Portillo Ledesma, S.. Universidad de la República. Facultad de Ciencias; UruguayFil: Rivarola, Marco Aurelio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Coitiño, E. L.. Universidad de la República. Facultad de Ciencias; UruguayFil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

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

An escalation for bivariate binary endpoints controlling the risk of overtoxicity (EBE-CRO ): managing efficacy and toxicity in early oncologyvClinical trials

For about a decade, early clinical development in oncology is facing new challenges. This is due to two main reasons. The first one is linked to the developed molecular targeted agents (MTA) themselves for which the maximum tolerated dose (MTD) is no longer the only dose of interest. The second reason is related to the fact that costs and attrition rates are huge. When selecting a dose, evidence of early activity signal becomes required for future engagements. This implies the need to handle both toxicity and activity endpoints in the analysis and also in the dose escalation design of early-phase trials. We propose a model-based design taking into account both safety and activity for dose escalation. The proposed model involves a bivariate Gaussian latent variable depending on a monotonic toxicity curve and a quadratic activity curve. This model is fitted under the Bayesian framework that allows the incorporation of prior information. The predictive distributions of dose-response curves are used to lead the dose recommendation. Uncertainty in the dose-response relationship is taken into account to calculate the probability of being an over-toxic or a target dose. The proposed design is compared to two other widely used methods

Studio del comportamento sperimentale del modello in scala 1:20 della facciata del palazzo della loggia nell’ipotesi di cedimento differenziale di un pilastro

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