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Background: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with coronavirus disease 2019 (COVID-19) who received remdesivir plus standard of care (SoC) compared with SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases., Methods: This post hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19. Any first AE that occurred between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves, and Kaplan-Meier estimates were calculated for event rates., Results: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (hazard ratio [HR], 1.0; 95% confidence interval [CI], .7-1.5; P = .98), even when serious and nonserious cardiac AEs were evaluated separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between the two groups in the occurrence of cardiac AE subclasses, including arrhythmic events (HR, 1.1; 95% CI, .7-1.7; P = .68)., Conclusions: Remdesivir treatment was not associated with an increased risk of cardiac AEs compared with control in patients hospitalized with moderate or severe COVID-19. These results are consistent with other randomized, controlled trials and meta-analyses. Clinical Trials Registration. NCT04315948; EudraCT 2020-000936-23., Competing Interests: Potential conflicts of interest. D. C. reports an human immunodeficiency virus grant from Janssen and lecture fees from Pfizer, outside the submitted work. F. M. reports grants and consulting fees from Pharmatheus, grants from Sanofi, and consulting fees from Ipsen, outside the submitted work. M. H. reports grants from the Belgian Center for Knowledge, the Fonds Erasme-COVID-Université Libre de Bruxelles, and the EU-Horizon programme, for the submitted work; support for attending meetings from Pfizer, MSD and Gilead, Pharmamar; support for participation on an advisory board for therapeutics on COVID-19 (DisCoVeRy trial); support for leadership for the Belgian guidelines on therapeutics for COVID-19; acting as president for the Belgian Society of Clinical Microbiology and Infectious Diseases; and payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Gilead, GKS, INSMED, and Shionogi. J. P. reports lecture fees from Gilead and MSD; support for attending meetings from Gilead, Eumedica, and Merck Sharp & Dohme, outside the submitted work. C. B. reports participation on a DSMB for 4Living Biotech and consulting fees from Da Volterra and Mylan Pharmaceuticals, outside the submitted work. R. G. reports consulting fees from Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankvo; lecture fees from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, and Daiichi Sankvo; support for attending meetings from Roche, Amgen, Janssen, AstraZeneca, Novartis, Merck Sharp & Dohme, Celgene, Gilead, Bristol Myers Squibb, AbbVie, and Daiichi Sankvo; participation on a DSMB for Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankyo; research grants from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, and Daiichi Sankyo; and stock or stock options from Novo Nordisk, Lilly. J.-A. P. reports consulting fees from Pfizer, Merck Sharp & Dohme, Janssen-Cilag, and AOP Orphan Pharmaceuticals; lecture fees from Cepheid, Pfizer, and Gilead; and support for attending meetings from Pfizer and Gilead. C. A. reports lecture fees from Insmed, GSK, Moderna, AstraZeneca, and Chiesi; grants or contracts from FEDER funding; support for attending meetings from Home perf; a leadership or fiduciary role as president of the Scientific Council of the French Respiratory Society; and serving as a member of the French ANRS-MIE for COVID and member of the COVID Group of the French Public Health High Council. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The non-essential amino acid L-serine is involved in a number of metabolic pathways and in the brain its level is largely due to the biosynthesis from the glycolytic intermediate D-3-phosphoglycerate by the phosphorylated pathway (PP). This cytosolic pathway is made by three enzymes proposed to generate a reversible metabolon named the "serinosome". Phosphoserine phosphatase (PSP) catalyses the last and irreversible step, representing the driving force pushing L-serine synthesis. Genetic defects of the PP enzymes result in strong neurological phenotypes. Recently, we identified the homozygous missense variant [NM_004577.4: c.398A > G p.(Asn133Ser)] in the PSPH, the PSP encoding gene, in two siblings with a neurodevelopmental syndrome and a myelopathy. The recombinant Asn133Ser enzyme does not show significant alterations in protein conformation and dimeric oligomerization state, as well as in enzymatic activity and functionality of the reconstructed PP. However, the Asn133Ser variant is less stable than wild-type PSP, a feature also apparent at cellular level. Studies on patients' fibroblasts also highlight a strong decrease in the level of the enzymes of the PP, a partial nuclear and perinuclear localization of variant PSP and a stronger perinuclear aggregates formation. We propose that these alterations contribute to the formation of a dysfunctional serinosome and thus to the observed reduction of L-serine, glycine and D-serine levels (the latter playing a crucial role in modulating NMDA receptors). The characterization of patients harbouring the Asn133Ser PSP substitution allows to go deep into the molecular mechanisms related to L-serine deficit and to suggest treatments to cope with the observed amino acids alterations., (© 2024. The Author(s).)

In the last 5 years, low-dimensional chiral metal-halide semiconductors have attracted great interest in the generation of chiroptical activity. Among this new family of materials, one-dimensional (1D) networks have appeared as the best candidates for strong circular dichroism (CD) and circularly polarized luminescence (CPL). Here, we present a new family of 1D chiral lead-bromide materials prepared from organic S / R / rac -1-hydroxypropyl-2-ammonium ( S / R / rac -HP2A) cations. The presence or absence of polarity in the crystal structure as well as the perovskite or nonperovskite nature of the inorganic network depends on the initial stoichiometry of metal-halide salt and chiral amine during the crystallization. The perovskite-type networks exhibit strong CD and second harmonic generation (SHG) responses, while the nonperovskite compounds show the presence of polymorphism in the crystal phase and weak natural optical activity in the final material. These results underline the impact of synthetic conditions and thin film morphology on the structural and optical properties of metal-halide hybrid networks.

Background: Biallelic pathogenic variants in SLC5A6 resulting in sodium-dependent multivitamin transporter (SMVT) defect have recently been described as a vitamin-responsive inborn error of metabolism mimicking biotinidase deficiency. To our knowledge, only 16 patients have been reported so far with various clinical phenotypes such as neuropathy and other neurologic impairments, gastro-intestinal dysfunction and failure to thrive, osteopenia, immunodeficiency, metabolic acidosis, hypoglycemia, and recently severe cardiac symptoms., Methods: We describe a case report of a 5-month-old girl presenting two recurrent episodes of metabolic decompensation and massive cardiac failure in the course of an infectious disease. We compare clinical, biological, and genetic findings of this patient to previous literature collected from Pubmed database (keywords: Sodium-dependent multivitamin transporter (SMVT), SMVT defect/disorder/deficiency, SLC5A6 gene/mutation)., Results: We highlight the life-threatening presentation of this disease, the stagnation of psychomotor development, the severe and persistent hypogammaglobulinemia, and additionally, the successful clinical response on early vitamin supplementation (biotin 15 mg a day and pantothenic acid 100 mg a day). Metabolic assessment showed a persistent increase of urinary 3-hydroxyisovaleric acid (3-HIA) as previously reported in this disease in literature., Conclusion: SMVT deficiency is a vitamin-responsive inborn error of metabolism that can lead to a wide range of symptoms. Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency. Prompt supplementation with high doses of biotin and pantothenic acid should be initiated while awaiting results of SLC5A6 sequencing as this condition may be life-threatening., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

