Enhancing Safety: the Challenge of Foresight - ESReDA Project Group Foresight in Safety

This Deliverable is the result of a joint effort by experts, working in the fields of risks management, accident analysis, learning from experience and safety management. They come from 10 countries mainly from Europe and also from USA and Australia. Their expertise covers several industrial sectors. They attempted to provide useful information, both from a theoretical and a practical point of views, about "Foresight in Safety". Safety is still an ongoing issue for which a number of subjects remain under debate (e.g. is goal of safety to ensure that 'as few things as possible go wrong' or to ensure that ‘as many things as possible go right’?). Anyway, we can assume that safety is to act in a way for both the process continues to be run right and that errors and failures to not lead to a major accident. Even if "foresight in safety" is the implicit underlying goal of every practitioner in safety, the outlines of its domain remain blurred and the relevant topics associated with it have never been clearly defined. A humble ambition of this Deliverable is to display some aspects of "foresight in safety" according to the current state of practices and scientific knowledge.JRC.G.10-Knowledge for Nuclear Security and Safet

High-Density 4T SRAM Bitcell in 14-nm 3-D CoolCube Technology Exploiting Assist Techniques

International audienceIn this paper, we present a high-density four-transistor (4T) static random access memory (SRAM) bitcell design for 3-D CoolCube technology platform based on 14-nm fully depleted-silicon on insulator MOS transistors to show the compatibility between the 4T SRAM and the 3-D design and the considerable density gain that they can achieve when combined. The 4T SRAM bitcell has been characterized to investigate the critical operations in terms of stability (retention and read) taking into account the post-layout parasitic elements. Thus, failure mechanisms are exposed and explained. Based on this paper, a data-dependent dynamic back-biasing scheme improving the bitcell stability is developed. A specific read-assist circuit is also proposed in order to enable a large number of bitcells per column in a memory array. Finally, the designed bitcell offers up to 30% area gain compared to a planar six-transistor SRAM bitcell in the same technology node

Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort

International audienceBackground: Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied.Objective: To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP).Methods: Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed.Results: Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type.Limitations: No record of standard diagnostic criteria of MUP used in the participating centers.Conclusions: Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case–control study

International audienceObjective To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma. Methods Case–control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression. Results 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs. Conclusion In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy

Association of Time From Primary Diagnosis to First Distant Relapse of Metastatic Melanoma With Progression of Disease and Survival

International audienceThe prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable.Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma.Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017.Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (24 months).Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment.Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival

The Permian–Triassic transition and the onset of Mesozoic sedimentation at the northwestern peri-Tethyan domain scale: Palaeogeographic maps and geodynamic implications

The main aim of this paper is to review Middle Permian through Middle Triassic continental successions in European. Secondly, areas of Middle–Late Permian sedimentation, the Permian–Triassic Boundary (PTB) and the onset of Triassic sedimentation at the scale of the westernmost peri-Tethyan domain are defined in order to construct palaeogeographic maps of the area and to discuss the impact of tectonics, climate and sediment supply on the preservation of continental sediment. At the scale of the western European peri-Tethyan basins, the Upper Permian is characterised by a general progradational pattern from playa-lake or floodplain to fluvial environments. In the northern Variscan Belt domain, areas of sedimentation were either isolated or connected to the large basin, which was occupied by the Zechstein Sea. In the southern Variscan Belt, during the Late Permian, either isolated endoreic basins occurred, with palaeocurrent directions indicating local sources, or basins underwent erosion and/or there was no deposition. These basins were not connected with the Tethys Ocean, which could be explained by a high border formed by Corsica–Sardinia palaeorelief and even parts of the Kabilia microplate. The palaeoflora and sedimentary environments suggest warm and semi-arid climatic conditions. At the scale of the whole study area, an unconformity (more or less angular) is observed almost everywhere between deposits of the Upper Permian and Triassic, except in the central part of the Germanic Basin. The sedimentation gap is more developed in the southern area where, in some basins,Upper Permian sediment does not occur. The large sedimentary supply, erosion and/or lack of deposition during the Late Permian, as well as the variable palaeocurrent direction pattern between theMiddle–Late Permian and the Early Triassic indicate a period of relief rejuvenation during the Late Permian. During the Induan, all the intra-belt basins were under erosion and sediment was only preserved in the extra-belt domains (the northern and extreme southern domains). In the northern domain (the central part of the Germanic Basin), sediment was preserved under the same climatic conditions as during the latest Permian, whereas in the extreme southern domain, it was probably preserved in the Tethys Ocean, implying a large amount of detrital components entering themarinewaters. Mesozoic sedimentation began in the early Olenekian; the ephemeral fluvial systems indicate arid climatic conditions during this period. Three distinct areas of sedimentation occur: a northern and southern domain, separated by an intra-belt domain. The latter accumulated sediments during the Early–Middle Permian and experienced erosion and/or no-deposition conditions between the Middle–Late Permian and the beginning of Mesozoic sedimentation, dated as Anisian to Hettangian. At the top of the Lower Triassic, another tectonically induced, more or less angular unconformity is observed: the Hardegsen unconformity, which is dated as intra-Spathian and is especially found in the North European basins. This tectonic activity created new source areas and a new fluvial style, with marine influences at the distal part of the systems. During the Anisian and Ladinian, continental sedimentation was characterised by a retrogradational trend. In other words, the fluvial system evolved into fluvio-marine environments, attesting to a direct influence of the Tethys Ocean in the southern and northern domains. Both at the end of the Olenekian (Spathian) and during the Anisian, the presence of palaeosols, micro- andmacrofloras indicate less arid conditions throughout this domai