Search

Background and Objectives: In multiple sclerosis (MS), immune cells invade the CNS and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. In this article, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuroregenerative effects., Methods: CD14 + CD16 - monocytes from patients with MS and healthy controls (HCs) were activated in vitro to obtain homeostatic-like, proinflammatory, and proregenerative macrophages. Macrophage activation profiles were assessed through RNA sequencing and metabolomics. Surface molecule expression of CD14, CD16, and HLA-DR and myelin phagocytic capacity were evaluated with flow cytometry. Macrophage supernatant capacity to influence oligodendrocyte precursor cell differentiation toward an astrocytic or oligodendroglia fate was also tested., Results: We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward the CD16 + phenotype, a subset of proinflammatory cells overrepresented in MS lesions. Functionally, MS patient macrophages display a decreased capacity to phagocytose human myelin and a deficit of processing myelin after ingestion. In addition, MS patient macrophage supernatant favors astrocytes over oligodendrocyte differentiation when compared with HC macrophage supernatant. Furthermore, even when exposed to homeostatic or proregenerative stimuli, MS patient macrophages uphold a proinflammatory transcriptomic profile with higher levels of cytokine/chemokine. Of interest, MS patient macrophages exhibit a distinct metabolic signature with a mitochondrial energy metabolism blockage. Transcriptomic data are further substantiated by metabolomics studies that reveal perturbations in the corresponding metabolic pathways., Discussion: Our results show an intrinsic defect of MS patient macrophages, reminiscent of innate immune cell memory in MS, lifting macrophage importance in the disease and as potential therapeutic targets.

The novel quaternary compound Rb 0.2 Ba 0.4 Cr 5 Se 8 was synthesized and characterized in both single crystal and polycrystalline forms. Crystallizing in the monoclinic crystal system (space group C 2/ m , cell parameters a = 18.7071(4) Å, b = 3.6030(1) Å, c = 8.9637(3) Å, β = 104.494(2)°) and isostructural to pseudo-hollandite compounds, it features mixed Rb and Ba occupancy within its one-dimensional channels. High-temperature X-ray diffraction revealed no decomposition up to 973 K, and the thermal expansion coefficient at 300 K was determined to be 2.6(1)·10 -5 K -1 . Spin-polarized density functional theory (DFT) calculations showed that the density of states for Rb 0.2 Ba 0.4 Cr 5 Se 8 is more polarized than that of Ba 0.5 Cr 5 Se 8 , resulting in a higher Seebeck coefficient, which was experimentally confirmed to reach a peak value of 400 μV·K -1 at 620 K. Resistivity measurements indicated a degenerate semiconducting behavior below 550 K, with a resistivity peak of 100 mΩ·cm at that temperature, leading to a maximum power factor of 0.21 mW·m -1 ·K -2 . Thermal conductivity measurements indicated low values around 0.8 W·m -1 ·K -1 in the 300-900 K range, resulting in a thermoelectric figure of merit of 0.22 at 873 K. Decorrelated transport properties observed in this double-inserted pseudo-hollandite compound make Rb 0.2 Ba 0.4 Cr 5 Se 8 a good example of beneficial synergistic effects for higher thermoelectric performance.

Higher efficiency in large-scale and long-term biodiversity monitoring can be obtained through the use of Essential Biodiversity Variables, among which species population sizes provide key data for conservation programs. Relevant estimations and assessment of actual population sizes are critical for species conservation, especially in the current context of global biodiversity erosion. However, knowledge on population size varies greatly, depending on species conservation status and ranges. While the most threatened or restricted-range species generally benefit from exhaustive counts and surveys, monitoring common and widespread species population size tends to be neglected or is simply more challenging to achieve. In such a context, citizen science (CS) is a powerful tool for the long-term monitoring of common species through the engagement of various volunteers, permitting data acquisition on the long term and over large spatial scales. Despite this substantially increased sampling effort, detectability issues imply that even common species may remain unnoticed at suitable sites. The use of structured CS schemes, including repeated visits, enables to model the detection process, permitting reliable inferences of population size estimates. Here, we relied on a large French structured CS scheme (EPOC-ODF) comprising 27,156 complete checklists over 3,873 sites collected during the 2021-2023 breeding seasons to estimate the population size of 63 common bird species using hierarchical distance sampling (HDS). These population size estimates were compared to the previous expert-based French breeding bird atlas estimations, which did not account for detectability issues. We found that population size estimates from the former French breeding bird atlas were lower than those estimated using HDS for 65% of species. Such a prevalence of lower estimations is likely due to more conservative estimates inferred from semi-quantitative expert-based assessments used for the previous atlas. We also found that species with long-range songs such as the Common Cuckoo ( Cuculus canorus ), Eurasian Hoopoe ( Upupa epops ) or the Eurasian Blackbird ( Turdus merula ) had, in contrast, higher estimated population sizes in the previous atlas than in our HDS models. Our study highlights the need to rely on sound statistical methodology to ensure reliable ecological inferences with adequate uncertainty estimation and advocates for a higher reliance on structured CS in support of long-term biodiversity monitoring., Competing Interests: The authors declare that they have no competing interests., (© 2024 Nabias et al.)

Alima, Perinatal Social Nutrition Centre, is an established community organization that adopts a perinatal social nutrition approach to provide multidimensional support to women living in vulnerable conditions, particularly those with a precarious migratory status. This study aims to ( i ) determine which maternal characteristics, pregnancy-related variables, and structural features of the Alima intervention are associated with breastfeeding; and ( ii ) examine whether the association between attending breastfeeding workshops and breastfeeding characteristics differ according to maternal factors. The Alima digital database was used to analyze data from women who received the perinatal intervention between 2013 and 2020. Infant feeding data were retrieved at 2 weeks postpartum (T0, n  = 2925), 2 months postpartum (T2, n  = 1475), and 4 months postpartum (T4, n  = 890). Logistic regressions were used to estimate the odds of overall and exclusive breastfeeding depending on sociodemographic characteristics, pregnancy-related variables, and features of the intervention. The prevalence of overall and exclusive breastfeeding was, respectively, 96.1% and 60.7% at T0; 93.0% and 58.5% at T2; 83.0% and 48.4% at T4. Higher education, previous breastfeeding experience, and recent immigration were associated with a higher likelihood of breastfeeding at each time point. Breastfeeding workshop attendance was associated with a greater likelihood of overall and exclusive breastfeeding at T2 and T4, with a stronger effect among women aged 35 or less, those with lower education, and those with excessive gestational weight gain. In conclusion, the Alima intervention is associated with positive breastfeeding outcomes, especially among vulnerable women living with precarious migratory status in Canada., Competing Interests: The authors declare there are no competing interests. SL works as a dietitian at Alima, Perinatal Social Nutrition Centre.