In the last decade, chirality-induced spin selectivity (CISS), the spin-selective electron transport through chiral molecules, has been described in a large range of materials, from insulators to superconductors. Because more experimental studies are desired for the theoretical understanding of the CISS effect, chiral metal-halide semiconductors may contribute to the field thanks to their chiroptical and spintronic properties. In this regard, this work uses new chiral organic cations S-HP1A and R-HP1A (HP1A = 2-hydroxy-propyl-1-ammonium) to prepare 2D chiral halide perovskites (HPs) which crystallize in the enantiomorphic space groups P4 3 2 1 2 and P4 1 2 1 2, respectively. The fourfold symmetry induces antiferroelectricity along the stacking axis which, combined to incomplete Rashba-like splitting in each individual 2D polar layer, results in rare spin textures in the band structure. As revealed by magnetic conductive-probe atomic force microscopy (AFM) measurements, these materials show CISS effect with partial spin polarization (SP; ±40-45%). This incomplete effect is efficient enough to drive a chiro-spintronic device as demonstrated by the fabrication of spin valve devices with magnetoresistance (MR) responses up to 250 K. Therefore, these stable lead-bromide HP materials not only represent interesting candidates for spintronic applications but also reveal the importance of polar symmetry-breaking topology for spin selectivity., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Halide perovskite solar cells are characterized by a hysteresis between current-voltage ( J - V) curves recorded on the reverse and on the forward scan directions, and the suppression of this phenomenon has focused great attention. In the present work, it is shown that a special family of 3D perovskites, that are rendered lead -and iodide- deficient (d-HPs) by incorporating large organic cations, are characterized by a large hysteresis. The strategy of passivating defects by K + , which has been successful in reducing the hysteresis of 3D perovskite perovskite solar cells, is inefficient with the d-HPs. By glow discharge optical emission spectroscopy (GD-OES), the existence of the classic iodide migration in these layers is unveiled, which is efficiently blocked by potassium cation insertion. However, it is also shown that it co-exists with the migration of the large organic cations characteristics of d-HPs which are not blocked by the alkali metal ion. The migration of those large cations is intrinsically linked to the special structure of the d-HP. It is suggested that it takes place through channels, present throughout the whole perovskite layer after the substitution of PbI + units by the large cations, making this phenomenon intrinsic to the original structure of d-HPs., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Exploration published by Henan University and John Wiley & Sons Australia, Ltd.)

A series of monolayered lead halide hybrid perovskites (HO 2 C(CH 2 ) n -1 NH 3 ) 2 PbX 4 , named (C n ) 2 PbX 4 ( n = 4-6, X = Cl, Br), exhibiting a low congruent melting temperature ( T m ) ( T m = 130 °C for (C4) 2 PbBr 4 ), high stability in the molten state, and whitish type emission, are reported. From the synthesis in the molten state, rare solid solutions of mixed organic cations (C n 1- x C n ' x ) 2 PbX 4 ( n , n ' = 4-6; X = Cl, Br; 0 ≤ x ≤1) as well as solid solutions of mixed halides (C n ) 2 Pb(X 1- y X' y ) 4 ( n = 4-6; X, X' = Cl, Br; 0 ≤ y ≤1) have been prepared and characterized (thermal behavior, powder X-ray diffraction (PXRD), photoluminescence properties). The impact of substitutions is significant on the thermal properties, lowering the T m down to 100 °C for (C4) 2 Pb(Br 0.25 Cl 0.75 ) 4 . The emission properties are slightly tuned in the case of mixed organic cation systems, whereas modifications are more dramatic in the case of mixed halide systems, leading to emission properties through the entire visible region. These results illustrate the great opportunities offered by the congruent melting properties of halide perovskites allowing syntheses in the molten state.

Setting: Health measures taken during the pandemic deeply modified the clinical research practices. At the same time, the demand for the results of the COVID-19 trials was urgent. Thus, the objective of this article is to share Inserm's experience in ensuring quality control in clinical trials in this challenging context., Objectives: DisCoVeRy is a phase III randomized study that aimed at evaluating the safety and efficacy of 4 therapeutic strategies in hospitalized COVID-19 adult patients. Between March, 22nd 2020 and January, 20th 2021, 1309 patients were included. In order to guarantee the best quality of data, the Sponsor had to adapt to the current sanitary measures and to their impact on clinical research activity, notably by adapting Monitoring Plan objectives, involving the research departments of the participating hospitals and a network of clinical research assistants (CRAs)., Results: Overall, 97 CRAs were involved and performed 909 monitoring visits. The monitoring of 100% of critical data for all patients included in the analysis was achieved, and despite of the pandemic context, a conform consent was recovered for more than 99% of patients. Results of the study were published in May and September 2021., Discussion/conclusion: The main monitoring objective was met thanks to the mobilization of considerable personnel resources, within a very tight time frame and external hurdles. There is a need for further reflection to adapt the lessons learned from this experience to the context of routine practice and to improve the response of French academic research during a future epidemic., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CFL, VT, ADI, VPS, NM, ADE, AM, FM, DB and FA have nothing to disclose. CB has received consulting fees from MYLAN and Da Volterra and participated on a DSMB for 4Living Biotech. MH has received funding from The Belgian Centre for Knowledge (KCE), the Fonds-Erasme-COVID-19-Université Libre de Bruxelles and an EU-Horizon 2020 grant, payement or honoraria for lectures from Pfizer, Gilead and INSM, support for attending meetings and/or travel from Pfizer and Gilead, participated on a DSMB for Gilead and is President of the Belgian Society of Infectious Diseases and Clinical Microbiology and expert for Belgian Taskforce on COVID therapeutics. The institution employing AF, CD, HE, JS, SCC, MD and SLM received support from the French government, the European Commission, the Region Ile de France, Gilead Sciences, Inc., Sanofi, Merck group and AbbVie for the DisCoVeRy study., (Copyright © 2023. Published by Elsevier Inc.)

