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Soins hospitaliers pour situations complexes à l'adolescence ˸ retours d'expérience & réflexions pour optimiser les dispositifs et les parcours
No full textThe care of young people with severe chronic psychiatric disorders requires care systems that are adapted to chronicity and life-threatening situations, while taking into account their need to attend school. Care relies on the coordinated action of teams from multiple fields (caregivers, educational, academical, administrative and technical), who must work together to provide secure systems. The Covid pandemic has had a particularly devastating impact on the mental health of young people and the teams working in the care facilities that receive them. The aim of this thesis is to explore the experiences and representations of the various care stakeholders - professionals, patients and their families - in facilities for young people with severe psychiatric disorders, in order to identify the factors that will ultimately optimize care pathways for complex situations in adolescence. The first part of the project assesses expectations and feedback on the implementation of an interprofessional exchange group in care-school clinics aimed at supporting post-COVID teams. We used a grounded theory approach to analyze focus groups conducted at the beginning and end of these groups.The second part aims to gather the expectations and feedback of young adolescents (aged 12-20) treated for anorexia nervosa in a specialized day hospital, based on their admission and goodbye letters, studied using a general inductive analysis approach.The third part explores the experiences of professionals and family involved in the care of a young girl suffering from severe and enduring anorexia nervosa, who died in palliative care at the age of 19 after more than 10 years of care. The first part showed how professionals dealt with the Covid health crisis, then an institutional crisis, thanks to solidarity and the bond with others. Taking care of caregivers by setting up such programs enables them to continue caring for patients and their families.The second part highlighted the value of school schemes in the management of severe disorders in adolescence: adolescents' involvement in school helps create a solid therapeutic alliance that enables them to accept long, constraining treatment while reinvesting in the schooling, essential to their psychosocial rehabilitation, and building on positive relations with caregivers.The third part highlighted both the struggle of the family and professionals against a particularly long and severe form of disorder, as well as their painful feeling of powerlessness within a highly compartmentalized care system. The situation of the young girl who died in palliative care reveals the extent to which this type of situation resonates with caregivers and family; this work also raises the question of the relevance of restraint in care, its experience and its limits in this type of situation.In a global discussion, this work underlines the importance of gathering the words of the protagonists of care (patients, family and caregivers) to understand the mechanisms of action of care systems, and what they bring to young people. Listening to young people's experiences of day-to-day care, and to those of caregivers and family in clinical situations where care fails, enables us to understand certain mechanisms that contribute to their effectiveness and those that contribute to impasses, and to support parents and caregivers. Finally, this work suggests ways of improving how teams operate and how care is articulated, in order to provide better care for young people and their families.La prise en soins des jeunes présentant des troubles psychiatriques chroniques sévères nécessite des dispositifs de soins adaptés à la chronicité et aux situations mettant en jeu le pronostic vital, tout en prenant en compte leurs besoins de suivre une scolarité. Les soins reposent sur l'action coordonnée d'équipes de différents champs (soignant, éducatif, pédagogiques, administratif et techniques) devant s'articuler pour proposer des dispositifs solides. La pandémie de Covid a particulièrement ébranlé la santé mentale des jeunes et les équipes des dispositifs de soins qui les accueillent. Cette thèse a pour objectif d'explorer les retours d'expériences et les représentations des différents acteurs du soins - professionnels, patients et entourage - dans des dispositifs accueillant des jeunes avec des troubles psychiatriques sévères afin d'identifier des leviers qui permettront à terme d'optimiser les parcours