Olo nutritional follow-up care offers vulnerable pregnant women food vouchers, multivitamin supplements, tools, and nutritional counselling to support healthy pregnancy outcomes. Purpose: To evaluate the contribution of Olo follow-up care to nutritional intakes and eating practices, as well as to assess the programme-related experience of participants. Methods: Participants (n = 30) responded to questionnaires and web-based 24-hour dietary recalls and participated in a semi-structured interview (n = 10). Results: Olo follow-up care reduced the proportion of participants below the recommended intake for groups for many micronutrients, with the greatest reduction for folate (by 96.7%), vitamin D (by 93.3%), iron (by 70.0%), calcium (by 50.0%), and zinc (by 30.0%), mainly due to the prenatal multivitamin supplements. Most participants (96.7%) did not follow Olo's typical recommendations but, if they had, hypothetically they would have consumed an average of 746 additional calories per day and be above the recommendations for excessive intakes of folic acid and iron (100% and 33.3%, respectively). More than half of the participants were moderately to severely food insecure. Olo contributed to reducing the impact of isolation and increased food accessibility and budget flexibility among participants. Conclusion: Olo follow-up care helped reduce the proportion of women below the recommended intake for micronutrients, but revising the food offered and strategies to address food insecurity may be necessary.

This article presents a comprehensive study on the synthesis and structural and thermal conductivity properties of cesium-inserted chromium tellurides of formula Cs x Cr 5 Te 8 . Single crystals of three different compositions ( x = 0.73, 0.91, and 0.97) were successfully synthesized and suggested the existence of a solid solution in the range 0.73 < x < 1. Through a detailed single-crystal characterization, the complete structure of these compounds is determined, revealing a distinct B -type hollandite-like structural form derived from the hollandite structure, in contrast to the more commonly observed A -type pseudo-hollandite in AM 5 X 8 -type chalcogenides (A = cation, M = transition metal, and X = chalcogen). Periodic density functional theory calculations predict the Cs 0.73 Cr 5 Te 8 composition as the most stable, with a metallic conductive behavior. The thermal conductivity of bulk Cs x Cr 5 Te 8 samples is measured to be 1.4 W m -1 K -1 at 300 K and increases with temperature up to 2 W m -1 K -1 at 673 K.

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated with congenital agenesis of the hands and feet and renal malformation. Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and electoneuromyographically in the patient. These results expand the LRP4 mutations spectrum associated with a previously undescribed clinical association involving impaired neuromuscular transmission and limb deformities and highlighting the critical role of a yet poorly described domain of LRP4 at the NMJ. This study raises the question of the frequency of this rare neuromuscular form and the future diagnosis and management of these cases., (© 2023. Springer Nature Limited.)

Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow-up with an odds ratio of 4.5 ( P =0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09-22.6]; P =0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan-Meier curves (log-rank P =0.045). Conclusions RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration URL: https://www.clinicaltrials.org; unique identifier: NCT02501083.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Declines in European bird populations are reported for decades but the direct effect of major anthropogenic pressures on such declines remains unquantified. Causal relationships between pressures and bird population responses are difficult to identify as pressures interact at different spatial scales and responses vary among species. Here, we uncover direct relationships between population time-series of 170 common bird species, monitored at more than 20,000 sites in 28 European countries, over 37 y, and four widespread anthropogenic pressures: agricultural intensification, change in forest cover, urbanisation and temperature change over the last decades. We quantify the influence of each pressure on population time-series and its importance relative to other pressures, and we identify traits of most affected species. We find that agricultural intensification, in particular pesticides and fertiliser use, is the main pressure for most bird population declines, especially for invertebrate feeders. Responses to changes in forest cover, urbanisation and temperature are more species-specific. Specifically, forest cover is associated with a positive effect and growing urbanisation with a negative effect on population dynamics, while temperature change has an effect on the dynamics of a large number of bird populations, the magnitude and direction of which depend on species' thermal preferences. Our results not only confirm the pervasive and strong effects of anthropogenic pressures on common breeding birds, but quantify the relative strength of these effects stressing the urgent need for transformative changes in the way of inhabiting the world in European countries, if bird populations shall have a chance of recovering.