Toxicity induced by the presence of lead and the rather poor stability of halide perovskite semiconductors represent the major issues for their large-scale application. We previously reported a new family of lead- and iodide-deficient MAPbI 3 and FAPbI 3 perovskites called d-HPs (for lead- and iodide-deficient halide perovskites) based on two organic cations: hydroxyethylammonium HO-(CH 2 ) 2 -NH 3 + (HEA + ) and thioethylammonium HS-(CH 2 ) 2 -NH 3 + (TEA + ). In this article, we report the use of an organic dication, 2-hydroxypropane-1,3-diaminium (2-propanol 1,3 diammonium), named PDA 2+ , to create new 3D d-HPs based on the MAPbI 3 and FAPbI 3 network with general formulations of (PDA) 0,88 x (MA) 1-0,76 x [Pb 1- x I 3- x ] and (PDA) 1,11 x (FA) 1-1,22 x [Pb 1- x I 3- x ], respectively. These d-HPs have been successfully synthesized as crystals, powders, and thin films and exhibit improved air stability compared to their reference MAPbI 3 and FAPbI 3 perovskite counterparts. PDA 2+ -based deficient MAPbI 3 was also tested in operational perovskite solar cells and exhibited an efficiency of 13.0% with enhanced stability., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-β1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Perovskite solar cells have become more and more attractive and competitive. However, their toxicity induced by the presence of lead and their rather low stability hinders their potential and future commercialization. Reducing lead content while improving stability then appears as a major axis of development. In the last years, we have reported a new family of perovskite presenting PbI + unit vacancies inside the lattice caused by the insertion of big organic cations that do not respect the Goldschmidt tolerance factor: hydroxyethylammonium HO-(CH 2 ) 2 -NH 3 + (HEA + ) and thioethylammonium HS-(CH 2 ) 2 -NH 3 + (TEA + ). These perovskites, named d-HPs for lead and halide-deficient perovskites, present a 3D perovskite corner-shared Pb 1-x I 3-x network that can be assimilated to a lead-iodide-deficient MAPbI 3 or FAPbI 3 network. Here, we propose the chemical engineering of both systems for solar cell optimization. For d-MAPbI 3 -HEA, the power conversion efficiency (PCE) reached 11.47% while displaying enhanced stability and reduced lead content of 13% compared to MAPbI 3 . On the other hand, d-FAPbI 3 -TEA delivered a PCE of 8.33% with astounding perovskite film stability compared to classic α-FAPI. The presence of TEA + within the lattice impedes α-FAPI degradation into yellow δ-FAPbI 3 by direct degradation into inactive Pb(OH)I, thus dramatically slowing the aging of d-FAPbI 3 -TEA perovskite.

Introduction: Amine oxidase copper containing 3 (AOC3) displays adhesion between leukocytes and endothelial cells and enzymatic functions. Given its controversial role in atherogenesis, we proposed to investigate the involvement of AOC3 in the formation of atherosclerotic plaques in ApoE -/- AOC3 -/- mice and human coronary arteries., Methods: Lesions, contractile markers, and AOC3 were studied in aortic tissues from 15- and 25-week-old mice and different stages of human coronary atherosclerotic arteries by immunohistochemistry (IHC) and/or western blot. Human VSMCs, treated or not with LJP1586, an AOC3 inhibitor, were used to measure differentiation markers by qPCR. AOC3 co-localization with specific cell markers was studied by using confocal microscopy in mice and human samples., Results: At 15 weeks old, the absence of AOC3 was associated with increased lesion size, α-SMA, and CD3 staining in the plaque independently of a cholesterol modification. At 25 weeks old, advanced plaques were larger with equivalent staining for α-SMA while CD3 increased in the media from ApoE -/- AOC3 -/- mice. At both ages, the macrophage content of the lesion was not modified. Contractile markers decreased whereas MCP-1 appeared augmented only in the 15-week-old ApoE -/- AOC3. AOC3 is mainly expressed by mice and human VSMC is slightly expressed by endothelium but not by macrophages., Conclusion: AOC3 knock-out increased atherosclerotic plaques at an early stage related to a VSMC dedifferentiation associated with a higher T cells recruitment in plaques explained by the MCP-1 augmentation. This suggests that AOC3 may have an important role in atherosclerosis independent of its canonical inflammatory effect. The dual role of AOC3 impacts therapeutic strategies using pharmacological regulators of SSAO activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Filip, Taleb, Bascetin, Jahangiri, Bardin, Lerognon, Fève, Lacolley, Jalkanen and Mercier.)

Lead halide 2D hybrid perovskites (HP) have emerged as promising materials for photovoltaic and lighting applications. Solvent-free preparations offer greener route, but require congruent melting of halide perovskite for thin films, which has been demonstrated only for monolayered HP (n=1 of the (A) 2 (MA) n-1 Pb n I 3n+1 series) at the quite high temperature T m (T melting ) of 171 °C. Here, we report on the solvent-free preparation (n=2, 4), thermal behaviour and melt-processed thin films of a series of HP (GABA) 2 (MA) n-1 Pb n I 3n+1 (n=1, 2, 4; GABA + : 4-ammoniumbutyric acid cation). The n=1 and n=2 HP have an exceptional low congruent T m of 126 °C and 136 °C, respectively, and, for n=1, a very good stability in the molten state. The liquid-solid reaction of molten (GABA) 2 PbI 4 or (GABA) 2 (MA)Pb 2 I 7 with MAPbI 3 in 1/1 (T=130 °C) or 1/2 (T=135 °C) ratio leads to pure phases of the n=2 HP and (GABA) 2 (MA) 3 Pb 4 I 11 (n=4, T m =185 °C), respectively. Melt-processed thin films of n=1, n=2 and n=4 HP have also been prepared., (© 2022 Wiley-VCH GmbH.)

The Riparo Mochi rock shelter, located on the Ligurian coast of Italy, is one of the most important early Upper Paleolithic sites on the Mediterranean rim. Its ∼10-m-deep stratigraphy comprises a Mousterian sequence, followed by various development stages of the Upper Paleolithic. A series of radiometric dates on marine shells bearing traces of human modification has provided a chronological framework for the final Mousterian and the Proto-Aurignacian of the site. Based on modeling results, the end of the Mousterian was dated between 44.0 and 41.8 ka cal BP (68% probability) and the beginning of the Proto-Aurignacian between 42.7 and 41.6 ka cal BP (68% probability). However, these estimates were based on a limited number of radiocarbon ages in the Mousterian levels. Here, we report new dating of the Mochi sequence using luminescence techniques, along with new radiocarbon measurements. The combination of these results using a Bayesian modeling approach allows for the first time the establishment of a more precise timing for the Mousterian occupation at the site. We show that Mousterian groups were already present at Riparo Mochi by at least 65 ka and continued to occupy the site for another 20 ka. The transition to the earliest Upper Paleolithic at the site is centered around 44.3-41.1 ka (95.4% probability), providing our best age estimate for the beginning of the Early Upper Paleolithic and the establishment of modern human groups in the Balzi Rossi. The sequence continues upward with a more evolved Aurignacian phase and a Gravettian phase starting at ∼26 ka or earlier., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic inflammation in atherosclerosis reflects a failure in the resolution of inflammation. Pro-resolving lipid mediators derived from omega-3 fatty acids reduce the development of atherosclerosis in murine models. The aim of the present study was to decipher the role of the specialized proresolving mediator (SPM) resolvin D2 (RvD2) in atherosclerosis and its signaling through the G-protein coupled receptor (GPR) 18. The ligand and receptor were detected in human coronary arteries in relation to the presence of atherosclerotic lesions and its cellular components. Importantly, RvD2 levels were significantly higher in atherosclerotic compared with healthy human coronary arteries. Furthermore, apolipoprotein E (ApoE) deficient hyperlipidemic mice were treated with either RvD2 or vehicle in the absence and presence of the GPR18 antagonist O-1918. RvD2 significantly reduced atherosclerosis, necrotic core area, and pro-inflammatory macrophage marker expression. RvD2 in addition enhanced macrophage phagocytosis. The beneficial effects of RvD2 were not observed in the presence of O-1918. Taken together, these results provide evidence of atheroprotective pro-resolving signalling through the RvD2-GPR18 axis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen responsible for significant human morbidity and mortality. Post-transcriptional regulation by small RNAs (sRNAs) has emerged as an important mechanism for controlling virulence. However, the functionality of the majority of sRNAs during infection is unknown. To address this, we performed UV cross-linking, ligation, and sequencing of hybrids (CLASH) in MRSA to identify sRNA-RNA interactions under conditions that mimic the host environment. Using a double-stranded endoribonuclease III as bait, we uncovered hundreds of novel sRNA-RNA pairs. Strikingly, our results suggest that the production of small membrane-permeabilizing toxins is under extensive sRNA-mediated regulation and that their expression is intimately connected to metabolism. Additionally, we also uncover an sRNA sponging interaction between RsaE and RsaI. Taken together, we present a comprehensive analysis of sRNA-target interactions in MRSA and provide details on how these contribute to the control of virulence in response to changes in metabolism., (© 2022. The Author(s).)

