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The difficulty of correlating continental deposits hinders predicting lacustrine and palustrine carbonate facies variations in time and space. This study aims to understand better the factors governing these facies heterogeneities by measuring carbonate isotopes and conducting facies, petrographic and sequence stratigraphic analyses of the Lutetian–Aquitanian deposits of the Paris Basin, that record the transition from marine to lacustrine environments. Large‐scale correlations enabled the definition of two lacustrine–palustrine carbonate facies models. (1) The coastal lacustrine system (Bartonian to Rupelian), consists of fine‐grained brackish carbonate exhibiting episodic marine inputs during short‐term relative sea‐level maxima and evaporite sedimentation during relative sea‐level minima. Lacustrine sediments differ notably from marine ones with more negative δ13C and δ18O compositions that co‐vary and a biota adapted to low salinity conditions. In the associated palustrine environment, depositional sequences evolve upwards from micritic lacustrine deposits to nodular and then laminar calcretes. Microbial‐coated grains and rhizoliths indicate biological processes during repeated subaerial exposure phases in sub‐tropical to arid climates. (2) The inland lacustrine system (Rupelian and Aquitanian) was disconnected from the marine domain and showed evidence of microbial activity with microbial crusts and oncoidal rudstones. Facies rich in micritic intraclasts composed of palustrine and lacustrine facies indicate the reworking of already lithified sediments along the margins. In the palustrine domain, the calcrete facies are less abundant than breccias formed in‐situ by desiccation, limestones with root traces, or organic‐rich wackestones and marls. This system reflects a more temperate climate with more developed microbial structures and less exposed carbonates than the coastal lacustrine system. The southward migration of the depocentre and the transition from marine environments to (1) coastal and then (2) inland systems are controlled by uplift phases induced by Pyrenean and Alpine orogenesis. Third‐order relative sea‐level variations appear to control only short‐term cycles in coastal systems. In this work focussing on the Cenozoic continental carbonates of the Paris Basin, new information is brought to light on the spatialisation of continental carbonates facies thanks to correlations between coastal and palustrine environments. It presents arguments for distinguishing between marine (lagoon‐type) and continental (lake‐type) deposits based on facies, microfacies, large‐scale correlation, palaeontology and isotope data. By providing two new facies models for lacustrine and palustrine carbonates, this manuscript illustrates the coupled impact of tectonics, climate and episodic connections to the marine domain on facies distribution and type.

