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People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy.We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity.Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses.Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.

Abstract Sudden unexpected death in epilepsy (SUDEP) is the leading epilepsy-related cause of premature mortality in people with intractable epilepsy, who are 27 times more likely to die than the general population. Impairment of the central control of breathing following a seizure has been identified as a putative cause of death, but the mechanisms underlying this seizure-induced breathing failure are largely unknown. Our laboratory has advanced a vascular theory of postictal behavioural dysfunction, including SUDEP. We have recently reported that seizure-induced death occurs after seizures invade brainstem breathing centres which then leads to local hypoxia causing breathing failure and death. Here we investigated the effects of caffeine and two adenosine receptors in two models of seizure-induced death. We recorded local oxygen levels in brainstem breathing centres as well as time to cessation of breathing and cardiac activity relative to seizure activity. The administration of the non-selective A1/A2A antagonist caffeine or the selective A1 agonist N6-cyclopentyladenosine reveals a detrimental effect on postictal hypoxia, providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, A2A activation with CGS-21680 was found to increase the lifespan of mice in both our models of seizure-induced death.

Objectives: A prolonged vasoconstriction/hypoperfusion/hypoxic event follows self-terminating focal seizures. The ketogenic diet (KD) has demonstrated efficacy as a metabolic treatment for intractable epilepsy and other disorders but its effect on local brain oxygen levels is completely unknown. This study investigated the effects of the KD on tissue oxygenation in the hippocampus before and after electrically elicited (kindled) seizures and whether it could protect against a seizure-induced learning impairment. We also examined the effects of the ketone β-hydroxybutyrate (BHB) as a potential underlying mechanism. Methods: Male and female rats were given access to one of three diet protocols 2 weeks prior to the initiation of seizures: KD, caloric restricted standard chow, and ad libitum standard chow. Dorsal hippocampal oxygen levels were measured prior to initiation of diets as well as before and after a 10-day kindling paradigm. Male rats were then tested on a novel object recognition task to assess postictal learning impairments. In a separate cohort, BHB was administered 30 min prior to seizure elicitation to determine whether it influenced oxygen dynamics. Results: The KD increased dorsal hippocampal oxygen levels, ameliorated postictal hypoxia, and prevented postictal learning impairments. Acute BHB administration did not alter oxygen levels before or after seizures. Interpretation: The ketogenic diet raised brain oxygen levels and attenuated severe postictal hypoxia likely through a mechanism independent of ketosis and shows promise as a non-pharmacological treatment to prevent the postictal state.

This paper is devoted to the modeling of finite deformations of elastic bodies under contact/impact conditions. In this kind of applications, it is well known that the total energy will be reduced versus time because of frictional effects. However, how to identify the dissipated energy in a quantitative way remains an open question. The aim of this work is to propose a numerical solution to this question. The proposed Bi-First algorithm combines the bi-potential method for contact modeling in dynamic cases and the first order algorithm for integration of the equation of motion. Numerical examples involve the impact of an elastic plate onto a rigid surface and the impact between two hyperelastic blocks and a rigid wall. The dissipated energy versus time will be plotted and the influence of friction coefficient on the dissipated energy will be discussed.

Abstract Background We aimed to investigate the association of intracranial complications diagnosed on neuroimaging with neurological outcomes of adults with severe pneumococcal meningitis. Methods We performed a retrospective multicenter study on consecutive adults diagnosed with pneumococcal meningitis requiring at least 48 h of stay in the intensive care unit (ICU) and undergoing neuroimaging, between 2005 and 2021. All neuroimaging were reanalyzed to look for intracranial complications which were categorized as (1) ischemic lesion, (2) intracranial hemorrhage (3) abscess/empyema, (4) ventriculitis, (5) cerebral venous thrombosis, (6) hydrocephalus, (7) diffuse cerebral oedema. The primary outcome was unfavorable outcome at 90 days after ICU admission, defined by a modified Rankin Scale (mRS) score > 2. Results Among the 237 patients included, intracranial complications were diagnosed in 68/220 patients (31%, 95%CI 0.25–0.37) who underwent neuroimaging at ICU admission and in 75/110 patients (68%, 95%CI 0.59–0.77) who underwent neuroimaging during ICU stay. At 90 days, 103 patients (44%, 95%CI 37–50) had unfavorable outcome, including 71 (30%) deaths. The most frequent intracranial complications were ischemic lesion (69/237 patients, 29%), diffuse cerebral oedema (43/237, 18%) and ventriculitis (36/237, 15%). Through multivariable analysis, we found that intracranial complications (adjusted odds ratio (aOR) 2.88, 95%CI 1.37–6.21) were associated with unfavorable outcome, along with chronic alcohol consumption (aOR 3.10, 95%CI 1.27–7.90), chronic vascular disease (aOR 4.41, 95%CI 1.58–13.63), focal neurological sign(s) (aOR 2.38, 95%CI 1.11–5.23), and cerebrospinal fluid leukocyte count

