Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol

Safety and Outcome of High-Flow Nasal Oxygen Therapy Outside ICU Setting in Hypoxemic Patients With COVID-19∗

OBJECTIVE: High-flow nasal oxygen (HFNO) therapy is frequently applied outside ICU setting in hypoxemic patients with COVID-19. However, safety concerns limit more widespread use. We aimed to assess the safety and clinical outcomes of initiation of HFNO therapy in COVID-19 on non-ICU wards. DESIGN: Prospective observational multicenter pragmatic study. SETTING: Respiratory wards and ICUs of 10 hospitals in The Netherlands. PATIENTS: Adult patients treated with HFNO for COVID-19-associated hypoxemia between December 2020 and July 2021 were included. Patients with treatment limitations were excluded from this analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes included intubation and mortality rate, duration of hospital and ICU stay, severity of respiratory failure, and complications. Using propensity-matched analysis, we compared patients who initiated HFNO on the wards versus those in ICU. Six hundred eight patients were included, of whom 379 started HFNO on the ward and 229 in the ICU. The intubation rate in the matched cohort (n = 214 patients) was 53% and 60% in ward and ICU starters, respectively (p = 0.41). Mortality rates were comparable between groups (28-d [8% vs 13%], p = 0.28). ICU-free days were significantly higher in ward starters (21 vs 17 d, p &lt; 0.001). No patient died before endotracheal intubation, and the severity of respiratory failure surrounding invasive ventilation and clinical outcomes did not differ between intubated ward and ICU starters (respiratory rate-oxygenation index 3.20 vs 3.38; Pao2:Fio2ratio 65 vs 64 mm Hg; prone positioning after intubation 81 vs 78%; mortality rate 17 vs 25% and ventilator-free days at 28 d 15 vs 13 d, all p values &gt; 0.05). CONCLUSIONS: In this large cohort of hypoxemic patients with COVID-19, initiation of HFNO outside the ICU was safe, and clinical outcomes were similar to initiation in the ICU. Furthermore, the initiation of HFNO on wards saved time in ICU without excess mortality or complicated course. Our results indicate that HFNO initiation outside ICU should be further explored in other hypoxemic diseases and clinical settings aiming to preserve ICU capacity and healthcare costs.</p

Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways

TDP-43 interacts with and coactivates NF-κB p65 in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, and an NF-κB inhibitor suppresses ALS disease symptoms and neuromuscular junction denervation in an ALS mouse model

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Contribution à l'étude de l'effet de la substance P sur la sécrétion d'aldostérone dans la glande surrénale humaine normale