de soins pour les situations complexes à l'adolescence. Le premier volet évalue les attentes puis le retour d'expérience sur la mise en place d'un espace d'échange interprofessionnel dans des cliniques soins-études visant à soutenir les équipes en post-COVID. Nous avons utilisé une approche par théorisation ancrée pour analyser des focus groups réalisés au début et à la fin de ces espaces. Le second volet vise à recueillir les attentes et le retour d'expériences de jeunes adolescents (12-20 ans) soignés pour anorexie mentale en hôpital de jour spécialisé soins-études à partir de leurs lettres d'admission et d'au revoir étudiées avec une approche par analyse inductive générale.Le troisième volet explore le vécu de professionnels et de l'entourage impliqués dans le parcours de soins d'une jeune fille souffrant d'anorexie mentale sévère chronique et résistante, décédée en soins palliatifs à l'âge de 19 ans après plus de 10 ans de soins. Le premier volet a permis de comprendre comment les professionnels ont géré la crise sanitaire Covid puis une crise institutionnelle grâce à la solidarité et le lien à l'autre. Prendre soin des soignants en mettant en place de tels dispositifs leur permet de continuer à prendre soin des patients et de leur famille.Le second volet a mis en évidence l'intérêt de dispositifs soins-études dans la prise en charge de troubles sévères à l'adolescence : l'investissement de l'école par les adolescents contribue à créer une alliance thérapeutique solide qui leur permet d'accepter des soins longs et contraignants tout en réinvestissant la scolarité indispensable à leur réhabilitation psychosociale et en s'appuyant sur des liens positifs avec les soignants.Le troisième volet a mis en exergue à la fois la lutte de la famille et des professionnels contre une forme de trouble particulièrement long et sévère, ainsi que leur douloureuse confrontation à l'impuissance, au sein d'un système de soins très cloisonné. La situation de la jeune fille décédée en soins palliatifs permet de percevoir à quelle point ce type de situation impacte les soignants et la famille ; ce travail soulève aussi la question de la pertinence de la contrainte dans les soins, de son vécu et de ses limites dans ce type de situations.Dans une discussion globale, ce travail souligne l'importance de recueillir la parole des protagonistes des soins (patients, entourage et soignant) pour comprendre les mécanismes d'action des dispositifs de soins, et ce qu'ils apportent aux jeunes. Ecouter le retour d'expérience des jeunes sur les soins au quotidien et ceux des soignants et de l'entourage dans les situations cliniques mettant en échec les soins permet à la fois de comprendre certains mécanismes contribuant à leur efficacité et ceux contribuant à des impasses et de soutenir les parents et les soignants. Enfin ce travail propose des pistes d'amélioration de fonctionnement des équipes et d'articulation des soins pour une meilleure prise en charge des jeunes et de leurs familles
Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control
No full textInternational audienceAbstract The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N -oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk
The genetic architecture of HIV-1 virulence
No full textInternational audienceThe virulence of Human Immunodeficiency Virus-1 (HIV-1) is partly determined by viral genetic variation. Finding individual genetic variants affecting virulence is important for our understanding of HIV pathogenesis and evolution of virulence; however, very few have been identified. To this end, within the “Bridging the Evolution and Epidemiology of HIV in Europe” (BEEHIVE) collaboration, we produced whole-genome HIV sequence data for 2294 seroconverters from European countries for a genome-wide association study (GWAS). We considered two phenotypes: (i) set-point viral load (SPVL), the approximately stable viral load from 6 to 24 months after infection, and (ii) the rate of CD4 cell count decline. We developed a GWAS method that corrects for population structure with random effects, accounts for two or more alleles at each locus, and tests for the effect of multiple genetic variants including single-nucleotide polymorphisms (SNPs), k-mers, insertions and deletions, within-host variant frequency, the number of rare point mutations, and drug resistance. We confirmed with this new approach that viral genomes explained 26% [95% CI 17%–35%] of the variance in SPVL, while they explained only 0.9% [0.0%–2.1%] of the variance in the rate of CD4 cell count decline. After correction for multiple testing, among all tested variants, only two significantly