Toll-Like Receptor 3 (TLR3) Plays a Major Role in the Formation of Rabies Virus Negri Bodies

Human neurons express the innate immune response receptor, Toll-like receptor 3 (TLR3). TLR3 levels are increased in pathological conditions such as brain virus infection. Here, we further investigated the production, cellular localisation, and function of neuronal TLR3 during neuronotropic rabies virus (RABV) infection in human neuronal cells. Following RABV infection, TLR3 is not only present in endosomes, as observed in the absence of infection, but also in detergent-resistant perinuclear inclusion bodies. As well as TLR3, these inclusion bodies contain the viral genome and viral proteins (N and P, but not G). The size and composition of inclusion bodies and the absence of a surrounding membrane, as shown by electron microscopy, suggest they correspond to the previously described Negri Bodies (NBs). NBs are not formed in the absence of TLR3, and TLR3−/− mice—in which brain tissue was less severely infected—had a better survival rate than WT mice. These observations demonstrate that TLR3 is a major molecule involved in the spatial arrangement of RABV–induced NBs and viral replication. This study shows how viruses can exploit cellular proteins and compartmentalisation for their own benefit

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

Background: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Reward Versus Nonreward Sensitivity of the Medial Versus Lateral Orbitofrontal Cortex Relates to the Severity of Depressive Symptoms

BackgroundThe orbitofrontal cortex (OFC) is implicated in depression. The hypothesis investigated was whether the OFC sensitivity to reward and nonreward is related to the severity of depressive symptoms.MethodsActivations in the monetary incentive delay task were measured in the IMAGEN cohort at ages 14 years (n = 1877) and 19 years (n = 1140) with a longitudinal design. Clinically relevant subgroups were compared at ages 19 (high-severity group: n = 116; low-severity group: n = 206) and 14.ResultsThe medial OFC exhibited graded activation increases to reward, and the lateral OFC had graded activation increases to nonreward. In this general population, the medial and lateral OFC activations were associated with concurrent depressive symptoms at both ages 14 and 19 years. In a stratified high-severity depressive symptom group versus control group comparison, the lateral OFC showed greater sensitivity for the magnitudes of activations related to nonreward in the high-severity group at age 19 (p = .027), and the medial OFC showed decreased sensitivity to the reward magnitudes in the high-severity group at both ages 14 (p = .002) and 19 (p = .002). In a longitudinal design, there was greater sensitivity to nonreward of the lateral OFC at age 14 for those who exhibited high depressive symptom severity later at age 19 (p = .003).ConclusionsActivations in the lateral OFC relate to sensitivity to not winning, were associated with high depressive symptom scores, and at age 14 predicted the depressive symptoms at ages 16 and 19. Activations in the medial OFC were related to sensitivity to winning, and reduced reward sensitivity was associated with concurrent high depressive symptom scores

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/)

La démographie des gynécologues médicaux et des gynécologues obstétriciens dans le Nord-Pas-de-Calais (quel avenir pour la profession dans la région en 2013 ?)

BUT L objectif de ce travail était de faire un état des lieux et d estimer les évolutions dans les 5 ans à 10 ans de la démographie des gynécologues médicaux et gynécologues-obstétriciens de la région Nord-Pas-De-Calais pour aider à l installation des internes en fin de cursus. METHODES Nous avons réalisé une étude prospective et descriptive en interrogeant à l aide de deux questionnaires l ensemble des praticiens en gynécologie de la région Nord-Pas-De-Calais (456 questionnaires envoyés par voie postale) et l ensemble des internes inscrits aux DES de gynécologie médicale et de gynécologie obstétrique de la région actuellement en formation (92 questionnaires envoyés par e-mail). Le questionnaire envoyé aux praticiens interrogeait sur le profil, le type d exercice, l activité et l évolution de carrière. Le questionnaire aux internes renvoyait aux mêmes types de questions et les interrogeait sur leur plan de carrière pour pouvoir comparer leurs réponses avec celles des praticiens. RESULTATS Nous avons obtenu 57% de réponses pour les praticiens et 66,3% pour les internes. Nous avons ainsi pu décrire les caractéristiques de nos populations ainsi que leur activité et leur type d exercice. Le taux de départ en retraite des praticiens en gynécologie médicale et en gynécologie obstétrique sera de 23% à 5 ans et de 43% à 10 ans. Ces arrêts importants d activité vont avoir un retentissement sur la pratique de la gynécologie médicale (lié à une diminution de la pratique de la gynécologie médicale chez les internes et au départ en retraite de nombreux praticiens exerçant cette activité) mais aussi sur la gynécologie de ville puisque l on constatait que les internes semblaient plus vouloir s orienter vers une pratique mixte (publique et libérale), délaissant peu à peu la pratique libérale (ils étaient 8,9% à envisager le secteur libéral exclusif). Ces départs en retraite massifs n épargnaient aucun territoire de santé de la région. Cependant, ils seront plus importants dans le territoire Artois - Douaisis que dans celui de Métropole Flandre intérieure . On notait également une nette féminisation de la profession puisque les internes sont des femmes pour 87% d entre eux tandis que les femmes sont 55% chez les praticiens installés. Enfin, au regard du nombre d internes formés dans la région et aux souhaits d installation de ceux-ci (seulement 54% envisagent de s nstaller dans le Nord-Pas-De-Calais), on peut s attendre à une pénurie de gynécologie médicaux et gynécologues-obstétriciens d ici 5 à 10 ans. SYNTHESE Le vieillissement des gynécologues et les départs en retraite, la désertification médicale et la féminisation de notre profession sont autant de phénomènes démographiques qui vont transformer la population des gynécologues obstétriciens dans notre région. Malheureusement cette évolution aura pour conséquence une diminution de l offre de soins en gynécologie obstétrique. Il faudra donc mettre en oeuvre des stratégies pour garder dans la région les internes qui y ont été formés.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

The spatial dimensions of medication management by home-dwelling older adults after hospital discharge

Ageing in place raises pressing questions about medication practices at home. Understanding how medication practices are integrated into older adults’ domestic settings requires an interest in where activities linked to medication take place and why. This study aimed to describe the medication practices and spatial dimensions of medication management for home-dwelling older adults after hospital discharge, using a qualitative research design. Semi-structured interviews were carried out with ten older adults aged 65 years old or more and discharged home from hospital, together with nine informal caregivers. Thematic content analysis identified two main themes dealing with the spatial dimensions of medication management in this specific context: the process of integrating medication changes into routines and familiar spaces, and the individual and collective management of medication changes linked to a renegotiation of the boundaries between public and private spaces