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The late Middle Pleistocene, starting at around 300 ka, witnessed large-scale biological and cultural dynamics in hominin evolution across Africa including the onset of the Middle Stone Age that is closely associated with the evolution of our species-Homo sapiens. However, archaeological and geochronological data of its earliest appearance are scarce. Here we report on the late Middle Pleistocene sequence of Wadi Lazalim, in the Sahara of Southern Tunisia, which has yielded evidence for human occupations bracketed between ca. 300-130 ka. Wadi Lazalim contributes valuable information on the spread of early MSA technocomplexes across North Africa, that likely were an expression of large-scale diffusion processes., (© 2022. The Author(s).)

We present a new methodology for the U/Th dating of carbonate materials using femtosecond laser ablation single-collector inductively coupled plasma sector field mass spectrometry (fsLA single-collector ICP-SFMS), isotopic mappings, and image processing. This approach allows working on samples at very low U levels (ng·g -1 ). One of the major advantages of this imaging method is that it allows us to exploit deteriorated samples that could not be analyzed by conventional bulk U/Th dating methods, thanks to the identification of contaminated or leached areas at the scale of a few tens of microns and the subsequent correction for detrital 230 Th incorporation. Only a few milligrams of material are required for measurement, which allows us to work on small samples such as shell fragments. The parameters of the fsLA single-collector ICP-SFMS coupling have been carefully optimized to ensure very high sensitivity detection and ultralow background while preserving good plasma robustness and a spatial resolution of 30 × 50 μm 2 . The accuracy was evaluated from low-level U speleothems previously dated by a conventional U/Th dating technique involving digestion, resin purification, double spike, and detection by multicollector inductively coupled plasma mass spectrometry (MC-ICPMS). U/Th ages of two archaeological samples with U at low ng·g -1 levels, a giant terrestrial snail shell and a burned ostrich eggshell, were determined. The measured U/Th ages are consistent with the expected ages determined by luminescence dating methods.

North African coastal Middle Stone Age (MSA) sites are key to study the development and expansion of early H. sapiens. El Mnasra cave on the Atlantic coast of Morocco (Témara region) is a crucial site associated with MSA archaeological materials considered advanced cognitive hallmarks of behavioural innovation, such as numerous Nassariidae perforated shells, hematite pigments, bones industry and coastal resources exploitation. We provide new trapped-charges dates (OSL and combined US-ESR ages). Our Bayesian modelling strengthens the new lithostratigraphic interpretation of the cave stratigraphic units (US) and we propose an updated chronostratigraphic model for the Middle Stone Age archaeo-sequence of El Mnasra Cave. We confirm a human presence between 124-104 ka, earlier than what the previous OSL and US-ESR data showed. Our time range intervals allowed us to also extend the age of the MSA occupations considerably to the MIS 4/3 (~62-30 ka), marked by the disappearance of the Nassariidae perforated shells. Outstandingly, our model pushed back the age of the largest record of Nassariidae perforated shells and placed the age of their use by the Aterian groups at El Mnasra from the MIS 5d-5b (~115-94 ka)., Competing Interests: The authors have declared that no competing interests exist.

Determining the extent of overlap between modern humans and other hominins in Eurasia, such as Neanderthals and Denisovans, is fundamental to understanding the nature of their interactions and what led to the disappearance of archaic hominins. Apart from a possible sporadic pulse recorded in Greece during the Middle Pleistocene, the first settlements of modern humans in Europe have been constrained to ~45,000 to 43,000 years ago. Here, we report hominin fossils from Grotte Mandrin in France that reveal the earliest known presence of modern humans in Europe between 56,800 and 51,700 years ago. This early modern human incursion in the Rhône Valley is associated with technologies unknown in any industry of that age outside Africa or the Levant. Mandrin documents the first alternating occupation of Neanderthals and modern humans, with a modern human fossil and associated Neronian lithic industry found stratigraphically between layers containing Neanderthal remains associated with Mousterian industries.

