491 research outputs found

    Empirical analysis of PGA-MAP-Elites for neuroevolution in uncertain domains

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    Quality-Diversity algorithms, among which MAP-Elites, have emerged as powerful alternatives to performance-only optimisation approaches as they enable generating collections of diverse and high-performing solutions to an optimisation problem. However, they are often limited to low-dimensional search spaces and deterministic environments. The recently introduced Policy Gradient Assisted MAP-Elites (PGA-MAP-Elites) algorithm overcomes this limitation by pairing the traditional Genetic operator of MAP-Elites with a gradient-based operator inspired by Deep Reinforcement Learning. This new operator guides mutations toward high-performing solutions using policy-gradients. In this work, we propose an in-depth study of PGA-MAP-Elites. We demonstrate the benefits of policy-gradients on the performance of the algorithm and the reproducibility of the generated solutions when considering uncertain domains. We first prove that PGA-MAP-Elites is highly performant in both deterministic and uncertain high-dimensional environments, decorrelating the two challenges it tackles. Secondly, we show that in addition to outperforming all the considered baselines, the collections of solutions generated by PGA-MAP-Elites are highly reproducible in uncertain environments, approaching the reproducibility of solutions found by Quality-Diversity approaches built specifically for uncertain applications. Finally, we propose an ablation and in-depth analysis of the dynamic of the policy-gradients-based variation. We demonstrate that the policy-gradient variation operator is determinant to guarantee the performance of PGA-MAP-Elites but is only essential during the early stage of the process, where it finds high-performing regions of the search space

    Considérations sur le poids et l'âge des zébus de boucherie du Soudan et de la Haute-Volta (A.O.F.)

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    Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies

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    Sickle cell disease (SCD) is due to a mutation in the O-globin gene causing production of the toxic sickle hemoglobin (HbS; ex2OS2). Transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vectors (LVs) expressing an anti-sickling O-globin (OAS) is a promising treatment; however, it is only partially effective, and patients still present elevated HbS levels. Here, we developed a bifunctional LV expressing OAS3-globin and an artificial microRNA (amiRNA) specifically downregulating OS-globin expression with the aim of reducing HbS levels and favoring OAS3 incorporation into Hb tetramers. Efficient transduction of SCD HSPCs by the bifunctional LV led to a substantial decrease of OS-globin transcripts in HSPC-derived erythroid cells, a significant reduction of HbS+ red cells, and effective correction of the sickling phenotype, outperforming OAS gene addition and BCL11A gene silencing strategies. The bifunctional LV showed a standard integration profile, and neither HSPC viability, engraftment, and multilineage differentiation nor the erythroid transcriptome and miRNAome were affected by the treatment, confirming the safety of this therapeutic strategy. In conclusion, the combination of gene addition and gene silencing strategies can improve the efficacy of current LV-based therapeutic approaches without increasing the mutagenic vector load, thus representing a novel treatment for SCD

    Selecting short-statured children needing growth hormone testing: Derivation and validation of a clinical decision rule

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    <p>Abstract</p> <p>Background</p> <p>Numerous short-statured children are evaluated for growth hormone (GH) deficiency (GHD). In most patients, GH provocative tests are normal and are thus in retrospect unnecessary.</p> <p>Methods</p> <p>A retrospective cohort study was conducted to identify predictors of growth hormone (GH) deficiency (GHD) in children seen for short stature, and to construct a very sensitive and fairly specific predictive tool to avoid unnecessary GH provocative tests. GHD was defined by the presence of 2 GH concentration peaks < 10 ng/ml. Certain GHD was defined as GHD and viewing pituitary stalk interruption syndrome on magnetic resonance imaging. Independent predictors were identified with uni- and multi-variate analyses and then combined in a decision rule that was validated in another population.</p> <p>Results</p> <p>The initial study included 167 patients, 36 (22%) of whom had GHD, including 5 (3%) with certain GHD. Independent predictors of GHD were: growth rate < -1 DS (adjusted odds ratio: 3.2; 95% confidence interval [1.3–7.9]), IGF-I concentration < -2 DS (2.8 [1.1–7.3]) and BMI z-score ≥ 0 (2.8 [1.2–6.5]). A clinical decision rule suggesting that patients be tested only if they had a growth rate < -1 DS and a IGF-I concentration < -2 DS achieved 100% sensitivity [48–100] for certain GHD and 63% [47–79] for GHD, and a specificity of 68% [60–76]. Applying this rule to the validation population (n = 40, including 13 patients with certain GHD), the sensitivity for certain GHD was 92% [76–100] and the specificity 70% [53–88].</p> <p>Conclusion</p> <p>We have derived and performed an internal validation of a highly sensitive decision rule that could safely help to avoid more than 2/3 of the unnecessary GH tests. External validation of this rule is needed before any application.</p

    POS0724 GENDER DIFFERENCES IN THROMBOTIC PRIMARY ANTIPHOSPHOLIPID SYNDROME IN A LARGE COHORT OF PATIENTS FROM FOUR EUROPEAN CENTERS