Polymorphic phases of copper pyrovanadate (α- and β-Cu 2 V 2 O 7 ) were synthesized by solid state reaction and the mechanisms governing the phase transitions have been highlighted by the ThermoGravimetric Analysis (TGA) and the Differential Scanning Calorimetry (DSC). The thermal evolution of the lattice parameters was determined by high temperature X-ray Diffraction revealing negative thermal expansion coefficients. The thermogravimetric analysis coupled with differential scanning calorimetry was also used to determine the optimal conditions to obtain a dense target in order to produce thin films by the Pulsed Laser Deposition (PLD) technique. Thin films elaborated under different oxygen pressures and temperatures exhibit a β-Cu 2 V 2 O 7 polycrystalline phase and their band gap indicates absorption in the visible range. These oxides can be used as photoanodes and their photoelectrochemical properties were studied for both bulk (α-Cu 2 V 2 O 7 ) and thin films (β-Cu 2 V 2 O 7 ), as a function of the wavelength and/or intensity of the luminous flux. The best photocurrent efficiency was obtained under 450 nm illumination. Moreover, in the case of thin films, we have observed a linear evolution of the current density with the luminous flux. Finally, the photostability of thin films was measured and shows a reduction in the photocurrent of 8% after 1 h of measurement. This photocorrosion phenomenon was also highlighted by the elemental mapping performed on thin films by Scanning Electron Microscopy (SEM) coupled with Energy Dispersive X-ray Spectrometry (EDS)., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE)., Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population., Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases., Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively., Conclusions: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments., Competing Interests: Funding Support and Author Disclosures This study was funded by grants from the Association Française contre les Myopathies (French Alliance against Myopathies), which was not involved in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review or approval of the manuscript; nor in the decision to submit the manuscript for publication. Dr Pitceathly is supported by a Medical Research Council (United Kingdom) Clinician Scientist Fellowship (MR/S002065/1). Drs Pitceathly and Hanna receive funding from a Medical Research Council (United Kingdom) strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) (MR/S005021/1). Dr Lopes is supported by a Medical Research Council (United Kingdom) clinical academic partnership (CARP) award. Dr Quinlivan was funded by National Institute for Health and Care Research Biomedical Research Centre, University College Hospitals Foundation Trust. The University College London Hospitals/University College London Queen Square Institute of Neurology sequencing facility receives a proportion of funding from the Department of Health's National Institute for Health and Care Research Biomedical Research Centre’s funding scheme. The clinical and diagnostic “Rare Mitochondrial Disorders” Service in London is funded by the U.K. NHS Highly Specialised Commissioners. Dr Elliott has received consultancy fees from Pfizer, Sanofi, Sarepta, DinaQor, Freeline, Novo Nordisk, and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized., Methods: A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted., Results: Thirty-five patients from 27 unrelated families carrying 17 different missense KCNJ2 mutations (four novel mutations) and a heterozygous KCNJ2 duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate-rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise-induced pain and myalgia attacks. Diagnostic delay was 14.4 ± 9.5 years. ENMG long-exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non-specific myopathic features in one patient; it was normal in four patients., Discussion: Recognition of atypical features (exercise-induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long-exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis., (© 2022 European Academy of Neurology.)

Objectives: A majority of women and families wish that their babies be breastfed. However, too many still receive insufficient or inappropriate initial care from health professionals (HPs) who have limited breastfeeding (BF) competencies. We investigated barriers and potential solutions to improve the undergraduate training programs for various HPs., Methods: Focus groups were carried out in three universities in Quebec and one in Ontario (Canada), with 30 faculty and program directors from medicine, midwifery, nursing, nutrition, and pharmacy. Discussions were subjected to thematic content analysis, before being validated in a strategic planning workshop with 48 participants from the same disciplines, plus dentistry and chiropractic., Findings: Substantive improvements of undergraduate training programs for BF could be obtained by addressing challenges related to the insufficient, or lack of, (i) interactions among various HPs, (ii) opportunities for practical learning, (iii) specific standards to guide course content, (iv) real-life experience with counselling, and (v) understanding of the influence of attitudes on professional practice. Several potential solutions were proposed and validated. The re-interpretation of the results in light of various literature led to an emerging framework that takes a systems perspective for enhancing the education of HPs on BF., Conclusions: To improve the education of HPs so as to enable them to provide relevant support for future mothers, mothers and their families, solutions need to be carried out to address challenges in the health system, the education system as well as regarding the curricular change process., Competing Interests: All authors confirmed that they have no conflict of interest related to the content of this paper., (© 2022 Michaud-Létourneau, Gayard, Lauzière, Beaudry, Pascual, Chartier, Herzhaft-LeRoy, Chiasson, Fontaine-Bisson, Pound, Gaboury; licensee Synergies Partners.)

The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including Wnt family morphogens. To investigate how these synaptic cues in NMJ development are transduced, particularly in the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane, we explored the function of Van Gogh-like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We found that conditional, muscle-specific ablation of Vangl2 in mice reproduced the NMJ differentiation defects seen in mice with global Vangl2 deletion. These alterations persisted into adulthood and led to NMJ disassembly, impaired neurotransmission, and deficits in motor function. Vangl2 and the muscle-specific receptor tyrosine kinase MuSK were functionally associated in Wnt signaling in the muscle. Vangl2 bound to and promoted the signaling activity of MuSK in response to Wnt11. The loss of Vangl2 impaired RhoA activation in cultured mouse myotubes and caused dispersed, rather than clustered, organization of AChRs at the postsynaptic or muscle cell side of NMJs in vivo. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and thus shed light on the molecular mechanisms underlying NMJ assembly.

There have been five Mass Extinction events in the history of Earth's biodiversity, all caused by dramatic but natural phenomena. It has been claimed that the Sixth Mass Extinction may be underway, this time caused entirely by humans. Although considerable evidence indicates that there is a biodiversity crisis of increasing extinctions and plummeting abundances, some do not accept that this amounts to a Sixth Mass Extinction. Often, they use the IUCN Red List to support their stance, arguing that the rate of species loss does not differ from the background rate. However, the Red List is heavily biased: almost all birds and mammals but only a minute fraction of invertebrates have been evaluated against conservation criteria. Incorporating estimates of the true number of invertebrate extinctions leads to the conclusion that the rate vastly exceeds the background rate and that we may indeed be witnessing the start of the Sixth Mass Extinction. As an example, we focus on molluscs, the second largest phylum in numbers of known species, and, extrapolating boldly, estimate that, since around AD 1500, possibly as many as 7.5-13% (150,000-260,000) of all ~2 million known species have already gone extinct, orders of magnitude greater than the 882 (0.04%) on the Red List. We review differences in extinction rates according to realms: marine species face significant threats but, although previous mass extinctions were largely defined by marine invertebrates, there is no evidence that the marine biota has reached the same crisis as the non-marine biota. Island species have suffered far greater rates than continental ones. Plants face similar conservation biases as do invertebrates, although there are hints they may have suffered lower extinction rates. There are also those who do not deny an extinction crisis but accept it as a new trajectory of evolution, because humans are part of the natural world; some even embrace it, with a desire to manipulate it for human benefit. We take issue with these stances. Humans are the only species able to manipulate the Earth on a grand scale, and they have allowed the current crisis to happen. Despite multiple conservation initiatives at various levels, most are not species oriented (certain charismatic vertebrates excepted) and specific actions to protect every living species individually are simply unfeasible because of the tyranny of numbers. As systematic biologists, we encourage the nurturing of the innate human appreciation of biodiversity, but we reaffirm the message that the biodiversity that makes our world so fascinating, beautiful and functional is vanishing unnoticed at an unprecedented rate. In the face of a mounting crisis, scientists must adopt the practices of preventive archaeology, and collect and document as many species as possible before they disappear. All this depends on reviving the venerable study of natural history and taxonomy. Denying the crisis, simply accepting it and doing nothing, or even embracing it for the ostensible benefit of humanity, are not appropriate options and pave the way for the Earth to continue on its sad trajectory towards a Sixth Mass Extinction., (© 2021 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