Major changes in the technological, economic, and social behavior of Middle Pleistocene hominins occurred at the onset of the Middle Paleolithic, 400-200 ka. However, until recently it was not possible to establish when, where, and how certain forms of Middle Paleolithic behavior appeared and spread into Southeastern Europe, mainly owing to gaps in the Paleolithic record. Here we report new results of dating, material culture, and the archaeological context of finds from the Balanica Cave Complex in Sićevo (Serbia). Two methods-thermoluminescence and electron spin resonance-were used to date the sequence. The geoarchaeological context was examined through sedimentology, micromorphology, and spatial analysis. Microfaunal remains were used to constrain the dates within an ecological zone, whereas macrofauna was analyzed for taxonomy and taphonomy to examine the source of accumulation and hominin behavior. Technological and typological features of the lithic assemblage were used to characterize lithic production at the site. Materials recovered from Layer 3 in Velika Balanica and from Layer 2 in Mala Balanica, both dated to MIS 9-7, include a distinctive set of archaeological assemblages which resemble contemporaneous Yabrudian assemblages from the Levant in important ways, and which are unlike contemporary material from the surrounding regions. In Velika Balanica, the lithic assemblages are associated with a large fireplace containing evidence of human activities similar to those from Qesem Cave (Israel). Dental remains uncovered in the same layer are consistent with Neanderthals. These findings suggest that the end of the Middle Pleistocene (before 300-240 ka) saw population movement and/or cultural transmission between Southwest Asia and the Balkans, which led eventually to a transfer of technology between Middle Eastern and European hominin populations and contributed to the shaping of Neanderthal behaviors throughout the eastern and northern Mediterranean., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Previous studies have suggested that the Lower-to-Middle Paleolithic transition was associated with the earliest Neanderthals, but recent research has established that the oldest Neanderthal fossils and the first signs of their technologies and behavior appear from MIS 11 or possibly earlier. To understand these changes, re-evaluation of the evidence is necessary to determine if this transition corresponds to a progressive evolution rather than abrupt change. Orgnac 3 is a key and appropriate site to study this research context. Located in southern France, it yields a long stratigraphic sequence testifying the evolution of technical and subsistence behaviors of pre-Neanderthal human groups during a Middle Pleistocene interglacial-glacial cycle. In this article, a new chronological framework is provided for the sequence based on results of dating methods applied to various types of geological materials. Speleothems and volcanic minerals, dated in previous studies by U-series and 40 Ar/ 39 Ar, respectively, show periods of calcitic crystallization and regional volcanic activity. Other materials, such as heated flints and herbivore teeth, are directly related to evidence of anthropogenic activities and are analyzed in the present work by trapped-charge dating methods such as thermoluminescence and electron spin resonance combined with uranium series (ESR/U-series). The new thermoluminescence and ESR/U-series dates confirm the attribution of the Orgnac 3 stratigraphic sequence to the MIS 10-MIS 8 period and are discussed in relation to paleoenvironmental data derived from bioarchaeological studies. The paleoanthropological levels, including the emergence of Levallois technology, are dated to ca. 275 ka (early MIS 8) and appear coeval to a wet and temperate period recorded locally, the Amargiers interstadial, defined in the regional palynological records. The implications of this reassessed chronology for the archaeological assemblages are discussed in the wider context of behavioral innovations from MIS 11 onward and their establishment in subsequent periods., Competing Interests: Conflict of interest statement We do not have any conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support., Methods: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely., Results: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms., Conclusion: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The association of the electron acceptor 4,4'-amino-bipyridinium (AmV 2+ ) dication and BiI 3 in an acidic solution affords three organic-inorganic hybrid materials, (AmV) 3 (BiI 6 ) 2 ( 1 ), (AmV) 2 (Bi 4 I 16 ) ( 2 ), and (AmV)BiI 5 ( 3 ), whose structures are based on isolated BiI 6 3- and Bi 4 I 16 4- anion clusters in 1 and 2 , respectively, and on a one-dimensional (1D) chain of trans -connected corner-sharing octahedra in 3 . In contrast with known methylviologen-based hybrids, these compounds are more soluble in polar solvents, allowing thin film formation by spin-coating. (AmV)BiI 5 exhibits a broad absorption band in the visible region leading to an optical bandgap of 1.54 eV and shows a PV effect as demonstrated by a significant open-circuit voltage close to 500 mV. The electronic structure of the three compounds has been investigated using first-principles calculations based on density functional theory (DFT). Unexpectedly, despite the trans -connected corner-shared octahedra, for (AmV)BiI 5 , the valence state shows no coupling along the wire direction, leading to a high effective mass for holes, while in contrast, the strong coupling between Bi 6p x orbitals in the same direction at the conduction band minimum suggests excellent electron transport properties. This contributes to the low current output leading to the low efficiency of perovskite solar cells based on (AmV)BiI 5 . Further insight is provided for trans - and cis -MI 5 1D model structures (M = Bi or Pb) based on DFT investigations.

Background: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome., Methods: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator., Discussion: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale., Trial Registration: clinicaltrial.gov NCT03784014 ., (© 2021. The Author(s).)

The success of the major opportunistic human Staphylococcus aureus relies on the production of numerous virulence factors, which allow rapid colonization and dissemination in any tissues. Indeed, regulation of its virulence is multifactorial, and based on the production of transcriptional factors, two-component systems (TCS) and small regulatory RNAs (sRNAs). Advances in high-throughput sequencing technologies have unveiled the existence of hundreds of potential RNAs with regulatory functions, but only a fraction of which have been validated in vivo . These discoveries have modified our thinking and understanding of bacterial physiology and virulence fitness by placing sRNAs, alongside transcriptional regulators, at the center of complex and intertwined regulatory networks that allow S. aureus to rapidly adapt to the environmental cues present at infection sites. In this review, we describe the recently acquired knowledge of characterized regulatory RNAs in S. aureus that are associated with metal starvation, nutrient availability, stress responses and virulence. These findings highlight the importance of sRNAs for the comprehension of S. aureus infection processes while raising questions about the interplay between these key regulators and the pathways they control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barrientos, Mercier, Lalaouna and Caldelari.)

The Ravin Blanc I archaeological occurrence, dated to MIS 5, provides unprecedented data on the Middle Stone Age (MSA) of West Africa since well-contextualized archaeological sites pre-dating MIS 4/3 are extremely rare for this region. The combined approach on geomorphology, phytolith analysis, and OSL date estimations offers a solid framework for the MSA industry comprised in the Ravin Blanc I sedimentary sequence. The paleoenvironmental reconstruction further emphasizes on the local effects of the global increase in moisture characterizing the beginning of the Upper Pleistocene as well as the later shift to more arid conditions. The lithic industry, comprised in the lower part of the sequence and dated to MIS 5e, shows core reduction sequences among which Levallois methods are minor, as well as an original tool-kit composition, among which pieces with single wide abrupt notches, side-scrapers made by inverse retouch, and a few large crudely shaped bifacial tools. The Ravin Blanc I assemblage has neither a chronologically equivalent site to serve comparisons nor a clear techno-typological correspondent in West Africa. However, the industry represents an early MSA technology that could either retain influences from the southern West African 'Sangoan' or show reminiscences of the preceding local Acheulean. A larger-scale assessment of behavioral dynamics at work at the transition period between the Middle to Upper Pleistocene is discussed in view of integrating this new site to the global perception of this important period in the MSA evolutionary trajectories., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although small regulatory RNAs (sRNAs) are widespread among the bacterial domain of life, the functions of many of them remain poorly characterized notably due to the difficulty of identifying their mRNA targets. Here, we described a modified protocol of the MS2-Affinity Purification coupled with RNA Sequencing (MAPS) technology, aiming to reveal all RNA partners of a specific sRNA in vivo. Broadly, the MS2 aptamer is fused to the 5' extremity of the sRNA of interest. This construct is then expressed in vivo, allowing the MS2-sRNA to interact with its cellular partners. After bacterial harvesting, cells are mechanically lysed. The crude extract is loaded into an amylose-based chromatography column previously coated with the MS2 protein fused to the maltose binding protein. This enables the specific capture of MS2-sRNA and interacting RNAs. After elution, co-purified RNAs are identified by high-throughput RNA sequencing and subsequent bioinformatic analysis. The following protocol has been implemented in the Gram-positive human pathogen Staphylococcus aureus and is, in principle, transposable to any Gram-positive bacteria. To sum up, MAPS technology constitutes an efficient method to deeply explore the regulatory network of a particular sRNA, offering a snapshot of its whole targetome. However, it is important to keep in mind that putative targets identified by MAPS still need to be validated by complementary experimental approaches.

Hybrid perovskite (HP) materials are of interest in photovoltaics and lighting applications. Here we report that hybrid perovskite composites, as crystallized powders, can behave as intelligent materials showing highly sensitive and reversible mechanochromic luminescence (MCL). Composites consisting of monolayered 2D HP and 3D HP components exhibit reversible tunable color emission upon mechanical strain. The bluish-whitish emission of the 2D HP turns into orange in the composite owing to an energy transfer process. The bright green emission, observed as soon as the composite is slightly crushed, originates from the 3D HP after efficient energy funneling from the multi-layered 2D HP produced at the 2D/3D interface by the mechanical treatment. Besides highlighting the key role of the interfaces in light emission of HP, our findings pave the way for hybrid perovskites as highly sensitive MCL smart materials for mechanosensors, security papers, or optical storage applications., (© 2020 Wiley-VCH GmbH.)