The Cenomanian to early Santonian interval is usually considered a time of postrifting tectonic quiescence around the northern margins of Iberia that preceded the onset of the Pyrenean convergence by crustal thrusting in the latest Santonian. However, plate kinematic models of the Mesozoic evolution of Iberia poorly constrain the Turonian-Santonian position of Iberia relative to Eurasia. This study reconstructs changes in the sedimentary facies and architecture of the Iberian carbonate platform throughout the Late Cretaceous and sheds new light on the geodynamic evolution of the Iberia-Eurasia relationship at that time. Sixteen outcrop sections were described and 24 sedimentary facies identified that define 5 depositional environments ranging from the deep marine basin to the continental setting. From these and previously published field data we reconstruct the evolution of the Pyrenean carbonate platform, on an east-west transect nearly 400 km long, on the basis of 11 short-term depositional sequences and 5 long-term hemicycles. In our interpretation, the Cenomanian and Turonian correspond to a postrift stage during which the European and Iberian margins, together with the deep basin between them, subside gently, as shown by accommodation rates varying from ∼15 to 30 m/My in the margins and ∼100 to 150 m/My in the basin. The Coniacian and early Santonian are characterized by a large-scale flexural response consisting of (1) uplift of the southern Iberian margin, with negative accommodation rates, karstified surfaces and paleosols, and (2) increasing subsidence rates in the basin and its edges (the northern Iberian margin and eastern Aquitaine platform), with accommodation rates several times greater than during the Turonian. We propose that far-field stress possibly related to the northeastward motion of Africa, and/or onset of shortening at the Iberia-Europe boundary in the central and eastern Pyrenees led to the incipient large-scale flexural deformation in the Pyrenean domain. The late Santonian and Campanian are an early orogenic stage marked by rapid subsidence throughout the Pyrenean domain, except at its western end. We evidence for the first time a pre-orogenic flexure at the Iberia-Europe plate boundary induced by regional plate reorganisation between Africa and Europe during the Coniacian and the early Santonian. L’intervalle Cénomanien à Santonien inférieur est considéré autour de la marge nord-ibérique comme une quiescence tectonique post-rift qui précède le début de la convergence pyrénéenne au Santonien terminal, mis en évidence par le début de l’épaississement crustal. Cependant, les modèles de cinématique des plaques montrent de sérieuses incertitudes sur la reconstitution de la position de l’Ibérie par rapport à l’Eurasie du Turonien au Santonien. Cette étude reconstruit les changements de faciès et d’architecture sédimentaires de la plateforme carbonatée ibérique au cours du Crétacé supérieur et jette un nouvel éclairage sur l’évolution géodynamique à la limite Ibérie-Eurasie à cette époque. Seize coupes sédimentaires d’affleurements ont été étudiées. Les 24 faciès sédimentaires identifiés se répartissent en 5 environnements de dépôt depuis le basin marin profond jusqu’au continent. À partir de ces nouvelles données et de données de terrain précédemment publiées, nous avons reconstruit l’évolution de la plateforme pyrénéenne le long d’une coupe SO-NE longue d’environ 400 km, sur la base de onze cycles de dépôt de court terme et cinq demi-cycles de long terme. D’après notre interprétation, l’intervalle Cénomanien à Turonien correspond à un stade postrift durant lequel les marges européenne et ibérique ainsi que le bassin entre elles subsident lentement, comme le montrent les taux d’accommodation variant entre 15 et 30 m/Ma pour les marges et 100 à 150 m/Ma pour le bassin. Le Coniacien enregistre une flexuration à grande échelle caractérisée par (1) un soulèvement de la marge ibérique sud, avec des taux d’accommodation négatifs, des surfaces karstifiées et des paléosols (∼20 m/Ma) et (2) une forte subsidence du bassin et de ses bordures (plateformes nord ibérique et sud européenne), avec des taux d’accommodation plusieurs fois supérieurs à ceux du Turonien. Nous proposons qu’une contrainte compressive « far-field » possiblement due au déplacement vers le Nord-Est de l’Afrique, et/ou le début de la convergence entre l’Ibérie et l’Europe dans la partie centrale et orientale des Pyrénées a entraîné cette déformation flexurale subtile à grande échelle du domaine pyrénéen et ouest-ibérique au cours du Coniacien. Le Santonien supérieur et le Campanien correspondent au stade orogénique précoce, marqué par une forte subsidence à l’échelle du domaine pyrénéen, excepté dans sa partie ouest. Nous mettons en évidence pour la première fois une flexure pré-orogénique à la limite Ibérie-Europe, induite par la réorganisation régionale des plaques entre l’Afrique et l’Europe au cours du Coniacien et du début du Santonien.