This study aims to assess the associations between structural features of the Montreal Diet Dispensary's social nutrition intervention and pregnancy (i.e., anemia, gestational diabetes mellitus (GDM), gestational weight gain (GWG), hypertension) and birthweight outcomes (i.e., small- or large-for-gestational-age) among pregnant women, most of them recent immigrants. The study consists of a secondary analysis of the digital client database of the Montreal Diet Dispensary ( n = 2925). Logistic regressions were used to estimate the odds of pregnancy and birthweight outcomes, depending on structural features of the intervention. Pregnant women who attended a welcoming group session presented lower odds of GDM and anemia compared to those who did not attend. A longer duration of intervention was also associated with lower odds of GDM and anemia. Each additional appointment with a dietitian was associated with higher odds of excessive GWG and lower odds of insufficient GWG only among women with a pre-pregnancy BMI lower than 25 kg/m 2 . This study emphasizes the importance of providing nutritional services early in pregnancy to reduce the risk of GDM and anemia. It also stresses the importance of using appropriate nutritional guidelines to avoid increasing the risk of excessive GWG.

The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid β (Aβ) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aβ-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22). Subsequent phenotype analysis of P2X7-deficient Tau mice revealed the instrumental impact of this purinergic receptor. Indeed, while P2X7-deficiency had a moderate effect on Tau pathology itself, we observed a significant reduction of microglia activation and of Tau-related inflammatory mediators, particularly CCL4. Importantly, P2X7 deletion ultimately rescued synaptic plasticity and memory impairments of Tau mice. Altogether, the present data support a contributory role of P2X7 dysregulation on processes governing Tau-induced brain anomalies. Due to the convergent role of P2X7 blockade in both Aβ and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies., (Copyright © 2021. Published by Elsevier Ltd.)

The diversity of insects is tremendous and so is the effort needed to assess it in order to better understand insect ecology as well as their role for the functioning of ecosystems. While the interest of academics and naturalists for these species has always existed, it is only recently that such interest started to reach society more generally. From insect taxonomy and distribution to the collection of large range and long scale monitoring data, the involvement of non-academics in research outputs is growing. Is this a sign of scientists not being able to meet expectations or of science getting more and more entrenched in society? We argue for the latter, highlighting the opportunities that such involvement of amateurs in insect science represent for insect conservation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD)., Methods and Results: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results., Conclusion: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

A series of new ternary isostructural R 4 Co 2 C 3 (R = Y, Gd, Tb) carbides was synthesized by annealing of arc-melted stoichiometric samples. The crystal structure of Tb 4 Co 2 C 3 [space group P2/m, Pearson symbol mP18, a = 12.754(2) Å, b = 3.6251(4) Å, c = 7.0731(9) Å, β = 105.601(6)°] was solved by direct methods from neutron powder diffraction data collected at 100 K. The room temperature unit cell parameters of the new phases were determined by X-ray powder diffraction technique. The crystal structure of Tb 4 Co 2 C 3 is characterized as an intergrowth structure resulting from the stacking of alternating TbCoC (YCoC-type) and Tb 2 C (anti-CdCl 2 type) fragments with a 2 : 1 ratio. Tb 4 Co 2 C 3 orders ferromagnetically at T C = 35(1) K, whereas the isostructural Gd 4 Co 2 C 3 reveals two magnetic transitions at T C1 = 82(3) K and T C2 = 13(2) K. Density functional theory (DFT) calculations confirm that the magnetic moments of the R 4 Co 2 C 3 (R = Gd, Tb) carbides are exclusively due to the rare-earth elements. Y 4 Co 2 C 3 is shown to be a Pauli-paramagnet by experimental and theoretical studies.

Around fifteen thousand fieldworkers annually count breeding birds using standardized protocols in 28 European countries. The observations are collected by using country-specific and standardized protocols, validated, summarized and finally used for the production of continent-wide annual and long-term indices of population size changes of 170 species. Here, we present the database and provide a detailed summary of the methodology used for fieldwork and calculation of the relative population size change estimates. We also provide a brief overview of how the data are used in research, conservation and policy. We believe this unique database, based on decades of bird monitoring alongside the comprehensive summary of its methodology, will facilitate and encourage further use of the Pan-European Common Bird Monitoring Scheme results.

