Search

ObjectiveWe aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients.MethodsIn this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation.ResultsBetween 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89).ConclusionThis trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

ObjectiveWe aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients.MethodsIn this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation.ResultsBetween 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89).ConclusionThis trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

Ixodes ricinus, the most common species of tick in Europe, is known to transmit major pathogens to animals and humans such as Babesia spp. or Borrelia spp. Its abundance and distribution have been steadily increasing in Europe during recent decades, due to global environmental changes. Indeed, as ticks spend most of their life in the environment, their activity and life cycle are highly dependent on environmental conditions and therefore, on climate or habitat changes. Simultaneously, wild ungulates have expanded their range and increased dramatically in abundance worldwide, in particular roe deer (Capreolus capreolus), allowing tick populations to grow and spread. Currently, tick infestation on newborn wild ungulates is poorly documented. However, newborn ungulates are considered more sensitive to tick bites and pathogen transmission because of their immature immune systems. Thus, improving knowledge about the factors influencing tick infestation on newborns is essential to better understand their health risks. This study was conducted at Trois-Fontaines Forest, Champagne-Ardenne, France (1992–2018). Based on a long-term monitoring of roe deer fawns, we used a novel Bayesian model of the infestation of fawns to identify which biotic or abiotic factors were likely to modify the level of infestation by ticks of 965 fawns over time. We show that tick burden increased faster during the first days of life of the fawns and became constant when fawns were five days old and more, which could be explained by the depletion of questing ticks or the turnover of ticks feeding on fawns. Moreover, despite the known positive influence of humidity on tick activity, the tick burdens were weakly related to this parameter. Our results demonstrate that tick infestation was highly variable among years, particularly between 2000–2009. We hypothesize that this results from a modification of habitat caused by Hurricane Lothar.

Large-scale national and transnational commercial land transactions, or Large-Scale Land Acquisitions (LSLAs), have been gaining a lot of academic attention since the late 2000s and since the reported rush for land, resulting in turn from an increase in demand for arable land. If many data exist to characterize land deals, the analysis of investment networks remain limited and predominantly portrays power asymmetries between countries from the Global North investing in the Global South. The aim of this work is to perform a deeper investigation on the land trade market, specifically focusing on cases that do not follow such narratives. For instance, almost 25% of the countries included in the transnational land trade network do not follow a strict investor/target dichotomy, thus being characterized by a double role, i.e., they both acquire and cede land in the transnational context. In order to globally acknowledge for what was currently considered as abnormal cases, we model open access data about LSLAs extracted from the Land Matrix Initiative (LMI) open-access database into a network graph, and adapt an eigenvector based centrality method originally conceived for online social networks, namely LurkerRank, to identify and rank anomalous profiles in the land trade market. We take into account three different network snapshots: a multi-sector network (including all the transnational deals in the LMI database), and three networks referring to specific investment sectors (agriculture,mines and biofuels). Experimental results show that emerging economies (e.g., China and Malaysia) play a central role in the land trade market, by creating alternative dynamics that escape the classic North/South one. Our analyses also show how African countries that are often seen as targets of land trade transactions in a specific sector, may often acquire foreign land in the context of investments in the same sector (i.e., Zimbabwe for biofuels and the Democratic Republic of Congo for the mining sector).

Land is a scarce resource and its depletion is related to a combination of demographic and economic factors. Hence, the changes in dietary habits and increase in world population that upturn the food demand, are intertwined with a context of increasing oil prices and rise of green capitalism that in turn impacts the demand in biofuel. A visible indicator of these phenomena is the increase, in recent years, of Large Scale Land Acquisitions (LSLAs) by private companies or states. Such land investments often lead to conflicts with local population and have raised issues regarding people's rights, the role of different production models and land governance. The aim of this work is to show how publicly available data about LSLAs can be modeled into complex network structures, thus showing how the application of advanced network analysis techniques can be used to better understand land trade dynamics. We use data collected by the Land Matrix Initiative on LSLAs to model three land trade networks: a multi-sector network, a network centered on the mining sector and a network centered on the agriculture one. Then we provide an extended analysis of such networks which includes: (i) a structural analysis, (ii) the definition of a score, namely LSLA-score, which allows to rank the countries based on their investing/target role in the land trade network, (iii) an analysis of the land trade context which takes into account the LSLA-score ranking and the correlation between network features and several country development indicators, (iv) an analysis centered on the discover and analysis of network motifs (i.e., recurring patterns in the land trade network), which provides insights into complex and diverse relations between countries. Our analyses showed how the land trade market is massively characterized by a Global North-Global South dynamic, even if the investing power of emerging economies also has a major impact in creating relations between different sub-regions of the world. Moreover, the analyses on the mining and agriculture sectors highlighted how the role of several countries in the trade network may drastically change depending of the investment sector, showing diverse hierarchies between investor, intermediate and target countries.