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    Background:Autoimmune diseases occur more frequently in females and their course and severity can be affected by gender. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which antiphospholipid antibodies (aPL) exert a pathogenic role resulting in vascular thrombosis and/or pregnancy morbidities. Data about gender differences in thrombotic APS (t-APS) are still scarce1,2.Objectives:To evaluate the differences in frequency, disease expression and severity between females and males affected by primary t-APS.Methods:Retrospective study enrolling subjects with a formal diagnosis of primary APS (Miyakis 2006) with vascular thrombosis at onset. Women who presented with obstetric events as first aPL-related manifestation were excluded. All the patients were followed from 1967 to 2019 in four European centers: three French centers and one Italian center.Results:The study included 433 patients (68% females, 32% males). Median age at t-APS onset [31 (24-46) vs 41 (29-53) years, p<0.001] and at diagnosis [34 (27-50) vs 46 (34-57) years, p<0.001] was significantly lower in females.The most common presenting manifestations were venous thrombosis (60%) followed by arterial events (37%) and catastrophic APS (3%). Venous events were more frequent in women as compared to men (64% vs 51% p:0.012 OR:1.7 [1.1-2.5]). Sites of venous thrombosis included: limbs (35%), pulmonary (17%), cerebral (3%), portal and inferior cava (2%) and retinal (1%) veins, without gender differences. The arterial events were more frequent among men (43% vs 34% p:0.053). Strokes (27%) and myocardial infarctions (4%) were the most frequent manifestations, followed by thrombosis of limbs (2%), retina (2%) and abdominal organs (1%). Noteworthy, only men presented with visceral ischemia.During the follow-up, new thrombosis occurred in 41% of patients (179/433). 33% out of them had at least two episodes and these occurred especially among males (22% vs 10% p:0.001 OR:2.5 [1.3-4.8]). New events were mostly of the same type, but â…“ of patients presented a switch from venous to arterial side and viceversa, with no gender differences.Complete aPL profile was available in 357 subjects: 33% had single aPL positivity, 24% double positivity and 43% triple positivity, with no differences between women and men. About 80% of the patients had a concomitant risk factor (RF) for thrombosis. Established cardiovascular RFs were more represented among men as shown in table 1. In women, estrogenic exposure was the main RFs, present in almost 40% of them.Table 1.MALESn= 137FEMALESn= 296POR [IC 95%]Traditional cardiovascular RFs, n (%)Smoke66 (48)81 (27)<0.0012.5 [1.6-3.8]Arterial hypertension59 (43)75 (25)<0.0012.2 [1.5-3.4]Dyslipidemia52 (38)72 (24)0.0041.9 [1.2-2.9]Diabetes16 (12)15 (5)0.0142.5 [1.8-5.1]Obesity13 (10)38 (13)nsOther thrombophilic factors, n (%)Estrogenic stimuli*0116 (39)-Trauma / surgery / immobilization21 (15)32 (11)nsCongenital thrombophilia9/94 (10)33/204 (16)nsData were compared using contingency tables, p value was calculated with Chi-Squared or Fisher exact test. *= hormonal therapy, pregnancy, post-partumConclusion:This gender-oriented analysis of patients with primary t-APS showed that women had the first vascular event at a younger age and mostly on the venous side, while men presented mainly with arterial events, later in life and suffered from more recurrent events. No differences were observed in the distribution of the aPL profile. The different frequency of arterial and venous events in the two groups could be attributed mainly to the presence of additional RFs rather than to biological gender-specific issues. However, it should be underlined that some RFs, such as the use of estrogens or classic cardiovascular RFs, are exclusive or more represented in one gender rather than the other, making it difficult to assess the link of causality between gender and manifestations of t-APS.References:[1]JF de Carvalho. Rheumatol Int. 2011.[2]LJ Jara. Lupus. 2005.Disclosure of Interests:None declare

    Relapsing polychondritis: state of the art on clinical practice guidelines

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    Due to the rarity of relapsing polychondritis (RP), many unmet needs remain in the management of RP. Here, we present a systematic review of clinical practice guidelines (CPGs) published for RP, as well as a list of the most striking unmet needs for this rare disease. We carried out a systematic search in PubMed and Embase based on controlled terms (medical subject headings and Emtree) and keywords of the disease and publication type (CPGs). The systematic literature review identified 20 citations, among which no CPGs could be identified. We identified 11 main areas with unmet needs in the field of RP: the diagnosis strategy for RP; the therapeutic management of RP; the management of pregnancy in RP; the management of the disease in specific age groups (for instance in paediatric-onset RP); the evaluation of adherence to treatment; the follow-up of patients with RP, including the frequency of screening for the potential complications and the optimal imaging tools for each involved region; perioperative and anaesthetic management (due to tracheal involvement); risk of neoplasms in RP, including haematological malignancies; the prevention and management of infections; tools for assessment of disease activity and damage; and patient-reported outcomes and quality of life indicators. Patients and physicians should work together within the frame of the ReCONNET network to derive valuable evidence for obtaining literature-informed CPGs
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