The end of the Palaeolithic represents one of the least-known periods in the history of western Africa, both in terms of its chronology and the identification of cultural assemblages entities based on the typo-technical analyses of its industries. In this context, the site of Fatandi V offers new data to discuss the cultural pattern during the Late Stone Age in western Africa. Stratigraphic, taphonomical and sedimentological analyses show the succession of three sedimentary units. Several concentrations with rich lithic material were recognized. An in situ occupation, composed of bladelets, segments, and bladelet and flake cores, is confirmed while others concentrations of lithic materials have been more or less disturbed by erosion and pedogenic post-depositional processes. The sequence is well-dated from 12 convergent OSL dates. Thanks to the dating of the stratigraphic units and an OSL date from the layer (11,300-9,200 BCE [13.3-11.2 ka at 68%, 14.3-10.3 ka at 95%]), the artefacts are dated to the end of Pleistocene or Early Holocene. Palaeoenvironmental data suggest that the settlement took place within a mosaic environment and more precisely at the transition between the open landscape of savanna on the glacis and the plateau, and the increasingly densely-wooded alluvial corridor. These humid areas must have been particularly attractive during the dry season by virtue of their rich resources (raw materials, water, trees, and bushes). The Fatandi V site constitutes the first stratified site of the Pleistocene/Holocene boundary in Senegal with both precise geochronological and palaeoenvironmental data. It complements perfectly the data already obtained in Mali and in the rest of western Africa, and thus constitutes a reference point for this period. In any case, the assemblage of Fatandi V, with its bladelets and segments and in the absence of ceramics and grinding material, fits with a cultural group using exclusively geometric armatures which strongly differs from another group characterized by the production of bifacial armatures, accompanied in its initial phase by ceramics (or stoneware) and grinding material., Competing Interests: The authors have declared that no competing interests exist.

Ictal vomiting is a rare condition easily misdiagnosed as a common disease. We report two children presenting with retching and vomiting as the main ictal manifestation. Patient 1 was a four-year-old girl with a history of daily nocturnal vomiting for two months, first interpreted as a functional disorder, then as a viral infection. She presented with vomiting accompanied by focal right-sided hemifacial clonic jerking, occurring multiple times per day. Video-EEG demonstrated ictal discharges associated with the retching and vomiting, over a normal background, and occasional interictal focal spikes. MRI was normal. PET demonstrated left-sided opercular hypometabolism. Patient 2 was a girl with a history of focal epilepsy, secondary to a right central dysembryoplastic tumour, first resected with subsequent seizure freedom at the age of three years. At five years of age, she presented with recurrent episodes of retching and vomiting initially diagnosed as migraine. Video-EEG showed ictal discharges, clinically correlating with retching, vomiting and clonic facial jerking, with normal interictal activity. Brain MRI showed a progression of the tumour. A second resection resulted in seizure freedom. Ictal vomiting often goes undiagnosed, especially in children, causing treatment delays. An ictal origin should be considered, particularly when the episodes are recurrent and stereotyped. [Published with video sequences].

Background: Updated WHO guidelines recommend a dolutegravir-based regimen as the preferred first-line treatment for HIV infection and low-dose efavirenz (400 mg) as an alternative. We aimed to report the non-inferior efficacy of dolutegravir compared with efavirenz 400 mg at week 96., Methods: We did a multicentre, randomised, open label, phase 3 trial in in three hospitals in Yaoundé, Cameroon, in HIV-1 infected antiretroviral-naive adults with an HIV RNA viral load of greater than 1000 copies per mL to compare dolutegravir 50 mg with efavirenz 400 mg (reference treatment), both combined with lamivudine and tenofovir disoproxil fumarate. The primary endpoint was the proportion with a viral load of less than 50 copies per mL at week 48 (10% non-inferiority margin). The study is registered with ClinicalTrials.gov, NCT02777229 and is ongoing., Findings: Between July, 2016, and August, 2019, of 820 patients assessed, 613 were randomly assigned to receive at least one dose of study medication, with 310 in the dolutegravir group and 303 in the efavirenz 400 mg group. At week 96 in the intention-to-treat analysis, 229 (74%) of 310 patients receiving dolutegravir and 219 (72%) of 303 patients receiving efavirenz, achieved plasma HIV-1 RNA less than 50 copies per mL (difference 1·6%, 95% CI -5·4 to 8·6; p=0.66). Viral load suppression was reached significantly more rapidly in the dolutegravir group (p<0·001). Virological failure (>1000 copies per mL) was observed in 27 patients (eight in the dolutegravir group, among which, three women switched to efavirenz 600 mg because of the dolutegravir teratogeneicity signal, and 19 in the efavirenz 400 mg group). No acquired resistance mutations to dolutegravir were observed against 17 mutations to efavirenz with or without mutations to lamivudine and tenofovir disoproxil fumarate among the 19 efavirenz 400 mg participants with virological failure. Weight gain was greater in the dolutegravir group (median weight gain, 5·0 kg in the dolutegravir group and 3·0 kg in the efavirenz 400 mg group, p<0·001, and incidence of obesity, 22% in the dolutegravir group and 16% in the efavirenz 400 mg group, p=0·043). The incidence of new WHO HIV-related stage 3 and 4 events was similar in each group (12 [4%] in each group). The two groups had similar rates of serious adverse events (28 [9%] of 310 in the dolutegravir group and 21 [7%] of 303 in the efavirenz 400 mg group). 18 deaths were observed during the 96-week follow-up (eight in the dolutegravir group and ten in the efavirenz 400 mg group)., Interpretation: The non-inferior efficacy of the dolutegravir-based regimen and non-emergence of dolutegravir resistance at 96 weeks supports its use as a first-line regimen for antiretroviral-naive adults with HIV-1 infection. Viral load suppression was reached more quickly in the dolutegravir group and weight gain was significantly higher., Funding: UNITAID and the French National Agency for AIDS Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Calcific aortic valve stenosis (CAVS) is a common disease associated with aging. Oxidative stress participates in the valve calcification process in CAVS. Semicarbazide-sensitive amine oxidase (SSAO), also referred to as vascular adhesion protein 1 (VAP-1), transforms primary amines into aldehydes, generating hydrogen peroxide and ammonia. SSAO is expressed in calcified aortic valves, but its role in valve calcification has remained largely unexplored. The aims of this study were to characterize the expression and the activity of SSAO during aortic valve calcification and to establish the effects of SSAO inhibition on human valvular interstitial cell (VIC) calcification., Methods: Human aortic valves from n = 80 patients were used for mRNA extraction and expression analysis, Western blot, SSAO activity determination, immunohistochemistry, and the isolation of primary VIC cultures., Results: SSAO mRNA, protein, and activity were increased with increasing calcification within human aortic valves and localized in the vicinity of the calcified zones. The valvular SSAO upregulation was consistent after stratification of the subjects according to cardiovascular and CAVS risk factors associated with increased oxidative stress: body mass index, diabetes, and smoking. SSAO mRNA levels were significantly associated with poly(ADP-ribose) polymerase 1 (PARP1) in calcified tissue. Calcification of VIC was inhibited in the presence of the specific SSAO inhibitor LJP1586., Conclusion: The association of SSAO expression and activity with valvular calcification and oxidative stress as well as the decreased VIC calcification by SSAO inhibition points to SSAO as a possible marker and therapeutic target to be further explored in CAVS., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Nathalie Mercier et al.)