explained SPVL: an epitope mutation allowing escape from the host HLA-B*57 allele and lowering SPVL by −0.26 copies/ml and an epitope mutation allowing escape from the host HLA-B*35 allele and increasing SPVL by +0.22 copies/ml. We attempted to replicate these two large effects in two additional independent datasets together encompassing 2445 seroconverters, with mixed results. Overall, the inferred effects of all SNPs and amino-acid variants weakly correlated (R2 ranging from 0.08 to 0.87%, P-values from 0.001 to 0.32) between our main dataset and these two additional datasets. Lastly, a lasso regression of phenotypes on genetic variants confirmed the heritability of SPVL and explained up to 6% of variance in SPVL in cross-validation datasets. These findings suggest that HIV SPVL is determined by viral genomes through HLA escape variants with potentially large, host-dependent effects that may not always be detected at the population level and many other variants with effects too weak to reach genome-wide significance in our GWAS
Systematic attribution of heatwaves to the emissions of carbon majors
No full textInternational audienceAbstract Extreme event attribution assesses how climate change affected climate extremes, but typically focuses on single events 1–4 . Furthermore, these attributions rarely quantify the extent to which anthropogenic actors have contributed to these events 5,6 . Here we show that climate change made 213 historical heatwaves reported over 2000–2023 more likely and more intense, to which each of the 180 carbon majors (fossil fuel and cement producers) substantially contributed. This work relies on the expansion of a well-established event-based framework 1 . Owing to global warming since 1850–1900, the median of the heatwaves during 2000–2009 became about 20 times more likely, and about 200 times more likely during 2010–2019. Overall, one-quarter of these events were virtually impossible without climate change. The emissions of the carbon majors contribute to half the increase in heatwave intensity since 1850–1900. Depending on the carbon major, their individual contribution is high enough to enable the occurrence of 16–53 heatwaves that would have been virtually impossible in a preindustrial climate. We, therefore, establish that the influence of climate change on heatwaves has increased, and that all carbon majors, even the smaller ones, contributed substantially to the occurrence of heatwaves. Our results contribute to filling the evidentiary gap to establish accountability of historical climate extremes 7,8
Clinical value of circulating bioactive adrenomedullin for prediction of outcome and hydrocortisone response in sepsis patients—a post-hoc analysis of the HYPRESS trial
No full textInternational audienceAbstract Purpose Sepsis requires stratification for host-directed therapies through the discovery of adequate biomarkers enabling prediction of outcomes and treatment responses. Adrenomedullin has previously demonstrated potential for prognostic enrichment. This study aimed to assess associations of bioactive adrenomedullin (bio-ADM) levels at ICU admission and sepsis outcomes and to evaluate the potential of bio-ADM as marker to identify subgroups of patients with moderate disease severity that might benefit from hydrocortisone treatment. Methods We used data from the HYPRESS trial (NCT00670254) to investigate, if bio-ADM is useful to predict sepsis outcomes (septic shock, 90- and 180-day mortality) and benefit or harm by hydrocortisone treatment. Optimal cut-offs for outcome predictions were determined by Youden’s index. Logistic regression was used to assess bio-ADM subgroups and treatment interaction. Results Bio-ADM levels differed significantly in patients with or without septic shock within 14 days (p = 0.011). While the area under the ROC curve (AUC) was only 0.603 (CI 0.531–0.676), patient subgrouping using bio-ADM levels showed significantly higher cumulative incidence of septic shock within 14 days in the subgroup of patients with bio-ADM levels ≥ 37 pg/mL (p < 0.001). The odds ratio for the development of septic shock in this group was 4.67 (95% CI 1.53, 20.3, p = 0.016). A bio-ADM cut-off of ≥ 136 pg/mL was predictive for 90-day (OR 8.21, 95% CI 2.46–27.9, p < 0.001) and 180-day mortality (OR 4.87, 95% CI 1.49–16.0, p = 0.008). Hydrocortisone therapy did not reduce the incidence of septic shock (OR 1.59, 95% CI 0.37–8.15, p = 0.54), 90-day (OR 1.53, p = 0.23) or 180-day mortality (OR 1.41, p = 0.25), regardless of bio-ADM stratification (interaction term p = 0.58 for septic shock; p = 0.31 for 90-day mortality; p = 0.51 for 180-day mortality). Conclusions Whereas bio-ADM levels are associated with sepsis outcomes, our data do not indicate usefulness of the marker to identify patients potentially benefitting from hydrocortisone therapy
Paleoproteomics reveals chromoblastomycosis as possible cause of King of France Louis XIV's death (1715)
No full textInternational audienc
The residential environment and blood pressure changes in adults: a longitudinal multi-cohort study
No full textInternational audienceWe aimed to study the associations between air pollution, noise and green spaces and longitudinal changes in systolic blood pressure (SBP) in three general population European cohorts: Constances, the Northern Finland Birth Cohort (NFBC1966) and the Dutch Famine Birth Cohort (DFBC). We included adults with no history of cardiovascular diseases and with at least two SBP measurements. We assessed air pollution exposure using yearly average PM2.5 and NO2 concentrations (in µg/m3); noise using daily average noise levels (Lden); and surrounding greenness using the Normalized Difference Vegetation Index (NDVI) within 300m from residence. For each participant we calculated the rate of change of SBP between baseline and follow-up, and we used linear regression to evaluate the associations with the residential environment in single-exposure models. We used weights to compensate for unavailable information at follow-up. Covariates were age, sex, smoking status, antihypertensive drugs, education, and occupation. We also included an interaction term with urban level (ie impervious density). We included 20,513 participants from Constances, 3,306 from NFBC1966, and 508 from DFBC, all with two SBP measures (mean age intervals 47-56, 31-47, and 50-58, respectively). SBP was overall higher at follow-up vs baseline. We found the highest mean levels of air pollution and noise in the DFBC (eg PM2.5: 30.6µg/m3±2.7), and of greenness in the NFBC1966 (0.58±0.11). After adjustment associations were overall close to the null and non-significant (eg in Constances, per 5 µg/m3 in PM2.5: β:0.06, 95%CI: -0.15,0.27; and per 0.1-unit NDVI: β:0.02, 95%CI: -0.07,0.10). However, in the NFBC1966, they were significant and in the opposite expected direction (eg PM2.5: β: -0.29, 95%CI: -0.43, -0.14). In a multi-cohort study of 3 EU countries the residential environment did not seem to play a major role in SBP changes. Future studies may use longer follow-ups and more SBP data to better capture changes. Key messages • Using three adult cohorts, we aimed to study if exposure to the residential living environment could slow down or speed up the rate of change in systolic blood pressure between baseline and follow-up. • Associations were overall close to the null and non-significant; we recommend that future studies use longer follow-ups to include more SBP measures and to better capture exposure trajectories
AI-enhanced profiling of phage-display-identified anti-TIM3 and anti-TIGIT novel antibodies
No full textInternational audienceAntibody discovery is a lengthy and labor-intensive process, requiring extensive laboratory work to ensure that an antibody demonstrates the appropriate efficacy, production, and safety characteristics necessary for its use as a therapeutic agent in human patients. Traditionally, this process begins with phage display or B-cells isolation campaigns, where affinity serves as the primary selection criterion. However, the initial leads identified through this approach lack sufficient characterization in terms of developability and epitope definition, which are typically performed at late stages. In this study, we present a pipeline that integrates early-stage phage display screening with AI-based characterization, enabling more informed decision-making throughout the selection process. Using immune checkpoints TIM3 and TIGIT as targets, we identified five initial leads exhibiting similar binding properties. Two of these leads were predicted to have poor developability profiles due to unfavorable surface physicochemical properties. Of the remaining three candidates, structural models of the complexes formed with their respective targets were generated for 2: T4 (against TIGIT) and 6E9 (against TIM3). The predicted epitopes allowed us to anticipate a competition with TIM3 and TIGIT binding partners, and to infer the antagonistic functions expected from these antibodies. This study lays the foundations of a multidimensional AI-driven selection of lead candidates derived from high throughput analysis
New representation of sea ice salt dynamics within NEMO-SI3: Evaluation and impacts
No full textInternational audienceMany large-scale sea ice models represent salt dynamics, yet, these remain insufficiently evaluated, with large uncertainty on several parameterization choices. To address this, we conduct global 1° resolution ice-ocean simulations with NEMO-SI3 v5, forced by climatological atmospheric data, and evaluate them against a new compilation of >1,200 ice-core observations. We specifically investigate the effects of (1) the treatment of vertical ice salinity variations (diagnostic vs. prognostic), (2) gravity drainage parameterization type (brine fraction–based vs. Rayleigh number–based), and (3) key parameter values. We show that mean ice salinity can be simulated within 0.1 g/kg (Arctic) and 0.4 g/kg (Antarctic) of the observed mean, provided careful adjustment of parameters. In particular, using a high value for the new ice liquid fraction parameter (75%) proves critical to simulate high salinity in the thin ice range. With appropriately adjusted parameters, the model captures the key large-scale ice salinity features, including the Arctic-Antarctic contrast, seasonal cycle, vertical profiles, and salinity-thickness relationship. A prognostic treatment of vertical salinity increases the variance of ice salinity and ice-ocean salt fluxes, yielding vertically-averaged salinity more in line with observations, however only in the Arctic. The choice of gravity drainage parameterization is influential through interactions with melt ponds, with Rayleigh number–based parameterizations performing best. While salt dynamics strongly affect sea ice mass budget terms, they moderately affect sea ice volume and the ocean due to compensation effects. Uncertainties are larger than in the Antarctic than in Arctic, reflecting less mature process understanding and possibly higher observational biases
ATICC : a mixed-methods study on addiction, trauma, and immigration among vulnerable young adults in the grand est youth network
No full textInternational audienceBackground : This research protocol for the study ATICC (Addiction, Trauma and Immigration, prevention and Cross-Cultural support for care with the Grand Est youth network) aims to model the complex interrelations between trauma, substance use behaviors, migration and representations of mental health among vulnerable youth residing in Transitional Housing for Young Adults. This study focuses on a specific and underexplored population, many of whom have experienced traumatic events and/or complex migratory trajectories. The ultimate objective of this research is to develop transferable models of understanding that can inform the design of prevention and support programs tailored to this demographic. Methods/Design We adopt a tripartite methodology approach: (1) a cross-sectional study using standardized questionnaires to identify factors associated with substance use, trauma, and barriers to healthcare access; (2) an in-depth qualitative study based on semi-structured individual interviews with substance users, exploring their subjective experiences and perceptions related to substance use and mental health care; and (3) a longitudinal interventional study involving various configurations of focus groups open to residents of transitional housing structures, aiming to assess the impact of these group sessions on participants’ psychological well-being and attitudes toward care. Quantitative analyses will include descriptive and multivariate statistical tests using R, while qualitative data will be analyzed through thematic analysis with NVivo. The effectiveness of the group intervention will be evaluated using pre/post-tests, mixed models, and appropriate statistical corrections. Discussion Analyses are expected to identify key psychosocial factors influencing addictive behaviors and mental health, highlight cultural and structural barriers to care, and assess the psychological benefits of the group intervention. The ATICC study aims to contribute to the development of culturally adapted prevention and support models for young adults in precarious situations. The results should assist healthcare professionals and policymakers in designing evidence-based interventions that effectively address the specific needs of this population. Trial registration This study is registered with the Biomedical Research Identification Number (n°ID-RCB) assigned in France by the National Agency for the Safety of Medicines and Health Products (ANSM): 2024-A01534-43, and have received the approval from the committee for the protection of persons (CPP) Ile-de-France on November 18, 2024. Cette étude a également été déposée sur clinicaltrials (NCT06922721, date assigned April 10, 2025)