Aldosterone secretion by the adrenal gland is principally under control of the circulating renin-angiotensin system (RAS) and kalemia. Aldosterone synthesis is also influenced by intra-adrenal paracrine factors including neuropeptides. Especially, tachykinins, like substance P (SP), can be released by nerve endings in the adrenal cortex. The role of SP in the regulation of the adrenal function has been evaluated in animals but only scarcely investigated in humans. The aim of the present study is to explore the role of SP in the control of mineralocorticoid synthesis in the human adrenal gland. In vitro experiments conducted in normal adrenal samples reveal expression of the TAC1 encoding SP which is detected by immunohistochemistry in non adrenergic non cholinergic nerve fibres in the zona glomerulosa. SP-positive fibres establish close contacts with aldosterone-producing cells which express the SP receptor, i.e. the NK1 receptor (NK1R). SP stimulates aldosterone production from cultured adrenocortical cells, an effect which is inhibited by the NK1R antagonist aprepitant. The action of SP is mediated by the ERK pathway and involves upregulation of several genes encoding steroidogenic enzymes. The physiological role of SP in the regulation of aldosterone secretion was further assessed through a prospective clinical placebo-controlled trial investigating the impact of aprepitant on plasma and urine aldosterone levels in healthy volunteers. Aprepitant reduced daily aldosterone production and plasma aldosterone concentration (PAC) in recumbency but did not modify PAC in upright position. These data show that SP exerts a stimulatory tone on aldosterone production in man.La sécrétion d'aldostérone par la glande surrénale est principalement contrôlée par le système rénine-angiotensine circulant (SRA) et la kaliémie. La synthèse de l'aldostérone est également influencée par les facteurs paracrines intra-surrénaliens, y compris les neuropeptides. En particulier, les tachykinines, comme la substance P (SP), peuvent être libérées par les terminaisons nerveuses dans le cortex surrénalien. Le rôle de la SP dans la régulation de la fonction surrénalienne a été évalué chez l'animal mais rarement étudié chez l'homme. Le but de la présente étude est d'explorer le rôle de la SP dans le contrôle de la synthèse des minéralocorticoïdes dans la glande surrénale humaine. Des expériences in vitro conduites dans des échantillons surrénaliens normaux révèlent l'expression de SP codée par TAC1 qui est détecté par immunohistochimie dans des fibres nerveuses non-adrénergiques non-cholinergiques dans la zone glomérulée. Les fibres SP-positives établissent des contacts étroits avec des cellules productrices d'aldostérone qui expriment le récepteur NK1 (NK1R), récepteur de la SP. La SP stimule la production d'aldostérone à partir de cellules corticosurrénales cultivées, un effet qui est inhibé par l'aprépitant, antagoniste NK1R. L'action de la SP est relayée par la voie ERK et implique une régulation à la hausse de plusieurs gènes codant pour des enzymes de la stéroïdogénèse. Le rôle physiologique de la SP dans la régulation de la sécrétion d'aldostérone a été évalué à l'aide d'un essai clinique prospectif, contrôlé par placebo, de l'impact de l'aprépitant sur les concentrations plasmatiques et urinaires d'aldostérone chez des volontaires sains. L'aprépitant a réduit la production quotidienne d'aldostérone et la concentration plasmatique d'aldostérone (CPA) dans le décubitus, mais n'a pas modifié les CPA en position debout. Ces données montrent que la SP exerce un tonus stimulant sur la production d'aldostérone chez l'homme

Role of substance P in the regulation of aldosterone secretion in normal human adrenal gland

La sécrétion d'aldostérone par la glande surrénale est principalement contrôlée par le système rénine-angiotensine circulant (SRA) et la kaliémie. La synthèse de l'aldostérone est également influencée par les facteurs paracrines intra-surrénaliens, y compris les neuropeptides. En particulier, les tachykinines, comme la substance P (SP), peuvent être libérées par les terminaisons nerveuses dans le cortex surrénalien. Le rôle de la SP dans la régulation de la fonction surrénalienne a été évalué chez l'animal mais rarement étudié chez l'homme. Le but de la présente étude est d'explorer le rôle de la SP dans le contrôle de la synthèse des minéralocorticoïdes dans la glande surrénale humaine. Des expériences in vitro conduites dans des échantillons surrénaliens normaux révèlent l'expression de SP codée par TAC1 qui est détecté par immunohistochimie dans des fibres nerveuses non-adrénergiques non-cholinergiques dans la zone glomérulée. Les fibres SP-positives établissent des contacts étroits avec des cellules productrices d'aldostérone qui expriment le récepteur NK1 (NK1R), récepteur de la SP. La SP stimule la production d'aldostérone à partir de cellules corticosurrénales cultivées, un effet qui est inhibé par l'aprépitant, antagoniste NK1R. L'action de la SP est relayée par la voie ERK et implique une régulation à la hausse de plusieurs gènes codant pour des enzymes de la stéroïdogénèse. Le rôle physiologique de la SP dans la régulation de la sécrétion d'aldostérone a été évalué à l'aide d'un essai clinique prospectif, contrôlé par placebo, de l'impact de l'aprépitant sur les concentrations plasmatiques et urinaires d'aldostérone chez des volontaires sains. L'aprépitant a réduit la production quotidienne d'aldostérone et la concentration plasmatique d'aldostérone (CPA) dans le décubitus, mais n'a pas modifié les CPA en position debout. Ces données montrent que la SP exerce un tonus stimulant sur la production d'aldostérone chez l'homme.Aldosterone secretion by the adrenal gland is principally under control of the circulating renin-angiotensin system (RAS) and kalemia. Aldosterone synthesis is also influenced by intra-adrenal paracrine factors including neuropeptides. Especially, tachykinins, like substance P (SP), can be released by nerve endings in the adrenal cortex. The role of SP in the regulation of the adrenal function has been evaluated in animals but only scarcely investigated in humans. The aim of the present study is to explore the role of SP in the control of mineralocorticoid synthesis in the human adrenal gland. In vitro experiments conducted in normal adrenal samples reveal expression of the TAC1 encoding SP which is detected by immunohistochemistry in non adrenergic non cholinergic nerve fibres in the zona glomerulosa. SP-positive fibres establish close contacts with aldosterone-producing cells which express the SP receptor, i.e. the NK1 receptor (NK1R). SP stimulates aldosterone production from cultured adrenocortical cells, an effect which is inhibited by the NK1R antagonist aprepitant. The action of SP is mediated by the ERK pathway and involves upregulation of several genes encoding steroidogenic enzymes. The physiological role of SP in the regulation of aldosterone secretion was further assessed through a prospective clinical placebo-controlled trial investigating the impact of aprepitant on plasma and urine aldosterone levels in healthy volunteers. Aprepitant reduced daily aldosterone production and plasma aldosterone concentration (PAC) in recumbency but did not modify PAC in upright position. These data show that SP exerts a stimulatory tone on aldosterone production in man