Hybrid halide perovskites (HP) have emerged in the last decade as a new class of semiconductors with superior performances in photovoltaic and electronic devices. The literature about these halide semiconductors is abundant and a lot of names/expressions are used to define networks, structures, or materials. In this context, there is a need to offer some discussions about the relevance of using the word "perovskite" and the associated expressions ("RP" (Ruddlesden-Popper), "DJ" (Dion-Jacobson), "ACI" (alternating cations in the interlayer space), "hexagonal perovskites", "hollow perovskites", "d-HP" (deficient 3D HP),…). Moreover, the description of perovskite networks through elimination/substitution processes from the ABX 3 structure will be compared to the known dimensional reduction concept., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

There is a relatively low amount of Middle Paleolithic sites in Europe dating to MIS 4. Of the few that exist, several of them lack evidence for anthropogenic fire, raising the question of how this period of global cooling may have affected the Neanderthal population. The Iberian Peninsula is a key area to explore this issue, as it has been considered as a glacial refugium during critical periods of the Neanderthal timeline and might therefore yield archaeological contexts in which we can explore possible changes in the behaviour and settlement patterns of Neanderthal groups during MIS 4. Here we report recent data from Abric del Pastor, a small rock shelter in Alcoy (Alicante, Spain) with a stratified deposit containing Middle Palaeolithic remains. We present absolute dates that frame the sequence within MIS 4 and multi-proxy geoarchaeological evidence of in situ anthropogenic fire, including microscopic evidence of in situ combustion residues and thermally altered sediment. We also present archaeostratigraphic evidence of recurrent, functionally diverse, brief human occupation of the rock shelter. Our results suggest that Neanderthals occupied the Central Mediterranean coast of the Iberian Peninsula during MIS 4, that these Neanderthals were not undergoing climatic stress and they were habitual fire users.

Background: Intravenous thrombolysis is a well-established treatment of ischemic stroke within 4.5 h. However, its effectiveness in acute ischemic myelopathy is unknown., Purpose: We describe a series of four acute ischemic myelopathy patients treated with intravenous thrombolysis within 4.5 h and review the current literature to explore this treatment feasibility, potential safety, and efficacy., Methods: We reviewed all routinely collected clinical, radiological, and follow-up data of patients with a final acute ischemic myelopathy diagnosis who received acute intravenous thrombolysis in our stroke network. We also reviewed thrombolyzed acute ischemic myelopathy patients in the literature., Results: Four patients (three women) aged 57 to 83 years presented with acute uni- or bilateral extremity paresis, considered initially as cerebral strokes in two of them. After excluding contraindications by brain imaging in three, spinal computed tomography in one and confirmation of acute ischemic myelopathy on spinal magnetic resonance imaging in one patient, intravenous thrombolysis was administered at 135, 190, 240, and 245 min accordingly. Subacute diffusion-weighted imaging-magnetic resonance imaging confirmed acute ischemic myelopathy in all but one patient. Favorable outcome was achieved in two patients rapidly and in three patients at three-month follow-up. We identified seven other thrombolyzed acute ischemic myelopathy patients in the literature, who showed variable recovery and no hemorrhagic complications., Conclusions: With appropriate acute imaging, intravenous thrombolysis after acute ischemic myelopathy is feasible and potentially safe within 4.5 h. Given the potential of benefit of thrombolysis in acute ischemic myelopathy, this treatment warrants further efficacy and safety studies.

Geißenklösterle Cave (Germany) is one of the most important Paleolithic sites in Europe, as it is characterized by human occupation during the Middle and early Upper Paleolithic. Aurignacian layers prior to 37-38 ka cal BP feature both musical and figurative art objects that are linked to the early arrival in Europe of Homo sapiens. Middle Paleolithic layers yielded lithic artifacts attributed to Homo neanderthalensis. Since human occupation at the site is attributed to both Neanderthals and modern humans, chronology is essential to clarify the issues of Neanderthal disappearance, modern human expansion in Europe, and the origin of the Aurignacian in Western Europe. Electron spin resonance (ESR) dating was performed on fossil tooth enamel collected from the Middle Paleolithic layers, which are beyond the radiocarbon dating range, and from the nearly sterile 'transitional' geological horizon (GH) 17 and the lower Aurignacian deposits, to cross-check ESR ages with previous radiocarbon, thermoluminescence and ESR age results. The Middle Paleolithic layers were dated between 94 ± 10 ka (GH 21) and 55 ± 6 ka (GH 18) by ESR on tooth enamel. Mean ages for GH 17, at 46 ± 3 ka, and for the lower Aurignacian layers, at 37 ± 3 ka, are in agreement with previous dating results, thus supporting the reliability of ESR chronology for the base of the sequence where dating comparisons are not possible. These results suggest that Neanderthals occupied the site from Marine Isotope Stage (MIS) 5 to the second half of MIS 3 and confirm the antiquity of early Aurignacian deposits. The presence of an almost sterile layer that separates Middle and Upper Paleolithic occupations could be related to the abandonment of the site by Neanderthals, possibly during Heinrich Stadial 5 (ca. 49-47 ka), thus before the arrival of H. sapiens in the area around 42 ka cal BP. These dates for the Middle Paleolithic of the Swabian Jura represent an important contribution to the prehistory of the region, where nearly all of the excavations were conducted decades ago and prior to the development of reliable radiometric dating beyond the range of radiocarbon., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We report room-temperature synthesis of lead- and iodide-deficient α-[HC(NH 2 ) 2 ]PbI 3 perovskites (abbreviated d-α-FAPI, FA + = formamidinium), with the general formula (A',FA) 1+ x [Pb 1- x I 3- x ] (with A' = hydroxyethylammonium (HEA + ) or thioethylammonium (TEA + ) cations, 0.04 ≤ x ≤ 0.15). These materials retain a 3D character of their perovskite network despite incorporation of large HEA + or TEA + cations, demonstrating that the Goldschmidt tolerance factor can be bypassed. We found that thin films of (TEA,FA) 1+ x [Pb 1- x I 3- x ] ( x = 0.04 and 0.13) show exceptional α-phase stability under ambient conditions, 1 order of magnitude higher than α-FAPI and α-(Cs,FA)PbI 3 thin films. d-α-FAPI phases are shown to maintain a direct band gap, which increases monotonously for x ranging from 0 up to 0.20, with characteristics of a p-type semiconductor for low concentrations of vacancies ( x ≤ 0.13) and n-type for larger ones. They offer alternatives to reach the methylammonium- and bromine-free stable α-FAPI-type phase and open new avenues in the field of perovskite solar cells, up to band gap tuning desirable for tandem solar cells.