The Mauléon Basin, in the northwestern Pyrenean Belt, is related to Early Cretaceous rifting and mantle denudation. Here we review the evolution of depositional systems in the Mauléon Rift Basin during Albian and Cenomanian time. This review includes the lithostratigraphy, regional distribution, boundaries, age and facies sedimentology of the basin’s syn-rift formations and their members. We construct paleogeographic maps to elucidate (1) the 3D distribution of sedimentary facies and depositional systems during the Albian and Cenomanian from the Iberian proximal margin to the hyperextended domain and (2) the link between major extensional structures and sedimentation during rifting and mantle denudation. The Mauléon Rift was supplied during most of the Albian by sediments from the Iberian proximal margin. The southern margin had a steep and abrupt topographic boundary related to a northward crustal rollover along the south-dipping Saint-Palais detachment. This feature controlled the deposition of coarse-grained turbidites at the base of the margin that abruptly gave way to low-density turbidites, then deep-basin deposits in the hyperextended domain. During uppermost Albian to Early Cenomanian time, mantle denudation occurred in the eastern Mauléon Basin and the vergence of the detachment systems reversed. Minor debris-flow deposits formed at the foot of fault scarps associated with the newly formed north-dipping detachments. Elsewhere, sediment from deltaic systems to the west in the Saint-Jean-de-Luz area deposited low-density turbidites in the hyperextended domain. During the post-rift stage, the flux of coarse sediment from the detachment footwall gradually declined as deformation waned, and low-density turbidites expanded onto the hyperextended domain from the European Upper Cretaceous carbonate platform. These paleogeographic reconstructions, in addition to offering a synthetic view of the evolution of sedimentary environments during rifting, offer new insight into the post-rifting exhumation of the lower crust and mantle. Le bassin de Mauléon, localisé dans les Pyrénées nord-occidentales, subit une phase de rifting aboutissant à la dénudation du manteau au cours du Crétacé inférieur. Dans ce travail, nous synthétisons l’évolution des systèmes de dépôts Albien à Cénomanien du bassin de Mauléon. Cette synthèse inclut les lithologies, la répartition régionale, les limites stratigraphiques, les âges et les faciès des différentes formations et membres syn-rifts du bassin de Mauléon. Ces derniers ont été temporellement et spatialement corrélés afin de reconstruire des cartes paléogéographiques offrant une meilleure compréhension: (1) de la distribution 3D des faciès sédimentaires et des systèmes de dépôts de l’Albien au Cénomanien entre la marge proximale ibérique et le domaine hyper-aminci du bassin de Mauléon et (2) du lien entre les principales structures extensives et la sédimentation au cours du rifting et de la dénudation du manteau. De l’Albien inférieur à supérieur, le bassin de Mauléon était essentiellement alimenté depuis la marge proximale ibérique. La forte pente topographique de cette marge, est due à un basculement vers le nord provoqué par le détachement à vergence sud de Saint-Palais. Cette géométrie a favorisé des dépôts de conglomérats de bassin profond au pied de la marge ibérique passant de manière brutale à des faciès hémipélagiques du domaine hyper-aminci. De l’Albien terminal au Cénomanien inférieur, la vergence des systèmes de détachements s’inverse. Cette étape finale de structuration du bassin conduit à la dénudation du manteau dans la partie orientale du bassin. Des debris flows mineurs, issus de l’érosion sous-marine du mur des détachements à vergence nord, sédimentent au pied des escarpements de failles. À la même époque, les turbidites de faible densité, se déposent dans le domaine hyper-aminci, alimentées par un système deltaïque de polarité Ouest-Est provenant du domaine occidental de Saint-Jean-de-Luz. Au cours du stade postrift, les flux sédimentaires grossiers provenant des escarpements des détachements diminuent corrélativement avec la diminution du jeu tectonique sur ces accidents tandis que les turbidites de faible densité se déposent dans le domaine hyper-aminci proviennent de la plateforme carbonatée européenne. En plus d’offrir une vision synthétique de l’évolution des milieux sédimentaires lors du rifting, ces reconstructions paléogéographiques apportent de nouvelles réflexions quant à l’évaluation de l’exhumation de la croûte inférieure et du manteau.

Interventions that have even quite modest effects at the individual level could drastically reduce the future burden of dementia associated with Alzheimer's disease at the population level. In the past three decades, both pharmacological and lifestyle interventions have been studied for the prevention of cognitive decline or dementia in randomised controlled trials of individuals mostly aged older than 50–55 years with or without risk factors for Alzheimer's disease. Several trials testing the effects of physical activity, cognitive training, or antihypertensive interventions showed some evidence of efficacy on a primary cognitive endpoint. However, most of these trials had short follow-up periods, and further evidence is needed to confirm effectiveness and establish the optimum design or dose of interventions and ideal target populations. Important innovations in ongoing trials include the development of multidomain interventions, and the use of biomarker or genetic inclusion criteria. Challenges include the use of adaptive trial designs, the development of standardised, sensitive outcome measures, and the need for interventions that can be implemented in resource-poor settings.

