More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients

BackgroundThe clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection.ObjectiveTo study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19.MethodsOne hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome.ResultsAlthough the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14–8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19.ConclusionThese findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs.Clinical trial registrationhttps://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Aging and older people who use illicit opioids, cocaine, or methamphetamine: a scoping review and literature map.

AIMS: To provide an overview of research literature on aging and older people who use illicit opioids and stimulants by documenting the conceptual frameworks used and content areas that have been investigated. METHODS: We conducted a scoping review of literature relating to aging and older people who use illicit stimulants and opioids, defining "older" as 40 years and above. Primary studies, secondary studies, and editorials were included. Searches were conducted in PubMed and Embase in July 2020 and March 2021; the Cochrane library was searched in November 2021. Charted data included methodological details, any conceptual frameworks explicitly applied by authors, and the content areas that were the focus of the publication. We developed a hierarchy of content areas and mapped this to provide a visual guide to the research area. RESULTS: Of the 164 publications included in this review, only 16 explicitly applied a conceptual framework. Seven core content areas were identified, with most publications contributing to multiple content areas: acknowledgement of drug use among older people (n = 64), health status (n = 129), health services (n = 109), drug use practices and patterns (n = 84), social environments (n = 74), the criminal legal system (n = 28), and quality of life (n = 15). CONCLUSIONS: The literature regarding older people who use illicit drugs remains under-theorized. Conceptual frameworks are rarely applied and few have been purposely adapted to this population. Health status and health services access and use are among the most frequently researched topics in this area

Le programme Namaste, une psychothérapie de groupe basée sur le yoga pour les jeunes ayant un vécu de traumas complexes : une série d’étude de cas

Introduction : Les enfants qui ont un vécu des traumas complexes sont à risque de développer de graves difficultés d’attachement, d’autorégulation et de comportement. Des études exploratoires démontrent que la pratique du yoga permet d’améliorer leur fonctionnement et diminuer leurs symptômes d’internalisation et d’externalisation.Objectifs : Le programme Namaste, une adaptation du manuel « Yoga-Based Psychotherapy » (Beltran et al. 2014) vise l’amélioration de l’autorégulation et de la santé mentale. Cette étude a pour objectif de documenter ses effets chez les enfants qui ont vécu des traumas complexes.Méthode : Douze séances ont été animées auprès d’enfants âgés de 6 à 13 ans suivis par un centre de protection de l’enfance. Les séances combinaient des postures de yoga, des exercices de respiration, et d’autres activités favorisant l’autorégulation et la socialisation. Le fonctionnement et les symptômes des enfants ont été mesurés avec le questionnaire BASC-3 avant et après l’intervention. Deux études de cas détaillées décrivent les impacts potentiels de cette intervention.Résultats : Les deux études de cas démontrent des impacts positifs sur les symptômes d’internalisation et d’externalisation ainsi que l’autorégulation, mais aucun effet sur l’estime de soi et les compétences sociales.Implications : Le programme Namaste pourrait être une intervention prometteuse pour améliorer le fonctionnement et réduire les symptômes psychologiques chez cette population. L’intégration des principes du yoga sensible aux traumas, la modalité de groupe et l’accent mis sur l’autorégulation semblent des éléments-clés. D’autres études de plus grande envergure sont nécessaires pour confirmer les impacts positifs potentiels de cette intervention

Intracellular VHHs to monitor and modulate GPCR signaling

International audienceSingle-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies primarily directed against cytosolic proteins or transcription factors have been described. In contrast, few of them target membrane proteins and even less recognize G protein-coupled receptors. These receptors are major therapeutic targets, which reflects their involvement in a plethora of physiological responses. Hence, they elicit a tremendous interest in the scientific community and in the industry. Comprehension of their pharmacology has been obscured by their conformational complexity, that has precluded deciphering their structural properties until the early 2010's. To that respect, intracellular VHHs have been instrumental in stabilizing G protein-coupled receptors in active conformations in order to solve their structure, possibly bound to their primary transducers, G proteins or b-arrestins. In contrast, the modulatory properties of VHHs recognizing the intracellular regions of G protein-coupled receptors on the induced signaling network have been poorly studied. In this review, we will present the advances that the intracellular VHHs have permitted in the field of GPCR signaling and trafficking. We will also discuss the methodological hurdles that linger the discovery of modulatory intracellular VHHs directed against GPCRs, as well as the opportunities they open in drug discovery

A rapid review of the impacts of "Big Events" on risks, harms, and service delivery among people who use drugs: implications for responding to COVID-19.