The performance of four polymorphs of manganese (Mn) dioxides as the catalyst for the oxygen evolution reaction (OER) in proton exchange membrane (PEM) electrolysers was examined. The comparison of the activity between Mn oxides/carbon (Mn/C), iridium oxide/carbon (Ir/C) and platinum/carbon (Pt/C) under the same condition in PEM electrolysers showed that the γ-MnO 2 /C exhibited a voltage efficiency for water electrolysis comparable to the case with Pt/C, while lower than the case with the benchmark Ir/C OER catalyst. The rapid decrease in the voltage efficiency was observed for a PEM electrolyser with the Mn/C, as indicated by the voltage shift from 1.7 to 1.9 V under the galvanostatic condition. The rapid deactivation was also observed when Pt/C was used, indicating that the instability of PEM electrolysis with Mn/C is probably due to the oxidative decomposition of carbon supports. The OER activity of the four types of Mn oxides was also evaluated at acidic pH in a three-electrode system. It was found that the OER activity trends of the Mn oxides evaluated in an acidic aqueous electrolyte were distinct from those in PEM electrolysers, demonstrating the importance of the evaluation of OER catalysts in a real device condition for future development of noble-metal-free PEM electrolysers., Competing Interests: We declare we have no competing interests.

The new antiepileptic drugs (AED) are not significantly more efficient than the older ones, but they are better tolerated and with a lower drug interactions. Despite the existing guidelines, the evidence-based medicine cannot answer unequivocally the question of the best AED for a given patient. The treatment must be individually tailored; in this article, we present some principles and important factors to guide that choice., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

New antiepileptic drugs are regularly approved for treatment and offer large therapeutic opportunities. Efficacy of these drugs is relatively similar on-label with different mechanisms to be combined for a synergic effect. Treatments such as cannabidiol have benefitted from large media coverage despite limited clinical evidence so far. The objective of antiepileptic drugs is to stop the recurrence of epileptic seizures with as few adverse events as possible. When confronted to a difficult-to-treat epilepsy, referral to a specialised centre is strongly advised. The aim is to confirm that the diagnosis is correct, that the treatment is well adapted (indication, pharmacokinetic and compliance) and to evaluate the indication for non-pharmacological treatments such as epilepsy surgery., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Training and repeated exposure to odorants leads to enhanced olfactory sensitivity. So far, the efficacy of intensive olfactory training on olfactory function in a healthy population and its underlying neurobiological basis remain poorly known. This study investigated the effects of a 6-week intensive and well-controlled olfactory training on olfactory function and brain structure/neuroplasticity. Thirty-six healthy young individuals were recruited and randomly distributed in three groups: (1) 12 participants underwent daily intensive olfactory training of at least 20 min that included an (a) odor intensity classification task, an (b) odor quality classification task and an (c) target odor detection task, (2) 12 participants underwent an equivalent visual control training, and (3) 12 control individuals did not participate in any training. Before and after the training period, all participants performed a series of olfactory tests and those from groups 1 and 2 underwent structural magnetic resonance (MR) imaging, from which we obtained measures such as cortical thickness and tissue density. Participants improved in the respectively trained tasks throughout the 6-weeks training period. Those who underwent olfactory training improved general olfactory function compared to control participants, especially in odor identification, thus showing intramodal transfer. Further, MR imaging analysis revealed that olfactory training led to increased cortical thickness in the right inferior frontal gyrus, the bilateral fusiform gyrus and the right entorhinal cortex. This research shows that intensive olfactory training can generally improve olfactory function and that this improvement is associated with changes in the structure of olfactory processing areas of the brain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hybrid halide perovskites are now superstar materials leading the field of low-cost thin film photovoltaics technologies. Following the surge for more efficient and stable 3D bulk alloys, multilayered halide perovskites and colloidal perovskite nanostructures appeared in 2016 as viable alternative solutions to this challenge, largely exceeding the original proof of concept made in 2009 and 2014, respectively. This triggered renewed interest in lower-dimensional hybrid halide perovskites and at the same time increasingly more numerous and differentiated applications. The present paper is a review of the past and present literature on both colloidal nanostructures and multilayered compounds, emphasizing that availability of accurate structural information is of dramatic importance to reach a fair understanding of quantum and dielectric confinement effects. Layered halide perovskites occupy a special place in the history of halide perovskites, with a large number of seminal papers in the 1980s and 1990s. In recent years, the rationalization of structure-properties relationship has greatly benefited from new theoretical approaches dedicated to their electronic structures and optoelectronic properties, as well as a growing number of contributions based on modern experimental techniques. This is a necessary step to provide in-depth tools to decipher their extensive chemical engineering possibilities which surpass the ones of their 3D bulk counterparts. Comparisons to classical semiconductor nanostructures and 2D van der Waals heterostructures are also stressed. Since 2015, colloidal nanostructures have undergone a quick development for applications based on light emission. Although intensively studied in the last two years by various spectroscopy techniques, the description of quantum and dielectric confinement effects on their optoelectronic properties is still in its infancy.

Our original claim, based on three independent numerical dating methods, of an age of ~185,000 years for the Misliya-1 modern human hemi-maxilla from Mount Carmel, Israel, is little affected by discounting uranium-series dating of adhering crusts. It confirms a much earlier out-of-Africa Homo sapiens expansion than previously suggested by the considerably younger (90,000 to 120,000 years) Skhul/Qafzeh hominins., (Copyright © 2018, American Association for the Advancement of Science.)

In the past few decades, a diverse array of research has emphasized the precocity of technically advanced and symbolic practices occurring during the southern African Middle Stone Age. However, uncertainties regarding the regional chrono-cultural framework constrain models and identification of the cultural and ecological mechanisms triggering the development of such early innovative behaviours. Here, we present new results and a refined chronology for the Pietersburg, a techno-complex initially defined in the late 1920's, which has disappeared from the literature since the 1980's. We base our revision of this techno-complex on ongoing excavations at Bushman Rock Shelter (BRS) in Limpopo Province, South Africa, where two Pietersburg phases (an upper phase called '21' and a lower phase called '28') are recognized. Our analysis focuses on the '28' phase, characterized by a knapping strategy based on Levallois and semi-prismatic laminar reduction systems and typified by the presence of end-scrapers. Luminescence chronology provides two sets of ages for the upper and lower Pietersburg of BRS, dated respectively to 73±6ka and 75±6ka on quartz and to 91±10ka and 97±10ka on feldspar, firmly positioning this industry within MIS5. Comparisons with other published lithic assemblages show technological differences between the Pietersburg from BRS and other southern African MIS5 traditions, especially those from the Western and Eastern Cape. We argue that, at least for part of MIS5, human populations in South Africa were regionally differentiated, a process that most likely impacted the way groups were territorially and socially organized. Nonetheless, comparisons between MIS5 assemblages also indicate some typological similarities, suggesting some degree of connection between human groups, which shared similar innovations but manipulated them in different ways. We pay particular attention to the end-scrapers from BRS, which represent thus far the earliest documented wide adoption of such tool-type and provide further evidence for the innovative processes characterizing southern Africa from the MIS5 onwards., Competing Interests: The authors have declared that no competing interests exist.