Context: Contrary to nutritional guidelines, accumulating evidence shows that pregnant women's energy intakes remain stable throughout trimesters. Although pregnant women may eat below their needs or underreport their energy intakes, it is also relevant to question how energy requirements - estimated through measurements of energy expenditure (EE) - change throughout pregnancy., Objective: This review examined prospective studies that measured EE during pregnancy, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Data Sources: PubMed/MEDLINE, Web of Science, Embase, and CINAHL databases were searched to identify relevant publications up to November 14, 2019., Study Selection: All studies that measured EE prospectively and objectively during pregnancy were included in this systematic review. Two authors independently screened 4852 references. A total of 32 studies were included in the final analysis., Data Extraction: One author extracted data and assessed the risk of bias and a second author did so for a random sample of studies (n = 7; 22%)., Data Analysis: Increases in resting EE ranged from 0.5% to 18.3% (8-239 kcal), from 3.0% to 24.1% (45-327 kcal), and from 6.4% to 29.6% (93-416 kcal) between early and mid-, mid- and late, and early and late pregnancy, respectively. Increases in total EE ranged from 4.0% to 17.7% (84-363 kcal), from 0.2% to 30.2% (5-694 kcal), and from 7.9% to 33.2% (179-682 kcal) between early and mid-, mid- and late, and early and late pregnancy, respectively. Participants were mainly of normal weight, although many studies did not report important covariates such as prepregnancy body mass index and gestational weight gain adequacy., Conclusions: Additional high-quality longitudinal studies (ie, with multiple objective measurements of EE in all periods of pregnancy while considering important confounding variables, like gestational weight gain) are required., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Canadian expert guidelines recommend low-risk women to consume a daily multivitamin supplement containing 400 µg of folic acid (FA) to prevent neural tube defects. Mandatory food fortification coupled with intake of prenatal vitamin/mineral supplements (PVS), most of which contain ≥ 1000 µg-FA, has resulted in an unprecedented shift in Canadian pregnant women folate status. This study assessed the knowledge, attitude and practice (KAP) of physicians regarding periconceptional FA recommendations, intake and health related outcomes, since they play an essential role in promoting appropriate FA intake. Seventy-seven physicians answered the self-administered KAP survey. Only half of physicians knew the correct dose and duration of FA for low-risk women. Approximately 70% were unsure of, or unfamiliar with the most recent guidelines and 60% of physicians most often recommend a ≥ 1000 µg-FA supplement. Knowledge score 1 (KS1), which related to low-risk women, was associated with physicians' attitude toward believing that most PVS contain the recommended amount of FA (p = 0.004). Significant correlations were also found between KS1 and the total practice score (TPS) (r = 0.45, p <  0.0001) as well as between the total knowledge score and TPS (r = 0.38, p  = 0.0007). Our findings show that physicians lacking knowledge regarding periconceptional FA is associated with their attitude and practice. Despite a vast majority of physicians being unsure or uncomfortable recommending PVS that are not in line with recommendations, a lack of knowledge and a widely accessible 400 µg-FA PVS, enables a contradictory practice in reality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2021 Published by Elsevier Inc.)

Two N-methylpyridinium compounds and analogous N-protonated salts of 2- and 2,7-substituted 4-pyridyl-pyrene compounds were synthesised and their crystal structures, photophysical properties both in solution and in the solid state, electrochemical and spectroelectrochemical properties were studied. Upon methylation or protonation, the emission maxima are significantly bathochromically shifted compared to the neutral compounds, although the absorption maxima remain almost unchanged. As a result, the cationic compounds show very large apparent Stokes shifts of up to 7200 cm -1 . The N-methylpyridinium compounds have a single reduction at ca. -1.5 V vs. Fc/Fc + in MeCN. While the reduction process was reversible for the 2,7-disubstituted compound, it was irreversible for the mono-substituted one. Experimental findings are complemented by DFT and TD-DFT calculations. Furthermore, the N-methylpyridinium compounds show strong interactions with calf thymus (ct)-DNA, presumably by intercalation, which paves the way for further applications of these multi-functional compounds as potential DNA-bioactive agents., (© 2020 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP., Objective: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background., Methods: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process., Results: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from CAI compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies., Conclusions: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.

Background: The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when left ventricular ejection fraction (LVEF) falls below 40%., Objective: To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy., Methods: From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and ≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to <35% in patients who received an ACE-i when LVEF fell below 40% (conventional treatment), versus below 50% (early treatment)., Results: From the 183 patients entered in our registry, we identified 85 whose LVEF was between 40 and 49%, 51 of whom received early and 34 received conventional ACE-i treatment. Among patients with early versus conventional treatments, 2 (3.9%) versus 4 (11.8%) were hospitalized for management of HF [hazard ratio (HR) 0.151; 95% confidence interval (CI) 0.028 to 0.822; p = 0.029], and 9 (17.6%) versus 10 (29.4%) had a decrease in LVEF below 35% (HR 0.290; 95% CI 0.121 to 0.694; p = 0.005)., Conclusions: The long-term cardiac outcome of patients presenting with Becker MD was significantly better when treatment with ACE-i was introduced after a decrease in LVEF below 50%, instead of below 40% as recommended in the current practice guidelines issued by professional societies.

Linezolid and beta-lactams are anti-infective drugs frequently used in intensive care unit patients. Critical illness could induce alterations of pharmacokinetic parameters due to changes in the distribution, the metabolism and the elimination process. Therapeutic drug monitoring (TDM) is therefore recommended to prevent mainly under-dosing of beta-lactams or hematological and neurological toxicities of linezolid. In Multi-or Extensively-Drugs Resistant-Tuberculosis Bacteria, the regimen could include linezolid with meropenem and amoxicillin/clavulanate justifying the development of a method allowing their simultaneous quantification. The aim of this work was to develop an in-house ultra-performance liquid chromatography method with UV detection (UHPLC-PDA) allowing the simultaneous determination of 8 beta-lactams (amoxicillin, aztreonam, cefepime, ceftazidime, ceftriaxone, cefuroxime, meropenem and piperacillin) and linezolid and to cross-validate the linezolid quantification with a new commercial immunoassay (ARK kit) tested on a Cobas analyzer. The main advantages of the immunoassay are a 24/24 h random access assay which is fully automated and results provided within 2 h. The interference due to potential co-administrated drugs was evaluated on both methods. The preanalytical factors (type of matrix, stability) for linezolid were also investigated. The influence of hemolysis, icteria or lipemia on the spectroscopic detection of the immunoassay was assessed. The analytical performances were evaluated using the accuracy profiles approach with acceptance limits fixed at ±30%. Seventy patient samples were measured using both methods. No cross-reaction with the tested anti-infective drugs as well as no influence of hemolysis, lipemia, icteria were observed. The linezolid concentration could be measured on heparinized plasma or serum without a significant difference and remained stable for at least 72h at 4°C.The UHPLC-PDA method performed well in the analytical range investigated (0.25-50 mg/L for meropenem, 0.75-50 mg/L for linezolid and 1-200 mg/L for other beta-lactams) with an intermediate precision and a relative bias below 7.6 and 7.7%, respectively. The analytical range of the immunoassay was narrower, from 0.85 to 18.5 mg/L. The precision and relative bias were lower than 8.1% and 4.2%, respectively. Results obtained on clinical samples showed an acceptable difference between methods with a mean bias of -1.8% [95% confidence interval: -5.2% - 1.6%]. To conclude, both methods showed acceptable performance to perform TDM of linezolid considering the therapeutic through target of 2-8 mg/L. The choice of the method should be made according to the degree of emergency of the response required and the field of application justifying or not the simultaneous quantification of beta-lactams and linezolid., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 ( SYT2 ) gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs)., Methods: Next-generation sequencing identified new homozygous intronic and frameshift mutations in the SYT2 gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ)., Results: The 2 infants presented a similar clinical phenotype evoking first a congenital myopathy characterized by muscle weakness and hypotonia. Next-generation sequencing allowed to the identification of 1 homozygous intronic mutation c.465+1G>A in patient 1 and another homozygous frameshift mutation c.328&#95;331dup in patient 2, located respectively in the 5' splice donor site of SYT2 intron 4 and in exon 3. Functional studies of the intronic mutation validated the abolition of the splice donor site of exon 4 leading to its skipping. In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects., Conclusions: This study identifies new homozygous recessive SYT2 mutations as the underlying cause of severe and early presynaptic form of CMS expanding the genetic spectrum of recessive SYT2 -related CMS associated with defects in neurotransmitter release., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications., (© 2020 Wiley Periodicals, Inc.)