BACKGROUND "Big Events" are major disruptions to physical, political, and economic environments that can influence vulnerability to drug-related harms. We reviewed the impacts of Big Events with relevance to the COVID-19 pandemic on drug-related risk and harms and access to drug treatment and harm reduction services. METHODS We conducted a rapid review of quantitative, qualitative, and mixed methods literature relating to the following Big Events: respiratory infection pandemics, natural disasters, financial crises, and heroin shortages. Included studies reported data on changes to risks, harms, and/or service provisioning for people who use illicit drugs (other than cannabis) in the context of these Big Events. Searches were conducted in PubMed in May 2020, and two reviewers screened studies for inclusion. Peer-reviewed studies published in English or French were included. We used a narrative synthesis approach and mapped risk pathways identified in the literature. RESULTS No studies reporting on respiratory infection pandemics were identified. Twelve studies reporting on natural disaster outcomes noted marked disruption to drug markets, increased violence and risk of drug-related harm, and significant barriers to service provision caused by infrastructure damage. Five studies of the 2008 global financial crisis indicated increases in the frequency of drug use and associated harms as incomes and service funding declined. Finally, 17 studies of heroin shortages noted increases in heroin price and adulteration, potentiating drug substitutions and risk behaviors, as well as growing demand for drug treatment. CONCLUSION Current evidence reveals numerous risk pathways and service impacts emanating from Big Events. Risk pathway maps derived from this literature provide groundwork for future research and policy analyses, including in the context of the COVID-19 pandemic. In light of the findings, we recommend responding to the pandemic with legislative and financial support for the flexible delivery of harm reduction services, opioid agonist treatment, and mental health care

The potential of keratinized matrices for the retrospective exploration of repeated ayahuasca use by patients

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Impact of the ingestion of titanium dioxide nanoparticles via breast milk on the respiratory health of young rabbits.

International audienceIntroductionThe perinatal period is critical for adequate maturation of the immune system, the microbiota and multiple organs, including the lungs. During this vulnerable phase of life, maternal exposure to environmental factors can potentially influence health trajectories of the offspring. Although banned from food applications in Europe since 2022, Titanium dioxide (TiO2) nanoparticles (NPs) are still massively used in most industrial sectors and their release into the air, water and soil, makes the exposure of mammals by oral, respiratory or skin routes likely. Emerging literature shows the presence of Ti in the breastmilk of rodents exposed orally or by inhalation but the consequences on the offspring’s lung development and its susceptibilities are unknown. The objective of our study was to evaluate the transfer of TiO2 NPs from orally exposed rabbit does, to the kits and the consequences on gut and lung microbiota and lung development.MethodsFrom parturition, lactating does were exposed per os to 2 forms of TiO2 NPs giving three groups: Rutile TiO2 (R), Anatase: Rutile TiO2 (AR) and the vehicle group (E). Fluids (milk, blood) and tissues (lung, jejunum) were analysed for Ti and Ti-NPs content using inductively coupled plasma mass spectrometry (ICP-MS). Offspring’s lung development and pathology was assessed by histology, bronchoalveolar lavage cell numeration and qPCR. Lung, fecal and caecal microbiota were analysed by sequencing the V3-V4 region of the 16SrRNA gene.ResultsWe observed an increase in Ti in the caeca and feces from the exposed offspring groups compared to control, suggesting a transfer of Ti via breastmilk and its elimination, at least partly, by the feces. Despite similar Ti levels in the lungs and jejunum between groups, histological analyses of the lungs showed increased severity of suppurative bronchopneumonia in TiO2-NPs exposed groups. In 3 exposed kits, there were Cilia-Associated Respiratory Bacillus and multinucleated giant cells that were not detected in the controls. Moreover, in the R group, pro-inflammatory cytokines mRNA levels increased whereas AR NPs decreased anti-inflammatory cytokines, collagen and elastin messengers, potentially explaining the increased incidence and severity of pulmonary pathologies described histologically in the lungs. Finally, the transfer of NPs to kits did not modify the overall microbial composition of the caeca but altered the relative abundances of bacterial families in the lungs, in particular in the AR group compared to the control group. The differential analysis of the OTUs showed that 14 OTUs were significantly different in the lungs of the AR rabbit rabbits in comparison with the E group.ConclusionThis study is the first to suggest an impact of TiO2 NPs, administered to mothers during breastfeeding, on lung defenses of the offspring, probably via alterations in the gut-lung axis