Retinol Improves In Vitro Differentiation of Pre-Pubertal Mouse Spermatogonial Stem Cells into Sperm during the First Wave of Spermatogenesis

International audienceTesticular tissue freezing has been proposed for fertility preservation in pre-pubertal boys. Thawed frozen testicular tissue must undergo a maturation process to restore sperm production. The purpose of the current study was to evaluate the ability of retinol to improve the in vitro differentiation of pre-pubertal mouse spermatogonial stem cells into sperm. Testes from pre-pubertal mice, aged 2.5 and 6.5 days post-partum, were cultured on agarose gel at a gas-liquid interphase for 34, 38 and 60 days (D) and for 16, 30 and 36 D respectively. Assessment of basal medium (BM) supplemented with retinol (RE) alone, FSH/LH alone or a combination of both, was performed. Stereological analyses and tissue lesion scoring were performed at the culture time points indicated above. Sperm production was quantified at D30 and D34 after mechanical dissection of the testicular tissues. FSH/LH significantly increased the percentage of round spermatids at D30 and D38, when compared to BM alone. However, RE significantly increased the percentages of round but also elongated spermatids at D30 and D34. Moreover, RE significantly increased the number of spermatozoa per milligram of tissue at D30 and D34 when compared to BM. Therefore, RE improved the in vitro production of spermatids and spermatozoa from pre-pubertal SSCs during the first wave of spermatogenesis. The use of RE could be a useful tool for in vitro spermatogenesis from pre-pubertal human testicular tissue

Comment on: Pharmacodynamic evaluation of intermittent versus extended and continuous infusions of piperacillin/tazobactam in a hollow-fibre infection model against Klebsiella pneumoniae

International audienc

Pharmacogenetics of Direct Oral Anticoagulants: A Systematic Review

Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). Their inter-individual variability in pharmacodynamics and pharmacokinetics (transport and metabolism) is high, and could result from genetic polymorphisms. As recommended by the French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity. This paper is a review of association studies between single nucleotide polymorphisms (SNPs) and systemic exposure variation of DOACs. Most of the results presented here have a lot to do with some SNPs of CES1 (rs2244613, rs8192935, and rs71647871) and ABCB1 (rs1128503, rs2032582, rs1045642, and rs4148738) genes, and dabigatran, rivaroxaban, and apixaban. Regarding edoxaban and betrixaban, as well as SNPs in the CYP3A4 and CYP3A5 genes, literature is scarce, and further studies are needed