Background: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families., Aims: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD., Results: Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence., Conclusions: This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data.

Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in CACNA1S coding for Ca V 1.1 and SCN4A coding for Na V 1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either Ca V 1.1 or Na V 1.4. Mutant channels have aberrant leak currents called 'gating pore currents', and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five hypokalaemic periodic paralysis cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other hypokalaemic periodic paralysis families. One case is R219K in Na V 1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in Ca V 1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of Ca V 1.1-R897K. Na V 1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by Na V 1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical hypokalaemic periodic paralysis phenotypes do not fit the canonical view that the essential defect in hypokalaemic periodic paralysis mutant channels is the gating pore current and raise the possibility that hypokalaemic periodic paralysis pathogenesis might be heterogeneous and diverse., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Relying on capacity increases and patient transfers to deal with the huge and continuous inflow of COVID-19 critically ill patients is a strategy limited by finite human and logistical resources., Rationale: Prioritising both critical care initiation and continuation is paramount to save the greatest number of lives. It enables to allocate scarce resources in priority to those with the highest probability of benefiting from them. It is fully ethical provided it relies on objective and widely shared criteria, thus preventing arbitrary decisions and guaranteeing equity. Prioritisation seeks to fairly allocate treatments, maximise saved lives, gain indirect life benefits from prioritising exposed healthcare and similar workers, give priority to those most penalised as a last resort, and apply similar prioritisation schemes to all patients., Prioritisation Strategy: Prioritisation schemes and their criteria are adjusted to the level of resource scarcity: strain (level A) or saturation (level B). Prioritisation yields a four level priority for initiation or continuation of critical care: P1-high priority, P2-intermediate priority, P3-not needed, P4-not appropriate. Prioritisation schemes take into account the patient's wishes, clinical frailty, pre-existing chronic condition, along with severity and evolution of acute condition. Initial priority level must be reassessed, at least after 48h once missing decision elements are available, at the typical turning point in the disease's natural history (ICU days 7 to 10 for COVID-19), and each time resource scarcity levels change. For treatments to be withheld or withdrawn, a collegial decision-making process and information of patient and/or next of kin are paramount., Perspective: Prioritisation strategy is bound to evolve with new knowledge and with changes within the epidemiological situation., (Copyright © 2020 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Depending on their theatre of operation, French soldiers may potentially be exposed to scorpion stings and snakebites. Following the recommendations of a French military health service (FMHS) technical committee for envenomation, the FMHS provides antivenoms appropriate to each deployment. This work aimed to evaluate this risk of envenomation and to assess the antivenoms used by the FMHS in operational theatres since the creation of this committee in 2015., Methods: Cases were identified based on a review of temporary authorization of use application forms for the use of antivenom. Data were collected retrospectively from these forms, and prescribing physicians were contacted for any missing data., Results: Between 2015 and 2017, 28 requests for temporary authorization of use were identified: 19 for Scorpifav (Sanofi-Pasteur, Lyon, France) and 9 for Fav-Afrique (Sanofi-Pasteur). The FMHS treated 15 soldiers and 4 civilians for scorpion envenomation with Scorpifav: 15 in Mali, 3 in Chad, and 1 in Niger. Systemic signs were observed in 7 patients. Two soldiers and 7 civilians were treated with Fav-Afrique for ophidian envenomation: 5 in Djibouti, 3 in Mali, and 1 in the Republic of Côte d'Ivoire. These 28 patients were treated without sequelae. Other than moderate erythema that resolved with an antihistamine, no adverse effects were reported. Medical evacuation to France was unnecessary., Conclusions: This study shows that the risk of envenomation for soldiers on deployment is low but real. Antivenoms used by the FMHS were efficient and well tolerated, preserving the operational capacity of deployed troops., (Copyright © 2020 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Despite growing concern over consequences of global changes, we still know little about potential interactive effects of anthropogenic perturbations and diversity loss on the stability of local communities, especially for taxa other than plants. Here we analyse the relationships among landscape composition, biodiversity and community stability looking at time series of three types of communities, i.e., bats, birds and butterflies, monitored over the years by citizen science programs in France. We show that urban and intensive agricultural landscapes as well as diversity loss destabilize these communities but in different ways: while diversity loss translates into greater population synchrony, urban and intensive agricultural landscapes mainly decrease mean population stability. In addition to highlight the stabilizing effects of diversity on ecologically important but overlooked taxa, our results further reveal new pathways linking anthropogenic activities to diversity and stability.