In patients with chronic coronary syndrome taking oral anticoagulants, adding aspirin led to higher risks of cardiovascular events, major bleeding, and death from any cause than anticoagulation alone.

The increased use of reperfusion therapy in ST-segment-elevation myocardial infarction (STEMI) patients in the past decades is generally considered the main determinant of improved outcomes. The aim was to assess 20-year trends in profile, management, and one-year outcomes in STEMI patients in relation with use or non-use of reperfusion therapy (primary percutaneous coronary intervention (pPCI) or fibrinolysis). We used data from 5 one-month French nationwide registries, conducted 5 years apart from 2005 to 2015, including 8579 STEMI patients (67% with and 33% without reperfusion therapy) admitted to cardiac intensive care units in France. Use of reperfusion therapy increased from 49% in 1995 to 82% in 2015, with a shift from fibrinolysis (37.5% to 6%) to pPCI (12% to 76%). Early use of evidence-based medications gradually increased over the period in both patients with and without reperfusion therapy, although it remained lower at all times in those without reperfusion therapy. One-year mortality decreased in patients with reperfusion therapy (from 11.9% in 1995 to 5.9% in 2010 and 2015, hazard ratio [HR] adjusted on baseline profile 0.40; 95% CI: 0.29-0.54, P < .001) and in those without reperfusion therapy (from 25.0% to 18.2% in 2010 and 8.1% in 2015, HR: 0.33; 95% CI: 0.24-0.47, P < .001). In STEMI patients, one-year mortality continues to decline, both related to increased use of reperfusion therapy and progress in overall patient management. In patients with reperfusion therapy, mortality has remained stable since 2010, while it has continued to decline in patients without reperfusion therapy.

Worm expulsion studies required to quantify worm burden have suboptimal accuracy, are laborious, and are rarely done. [...]STH programs employ indirect methods to infer worm burden, such as microscopy-based technologies for visual identification and quantification of STH-specific eggs from a stool sample. Other considerations include external quality assurance requirements and regulatory pathway as well as program recommendations, policies, and guidelines. Because diagnostics only approximate a true state of infection, mathematical models can be used to further inform performance requirements by estimating the impact of different levels of uncertainty on the accuracy of program decision-making and ultimately on health outcomes [37]. Only the lower LOD needs to be defined for a qualitative test and set below the confidence intervals for a diagnostic cutoff. Since this cutoff cannot yet be defined, key opinion leaders agreed that a test must have superior analytical sensitivity compared to current FEC methods. Because targeted population-level data are required for the program decision, minimum data requirements also include geospatial information.