Abstract Background The development of controlled donation after circulatory death (cDCD) is both important and challenging. The tension between end-of-life care and organ donation raises significant ethical issues for healthcare professionals in the intensive care unit (ICU). The aim of this prospective, multicenter, observational study is to better understand ICU physicians’ and nurses’ experiences with cDCD. Methods In 32 ICUs in France, ICU physicians and nurses were invited to complete a questionnaire after the death of end-of-life ICU patients identified as potential cDCD donors who had either experienced the withdrawal of life-sustaining therapies alone or with planned organ donation (OD(-) and OD( +) groups). The primary objective was to assess their anxiety (State Anxiety Inventory STAI Y-A) following the death of a potential cDCD donor. Secondary objectives were to explore potential tensions experienced between end-of-life care and organ donation. Results Two hundred six ICU healthcare professionals (79 physicians and 127 nurses) were included in the course of 79 potential cDCD donor situations. STAI Y-A did not differ between the OD(-) and OD( +) groups for either physicians or nurses (STAI Y-A were 34 (27–38) in OD(-) vs. 32 (27–40) in OD( +), p = 0.911, for physicians and 32 (25–37) in OD(-) vs. 39 (26–37) in OD( +), p = 0.875, for nurses). The possibility of organ donation was a factor influencing the WLST decision for nurses only, and a factor influencing the WLST implementation for both nurses and physicians. cDCD experience is perceived positively by ICU healthcare professionals overall. Conclusions cDCD does not increase anxiety in ICU healthcare professionals compared to other situations of WLST. WLST and cDCD procedures could further be improved by supporting professionals in making their intentions clear between end-of-life support and the success of organ donation, and when needed, by enhancing communication between ICU physician and nurses. Trial registration This research was registered in ClinicalTrials.gov (Identifier: NCT05041023, September 10, 2021).

Abstract Background People living with HIV (PLWH) are at risk of frailty, which is predictive for death. As an overactivity of the immune system is thought to fuel frailty, we characterized the immune activation profiles linked to frailty. Methods We quantified twenty-seven activation markers in forty-six virological responders (four females and forty-two males; median age, 74 years; median duration of infection, 24 years; median duration of undetectability, 13 years), whose frailty was determined according to the Fried criteria. T cell and NK cell activation was evaluated by flow cytometry, using a panel of cell surface markers. Soluble markers of inflammation, and monocyte activation and endothelial activation were measured by ELISA. The participants’ immune activation was profiled by an unsupervised double hierarchical clustering analysis. We used ANOVA p-values to rank immunomarkers most related to Fried score. A Linear Discriminant Analysis (LDA) was performed to link immune activation markers to frailty. Results 41% of the participants were pre-frail, including 24% with a Fried score of 1, and 17% with a Fried score of 2. ANOVA identified the 14 markers of T cell, monocyte, NK cell, endothelial activation, and inflammation the most linked to Fried 3 classes. The LDA performed with these 14 markers was capable of discriminating volunteers according to their Fried score. Two out of the 5 immune activation profiles revealed by the hierarchical clustering were linked to and predictive of pre-frailty. These two profiles were characterized by a low percentage of CD4 T cells and a high percentage of CD8 T cells, activated CD4 T cells, CD8 T cells, and NK cells, and inflammation. Conclusions We identified a particular immune activation profile associated with pre-frailty in PLWH. Profiling participants at risk of developing frailty might help to tailor the screening and prevention of medical complications fueled by loss of robustness. Further studies will indicate whether this frailty signature is specific or not of HIV infection, and whether it also precedes frailty in the general population.

Abstract Background and objectives Henoch–Schönlein purpura (HSP) is the most common immunoglobulin A-mediated systemic vasculitis in childhood. We studied immune dysregulation in HSP by analyzing regulatory T (Treg), T helper 3 (Th3), and regulatory B cell (Breg) subpopulations that might intervene in immune activation, IgA production, and HSP clinical manifestations. Methods This prospective study included 3 groups of children: 30 HSP on acute phase, 30 HSP on remission, and 40 healthy controls (HCs) matched on age. Treg, Breg, and Th3 were analyzed by flow cytometry. Serum immunoglobulin and cytokine levels were quantified by ELISA and Luminex. Results Treg frequencies were higher in acute HSP than in remitting HSP and HCs (6.53% [4.24; 9.21] vs. 4.33% [3.6; 5.66], p = 0.002, and vs. 4.45% [3.01; 6.6], p = 0.003, respectively). Activated Th3 cells (FoxP3 + Th3 cells) tend to be more abundant in HSP than in HCs (78.43% [50.62; 80.84] vs. 43.30% [40.20; 49.32], p = 0.135). Serum IgA, IL-17, and latency-associated peptide (a marker of the anti-inflammatory cytokine TGF-beta production) were significantly and inflammatory cytokines TNF-alpha, IL-1-beta, and IL-6 were non-significantly higher in HSP than HCs. Bregs were identical between the groups, but, in patients with renal impairment, Breg percentage was lower compared to those without. Treg removal in PBMC culture resulted in an increase in IgA production in HSP proving a negative regulatory role of Tregs on IgA production. Conclusions In pediatric HSP, immune activation persists in spite of an increase in Th3 and Tregs. Th3 could be involved in IgA hyperproduction, inefficiently downregulated by Tregs. Lack of Bregs appears linked to renal impairment.