By monitoring biodiversity through citizen science programs, volunteers help scientists gather data at unprecedented temporal and geographical scales, and increase their knowledge and awareness of the surrounding biodiversity. While scientific outcomes of such programs may in the long run improve the state of biodiversity by informing environmental policies, direct benefits to biodiversity could arise locally if such experience of nature leads to biodiversity-friendly behaviors in volunteers. However, whether engagement into nature-based CS programs promotes individual behavioral changes remains poorly known. Here, we explored whether sustained participation in a nature-based citizen science program, called the French Butterfly citizen science project, is associated with changes in individual gardening practices. Specifically, using information provided by volunteers (n = 2362, from 2006 to 2013), we quantified gardening practices that directly affect butterflies, through two different indices: provision of nectar resources, and pesticide use. We found quantitative evidence that individual gardening practices shifted with multi-year participation, towards increased provision of nectar resources and decreased use of pesticides. However, the reduction in pesticide use was weakened if the backyard was used to grow fruits or vegetables. Other variables such as the size of the backyard affected gardening practices. This study reveals that participation in a nature-based citizen science program can prompt biodiversity-friendly behaviors, and highlights citizen science not only as a way to collect ecologically sound data but also as a direct conservation tool. Yet, future interdisciplinary research remains critical to overcome factors limiting firm adoption of pro-biodiversity behaviors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: The aim of this study was to compare the efficacy and maternal-neonatal morbidity between balloon catheter and oxytocin for induction of labor in women with a previous cesarean section and an unfavorable cervix., Material and Methods: This open-label randomized controlled trial took place in seven French hospitals. Inclusion criteria were medical indication for labor induction in pregnant women, ≥37 weeks, with lower segment cesarean section, Bishop score ≤4, no pre-labor rupture of membranes, singleton fetus in cephalic presentation. Women were allocated randomly to induction with a 50-mL balloon catheter for 12 hours or a low-dose oxytocin infusion. Primary outcome was the rate of vaginal birth. Secondary outcomes were maternal and neonatal complications., Results: The study enrolled 204 women from 26 December 2010 to 31 December 2013: 101 were allocated to receive balloon catheter and 103 to oxytocin. Vaginal birth rate was 50% (n = 51) in the balloon catheter group vs 37% (n = 38) in the oxytocin group (P = 0.050). Maternal and neonatal morbidity did not differ between balloon catheter and oxytocin groups: two uterine dehiscences vs one, one vs four maternal infections, five vs two hemorrhages and 11 vs five neonatal transfers, respectively. Heterogeneity of treatment effect for vaginal delivery was observed across initial Bishop scores. Balloon catheter was more effective for low values of bishop score., Conclusions: Balloon catheter tended to be associated with a higher probability of vaginal delivery as compared with low-dose intravenous oxytocin when used for induction of labor in women with a previous cesarean section and low Bishop score at induction., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly ( p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset ( p = 3.17 × 10 -4 ). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.

Single neurons function along a spectrum of neuronal operating modes whose properties determine how the output firing activity is generated from synaptic input. The auditory brain stem contains a diversity of neurons, from pure coincidence detectors to pure integrators and those with intermediate properties. We investigated how intrinsic spike initiation mechanisms regulate neuronal operating mode in the avian cochlear nucleus. Although the neurons in one division of the avian cochlear nucleus, nucleus magnocellularis, have been studied in depth, the spike threshold dynamics of the tonically firing neurons of a second division of cochlear nucleus, nucleus angularis (NA), remained unexplained. The input-output functions of tonically firing NA neurons were interrogated with directly injected in vivo-like current stimuli during whole cell patch-clamp recordings in vitro. Increasing the amplitude of the noise fluctuations in the current stimulus enhanced the firing rates in one subset of tonically firing neurons ("differentiators") but not another ("integrators"). We found that spike thresholds showed significantly greater adaptation and variability in the differentiator neurons. A leaky integrate-and-fire neuronal model with an adaptive spike initiation process derived from sodium channel dynamics was fit to the firing responses and could recapitulate >80% of the precise temporal firing across a range of fluctuation and mean current levels. Greater threshold adaptation explained the frequency-current curve changes due to a hyperpolarized shift in the effective adaptation voltage range and longer-lasting threshold adaptation in differentiators. The fine-tuning of the intrinsic properties of different NA neurons suggests they may have specialized roles in spectrotemporal processing. NEW & NOTEWORTHY Avian cochlear nucleus angularis (NA) neurons are responsible for encoding sound intensity for sound localization and spectrotemporal processing. An adaptive spike threshold mechanism fine-tunes a subset of repetitive-spiking neurons in NA to confer coincidence detector-like properties. A model based on sodium channel inactivation properties reproduced the activity via a hyperpolarized shift in adaptation conferring fluctuation sensitivity.

The present study aimed to characterize dietary intake and diet quality from late pregnancy to six months postpartum. Participants ( n = 28) completed 2-3 Web-based 24 h recalls at three distinct periods: (1) during the third trimester of pregnancy; (2) three months and (3) six months after delivery. Energy, macro-and micronutrient intakes (from foods and supplements), as well as the Canadian healthy eating index (C-HEI) were derived from the dietary recalls. No significant variation in energy and macronutrient intakes was observed between time points. The proportion of women taking at least one supplement decreased over time ( p = 0.003). The total intake of several micronutrients (vitamins A, C, D, group B vitamins, iron, magnesium, zinc, calcium, phosphorus, manganese, and copper) decreased significantly over time ( p < 0.05 for all micronutrients). The total C-HEI score and its components did not change, except for the total vegetables and fruit subscore, which decreased over time (8.2 ± 2.0 in the 3rd trimester, 7.1 ± 2.2 at three months postpartum, 6.9 ± 2.4 at 6 months postpartum, p = 0.04). In conclusion, we observed a general stability in diet quality, energy, and macronutrient intakes from the third trimester of pregnancy to six months postpartum. However, several micronutrient intakes decreased over time, mostly due to changes in supplement use.