As climate change continues to exert increasing pressure upon the livelihoods and agricultural sector of many developing and developed nations, a need exists to understand and prioritise at the sub national scale which areas and communities are most vulnerable. The purpose of this study is to develop a robust, rigorous and replicable methodology that is flexible to data limitations and spatially prioritizes the vulnerability of agriculture and rural livelihoods to climate change. We have applied the methodology in Vietnam, Uganda and Nicaragua, three contrasting developing countries that are particularly threatened by climate change. We conceptualize vulnerability to climate change following the widely adopted combination of sensitivity, exposure and adaptive capacity. We used Ecocrop and Maxent ecological models under a high emission climate scenario to assess the sensitivity of the main food security and cash crops to climate change. Using a participatory approach, we identified exposure to natural hazards and the main indicators of adaptive capacity, which were modelled and analysed using geographic information systems. We finally combined the components of vulnerability using equal-weighting to produce a crop specific vulnerability index and a final accumulative score. We have mapped the hotspots of climate change vulnerability and identified the underlying driving indicators. For example, in Vietnam we found the Mekong delta to be one of the vulnerable regions due to a decline in the climatic suitability of rice and maize, combined with high exposure to flooding, sea level rise and drought. However, the region is marked by a relatively high adaptive capacity due to developed infrastructure and comparatively high levels of education. The approach and information derived from the study informs public climate change policies and actions, as vulnerability assessments are the bases of any National Adaptation Plans (NAP), National Determined Contributions (NDC) and for accessing climate finance.

Antennal sensory units in nymphs and adults of the spotted Lanternfly, Lycorma delicatula (White) (Hemiptera: Fulgoromorpha: Fulgoridae), an economically important plant pest, are studied with scanning electron microscopy. Sensilla trichodea / chaetica type recognition is based on their external morphology and ratio of their size to diameter. The flagellum Bourgoin's organ is a complex sensory unit with 2-3 internal sensilla coeloconica. During nymphal stages, the sensory surface available for a chemoreceptive function particularly increases with the number and size of sensilla placodea on the antennal pedicel. From first to fourth instar and to adult males and females, plate organ sensory surface is estimated to increase respectively by 33x, 68x and 125x (= 2.72 mm2 and 5.02 mm2 respectively for males and females). The most important increase (5x) occurs between second and third instar. In parallel, a distinctive pair of plate organs on the flagellum decreases in size from first to third instar, and disappears. Sexual dimorphism occurs in sensilla placodea in adults. Diversity, disparity and evolution of nymphal sensilla, and their sexual dimorphism in adults are discussed in the context of the species and planthopper behaviour.

We present a consensus classification of life to embrace the more than 1.6 million species already provided by more than 3,000 taxonomists' expert opinions in a unified and coherent, hierarchically ranked system known as the Catalogue of Life (CoL). The intent of this collaborative effort is to provide a hierarchical classification serving not only the needs of the CoL's database providers but also the diverse public-domain user community, most of whom are familiar with the Linnaean conceptual system of ordering taxon relationships. This classification is neither phylogenetic nor evolutionary but instead represents a consensus view that accommodates taxonomic choices and practical compromises among diverse expert opinions, public usages, and conflicting evidence about the boundaries between taxa and the ranks of major taxa, including kingdoms. Certain key issues, some not fully resolved, are addressed in particular. Beyond its immediate use as a management tool for the CoL and ITIS (Integrated Taxonomic Information System), it is immediately valuable as a reference for taxonomic and biodiversity research, as a tool for societal communication, and as a classificatory "backbone" for biodiversity databases, museum collections, libraries, and textbooks. Such a modern comprehensive hierarchy has not previously existed at this level of specificity.

In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3-10 mg/kg s.c.) and tapentadol (10-20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.

BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for developing an HCC. MacroH2A1, a histone protein generally associated with the repressed regions of chromosomes, is involved in hepatic lipid metabolism and is present in two alternative spliced isoforms, macroH2A1.1 and macroH2A1.2. These isoforms have been shown to predict lung and colon cancer recurrence but to our knowledge, their role in fatty-liver associated HCC has not been investigated previously.MethodsWe examined macroH2A1.1 and macroH2A1.2 protein expression levels in the liver of two murine models of fat-associated HCC, the high fat diet/diethylnistrosamine (DEN) and the phosphatase and tensin homolog (PTEN) liver specific knock-out (KO) mouse, and in human liver samples of subjects with steatosis or HCC, using immunoblotting and immunohistochemistry.ResultsProtein levels for both macroH2A1 isoforms were massively upregulated in HCC, whereas macroH2A1.2 was specifically upregulated in steatosis. In addition, examination of human liver samples showed a significant difference (pConclusionsThese data obtained in mice and humans suggest that both macroH2A1 isoforms may play a role in HCC pathogenesis and moreover may be considered as novel diagnostic markers for human HCC.

Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid β-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid β-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.

BACKGROUND:The functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments. METHODOLOGY/PRINCIPAL FINDINGS:Here we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously. CONCLUSION/SIGNIFICANCE:We have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The "freezing" of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis.