AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

High production of pro-inflammatory cytokines by maternal blood mononuclear cells is associated with reduced maternal malaria but increased cord blood infection

BACKGROUND: Increased susceptibility to malaria during pregnancy is not completely understood. Cellular immune responses mediate both pathology and immunity but the effector responses involved in these processes have not been fully characterized. Maternal and fetal cytokine and chemokine responses to malaria at delivery, and their association with pregnancy and childhood outcomes, were investigated in 174 samples from a mother and child cohort from Mozambique. Peripheral and cord mononuclear cells were stimulated with Plasmodium falciparum lysate and secretion of IL-12p70, IFN-gamma, IL-2, IL-10, IL-8, IL-6, IL-4, IL-5, IL-1beta, TNF, TNF-beta was quantified in culture supernatants by multiplex flow cytometry while cellular mRNA expression of IFN-gamma, TNF, IL-2, IL-4, IL-6, IL-10 and IL-13 was measured by quantitative PCR. RESULTS: Higher concentrations of IL-6 and IL-1beta were associated with a reduced risk of P. falciparum infection in pregnant women (p < 0.049). Pro-inflammatory cytokines IL-6, IL-1beta and TNF strongly correlated among themselves (rho > 0.5, p < 0.001). Higher production of IL-1beta was significantly associated with congenital malaria (p < 0.046) and excessive TNF was associated with peripheral infection and placental lesions (p < 0.044). CONCLUSIONS: Complex network of immuno-pathological cytokine mechanisms in the placental and utero environments showed a potential trade-off between positive and negative effects on mother and newborn susceptibility to infection

Predicting 3D lip shapes using facial surface EMG

Aim: The aim of this study is to prove that facial surface electromyography (sEMG) conveys sufficient information to predict 3D lip shapes. High sEMG predictive accuracy implies we could train a neural control model for activation of biomechanical models by simultaneously recording sEMG signals and their associated motions. Materials and methods: With a stereo camera set-up, we recorded 3D lip shapes and simultaneously performed sEMG measurements of the facial muscles, applying principal component analysis (PCA) and a modified general regression neural network (GRNN) to link the sEMG measurements to 3D lip shapes. To test reproducibility, we conducted our experiment on five volunteers, evaluating several sEMG features and window lengths in unipolar and bipolar configurations in search of the optimal settings for facial sEMG. Conclusions: The errors of the two methods were comparable. We managed to predict 3D lip shapes with a mean accuracy of 2.76 mm when using the PCA method and 2.78 mm when using modified GRNN. Whereas performance improved with shorter window lengths, feature type and configuration had little influence

Restoration in applied ecology: editor's introduction

1. The need to rehabilitate and restore ecological resources degraded by overuse was already established when the Journal of Applied Ecology was launched in 1964. In the intervening 40 years, submissions on restoration have increased and now contribute at least 8–12% of the papers published annually. Examples from subjects such as conservation biology, pollution ecology and ecological modelling show that notions of restoration or recovery are now implicit in the philosophy of applied ecology. 2. The terminology of restoration ecology is increasingly clear, but there is still debate about the definition of restoration end-points. Although restoration constitutes the process of assisting recovery, success ultimately depends on whether populations, communities and ecological functions attain limits typical of un-degraded reference systems. With evidence increasing that the removal of stressors is not always sufficient to guarantee restoration success, the true arbiters will be the organisms and processes at which restoration is aimed. Stringent appraisal on these ecological criteria will be required if restored systems are to conserve biodiversity and deliver ecosystem services to the extent that many restoration ecologists believe is possible. 3. Botanical systems have figured most prominently among the Journal's restoration papers, but there is increasing emphasis on the restoration of individual populations or species, often invertebrates or vertebrates such as birds. 4. Recent contributions on restoration to the Journal of Applied Ecology include projects seeking the ideal technical solutions to specific restoration problems. Other papers are distinguished for their seminal value and often show that intervention is preferable to natural succession in delivering a successful outcome. Examples range from species and ecosystem-level restoration to real evidence that large-scale restoration can be achieved by policy instruments such as agri-environment. Papers published in the Journal also show how restoration can bring ecological value to urban locations, where many people now gain their first-ever wildlife experiences. 5. Synthesis and applications. This special profile of five papers follows these themes in developing the assessment of restoration end-points, in understanding the restoration process, and in identifying factors that promote success or bring failure. Restoration ecology offers yet another example where the application of ecology simultaneously provides academic leadership and solutions to real environmental problems. In an era in which the adverse economic and ecological consequences of environmental degradation are increasingly unacceptable, restoration ecology is emerging as one of the most important disciplines in the whole of environmental science

Heart rate pattern and resting heart rate variability mediate individual differences in contextual anxiety and conditioned responses

Cardiac activity provides possible markers for the identification of those at risk for the development of anxiety disorders. Cardiac deceleration has been linked to impaired fear conditioning while low heart rate variability (HRV) has been associated with elevated contextual anxiety and enhanced startle potentiation to affective stimuli. In the current study we examined individual differences in conditioned responses as a function of cardiac activity. In addition to classifying participants as decelerators and accelerators, we examined baseline fear responding and conditioned responses in participants with low and high resting state heart rate variability. We complemented well-established physiological measures (startle response and skin conductance) and online distress and retrospective expectancy ratings of fear conditioning with measures of heart rate (HR). In contrast to accelerators, decelerators did not show any sign of startle fear conditioning, but demonstrated increased differential conditioning of online distress. Only marginal differences in contextual anxiety and conditioned fear responding were observed for low and high HRV individuals. These results may contribute to the identification of individuals who are at risk for the development of anxiety disorders

Immunocompromised patients with acute respiratory distress syndrome: Secondary analysis of the LUNG SAFE database

Background: The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p &lt; 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p &lt; 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013