Background: Although lung protection with low tidal volume and limited plateau pressure (P plat ) improves survival in acute respiratory distress syndrome patients (ARDS), the best way to set positive end-expiratory pressure (PEEP) is still debated., Methods: This study aimed to compare two strategies using individual PEEP based on a maximum P plat (28-30 cmH 2 O, the Express group) or on keeping end-expiratory transpulmonary pressure positive (0-5 cmH 2 O, P Lexpi group). We estimated alveolar recruitment (Vrec), end-expiratory lung volume and alveolar distension based on elastance-related end-inspiratory transpulmonary pressure (P L,EL )., Results: Nineteen patients with moderate to severe ARDS (PaO 2 /FiO 2  < 150 mmHg) were included with a baseline PEEP of 7.0 ± 1.8 cmH 2 O and a PaO 2 /FiO 2 of 91.2 ± 31.2 mmHg. PEEP and oxygenation increased significantly from baseline with both protocols; PEEP Express group was 14.2 ± 3.6 cmH 2 O versus 16.7 ± 5.9 cmH 2 O in P Lexpi group. No patient had the same PEEP with the two protocols. Vrec was higher with the latter protocol (299 [0 to 875] vs. 222 [47 to 483] ml, p = 0.049) and correlated with improved oxygenation (R 2  = 0.45, p = 0.002). Two and seven patients in the Express and P L,expi groups, respectively, had P L,EL  > 25 cmH 2 O., Conclusions: There is a great heterogeneity of P Lexpi when P plat is used to titrate PEEP but with limited risk of over-distension. A PEEP titration for a moderate positive level of P Lexpi might slightly improve alveolar recruitment and oxygenation but increases the risk of over-distension in one-third of patients.

Objective: We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 ( SPG7 )., Methods: We analyzed clinical and genetic data from 241 patients with SPG7 , integrating neurologic follow-up data. One case was examined neuropathologically., Results: Patients with SPG7 had a mean age of 35.5 ± 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria ( p < 0.05), deep sensory loss ( p < 0.01), muscle wasting ( p < 0.01), ophthalmoplegia ( p < 0.05), and sphincter dysfunction ( p < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs ( p < 0.05), diminished visual acuity due to optic atrophy ( p < 0.0001), and deep sensory loss ( p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs 32.8 ± 14.6 years, p < 0.05) and showed ataxia at onset ( p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons., Conclusions: This is the largest SPG7 cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant., (© 2019 American Academy of Neurology.)

Mo-based cluster compounds are a large class of materials with complex crystal structures that give rise to very low lattice thermal conductivity. Here, we report on the crystal structure and transport property measurements (5-800 K) of the novel Tl-filled compound Ag 3 Tl 2 Mo 15 Se 19 . This compound adopts a crystal structure described in the rhombohedral R3 c space group [ a = 9.9601(1) Å, c = 57.3025(8) Å, and Z = 6] built by the covalent arrangement of octahedral Mo 6 and bioctahedral Mo 9 clusters in a 1:1 ratio, with the Ag and Tl atoms filling the large cavities between them. Transport property measurements performed on polycrystalline samples indicate that this compound behaves as a heavily doped semiconductor with mixed electrical conduction. Electronic band structure calculations combined with a semiclassical approach using the Boltzmann transport equation are in good agreement with these measurements. This compound exhibits a lattice thermal conductivity as low as 0.4 W m -1 K -1 because of highly disordered Ag and Tl atoms. Because of the low thermopower values induced by the mixed electrical conduction, the dimensionless thermoelectric figure of merit ZT remains moderate with a peak value of 0.18 at 750 K.

Introduction: Animal studies suggested that NFKB1 , IKBKB , and SOCS3 genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and macronutrient intakes affecting obesity-related phenotypes. Methods: We used a traditional statistical method, logistic regression, and compared it to alternative statistical method, multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR), to better detect genes/environment interactions in the Toronto Nutrigenomics and Health Study ( n = 1639) using dichotomized body mass index (BMI) and waist circumference as obesity-related phenotypes. Exposure variables included genotype on 54 single nucleotide polymorphisms ( NFKB1 : 18, IKBKB : 9, SOCS3 : 27), macronutrient (carbohydrates, protein, fat) and alcohol intakes and ethno-cultural background. Results: After correction for multiple testing, no interaction was found using logistic regression. MDR identified interactions between SOCS3 rs6501199 and rs4969172, and IKBKB rs3747811 affecting BMI in the Caucasian population; SOCS3 rs6501199 and NFKB1 rs1609798 affecting WC in the Caucasian population; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in the South Asian population. PLR found a main effect of SOCS3 rs12944581 on BMI among the South Asian population. Conclusion: While MDR and PLR had discordant results, some models support results from previous studies. These results emphasize the need to use alternative statistical methods to investigate high-order interactions and suggest that variants in the nutrient-responsive hypothalamic IKKB/NF-kB signaling pathway may be involved in obesity pathogenesis.

Evidence for a relationship between omega-6/omega-3 (n-6/n-3) polyunsaturated fatty acid (PUFA) ratio and obesity in humans is inconsistent, perhaps due to differences in dietary intake or metabolism of PUFAs between different subsets of the population. Since chronic inflammation is central to obesity and inflammatory pathways are regulated by PUFAs, the objective of this study was to examine whether variants in the NFKB1 gene, an upstream regulator of the inflammatory response, modify the association between the n-6/n-3 ratio (from diet and plasma) and anthropometric traits in a multiethnic/multiracial population of young adults. Participants' ( n = 898) dietary PUFA intake was assessed using a food frequency questionnaire and plasma PUFA concentrations by gas chromatography. Nine tag single nucleotide polymorphisms (SNP) in NFKB1 were genotyped. Significant interactions were found between racial/ethnic groups and plasma n-6/n-3 ratio for body mass index (BMI) ( p = 0.02) and waist circumference (WC) ( p = 0.007). Significant interactions were also observed between racial/ethnic groups and three NFKB1 genotypes (rs11722146, rs1609798, and rs230511) for BMI and WC (all p ≤ 0.04). Significant interactions were found between two NFKB1 genotypes and plasma n-6/n-3 ratio for BMI and WC (rs4648090 p = 0.02 and 0.03; rs4648022 p = 0.06 and 0.04, respectively). Our findings suggest that anthropometric traits may be influenced by a unique combination of n-6/n-3 ratio, racial/ethnic background, and NFKB1 genotypes.