Climate evolution of the Mediterranean region during the Holocene exhibits strong spatial and temporal variability, which is notoriously difficult for models to reproduce. We propose here a new proxy-based climate synthesis synthesis and its comparison – at a regional (∼ 100 km) level – with a regional climate model to examine (i) opposing northern and southern precipitation regimes and (ii) an east-to-west precipitation dipole during the Holocene across the Mediterranean basin. Using precipitation estimates inferred from marine and terrestrial pollen archives, we focus on the early to mid-Holocene (8000 to 6000 cal yr BP) and the late Holocene (4000 to 2000 cal yr BP), to test these hypotheses on a Mediterranean-wide scale. Special attention was given to the reconstruction of season-specific climate information, notably summer and winter precipitation. The reconstructed climatic trends corroborate the north–south partition of precipitation regimes during the Holocene. During the early Holocene, relatively wet conditions occurred in the south–central and eastern Mediterranean regions, while drier conditions prevailed from 45° N northwards. These patterns then reverse during the late Holocene. With regard to the existence of a west–east precipitation dipole during the Holocene, our results show that the strength of this dipole is strongly linked to the reconstructed seasonal parameter; early-Holocene summers show a clear east–west division, with summer precipitation having been highest in Greece and the eastern Mediterranean and lowest over Italy and the western Mediterranean. Summer precipitation in the east remained above modern values, even during the late-Holocene interval. In contrast, winter precipitation signals are less spatially coherent during the early Holocene but low precipitation is evidenced during the late Holocene. A general drying trend occurred from the early to late Holocene, particularly in the central and eastern Mediterranean. For the same time intervals, pollen-inferred precipitation estimates were compared with model outputs, based on a regional-scale downscaling (HadRM3) of a set of global climate-model simulations (HadAM3). The high-resolution detail achieved through the downscaling is intended to enable a better comparison between site-based paleo-reconstructions and gridded model data in the complex terrain of the Mediterranean; the model outputs and pollen-inferred precipitation estimates show some overall correspondence, though modeled changes are small and at the absolute margins of statistical significance. There are suggestions that the eastern Mediterranean experienced wetter summer conditions than present during the early and late Holocene; the drying trend in winter from the early to the late Holocene also appears to be simulated. The use of this high-resolution regional climate model highlights how the inherently patchy nature of climate signals and paleo-records in the Mediterranean basin may lead to local signals that are much stronger than the large-scale pattern would suggest. Nevertheless, the east-to-west division in summer precipitation seems more marked in the pollen reconstruction than in the model outputs. The footprint of the anomalies (like today, or dry winters and wet summers) has some similarities to modern analogue atmospheric circulation patterns associated with a strong westerly circulation in winter (positive Arctic Oscillation–North Atlantic Oscillation (AO–NAO)) and a weak westerly circulation in summer associated with anticyclonic blocking; however, there also remain important differences between the paleo-simulations and these analogues. The regional climate model, consistent with other global models, does not suggest an extension of the African summer monsoon into the Mediterranean. Therefore, the extent to which summer monsoonal precipitation may have existed in the southern and eastern Mediterranean during the mid-Holocene remains an outstanding question.

Abstract Plant architectural traits have been reported to impact pest and disease, i.e., attackers, incidence on several crops and to potentially provide alternative, although partial, solutions to limit chemical applications. In this paper, we introduce the major concepts of plant architecture analysis that can be used for investigating plant interactions with attacker development. We briefly review how primary growth, branching and reiteration allow the plant to develop its 3D structure which propertiesmay allow it (or not) to escape or survive to attacks. Different scales are considered: (i) the organs, in which nature, shape and position may influence pest and pathogen attack and development; (ii) the individual plant form, especially the spatial distribution of leaves in space which determines the within-plant micro-climate and the shoot distribution, topological connections which influence the within-plant propagation of attackers; and (iii) the plant population, in which density and spatial arrangement affect the micro-climate gradients within the canopy and may lead to different risks of propagation fromplant to plant. At the individual scale,we show how growth, branching and flowering traits combine to confer to every plant species an intrinsic architectural model. However, these traits vary quantitatively between genotypes within the species. In addition, we analyze how they can bemodulated throughout plant ontogeny and by environmental conditions, here considered lato sensu, i.e. including climatic conditions and manipulations by humans. Examples from different plant species with various architectural types, in particular for wheat and apple, are provided to draw a comprehensive view of possible plant protection strategies which could benefit from plant architectural traits, their genetic variability as well as their plasticity to environmental conditions and agronomic manipulations. Associations between species and/or genotypes having different susceptibility and form could also open new solutions to improve the tolerance to pest and disease at whole population scale.

Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of “exceptional responders (ExRs)” compared to “rapid non-responders (NRs)” increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole-exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients ( P  = 0.07), while more significantly pronounced in copy number gains ( P  = 0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within Chr8 ( P  = 0.02) and in Chr17 ( P  = 0.06) and conferred a statistically significant benefit in overall survival. Clinical trial number: NCT01722890 [ICORG 12/09].