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Detecting emotion in individuals with disorders of consciousness: a pilot study of heart rate deceleration on affective auditory stimuli
No full textInternational audienceObjective: To evaluate heart rate deceleration on affective auditory stimulations as an objective marker of purposeful affective behaviour, as used in the diagnosis of minimally conscious state (MCS) in brain-injured individuals with disorders of consciousness (DoC), awake but unable to communicate.Methods: We recorded the heart rate of participants (14 healthy controls and 10 brain injured individuals, conscious or with DoC) on repeated exposure to a random sequence of three emotional sounds of neutral, positive, and negative valence, in an unconditioned manner (experiment 1) or in a trace-conditioning procedure (experiment 2), with successful trace-conditioning assumed to indicate consciousness.Results: In experiment 1, heart rate deceleration after aversive acoustic stimulus was significantly higher in healthy subjects at the group level from the second to the seventh inter-beat interval, with limited sensitivity at the individual level. In experiment 2, there was no evidence of trace-conditioned learning in healthy subjects, precluding any extrapolation to brain-injured individuals.Conclusions: Heart rate deceleration after aversive acoustic stimulus was significant in passive hearing but not in a trace-conditioning paradigm and was of limited sensitivity at the individual level. Significance: Heart rate deceleration may constitute an objective marker of purposeful affective behaviour triggered by emotional sounds. The question of whether this response is a reflex or a marker of conscious access needs further study
Cerebellar-cortical beta oscillations emerge as a predictive signal facilitating the stability of behavioral performance
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Consecutive non-Aspergillus Fungal Invasive Infections in Chronic Granulomatous Disease: Data from the French National Reference Center for Primary ImmunoDeficiencies and literature review
No full textInternational audienceBackground: Non-Aspergillus invasive fungal infections (NAFI) are increasingly reported in patients with Chronic Granulomatous Disease (CGD), but precise clinical descriptions remain scarce.Objective and methods: We conducted a retrospective analysis of NAFI cases among CGD patients in the French National Registry of Primary Immunodeficiencies (CEREDIH) and in a comprehensive literature review.Results: We identified 16 proven NAFI (9 molds, 6 yeasts and 1 Pneumocystis) among 263 CGD patients from CEREDIH and included an additional 106 probable/proven NAFI from a literature review (75 molds, 29 yeasts, 1 Pneumocystis, 1 dimorphic). Mold NAFI occurred at a median age of 17 years [IQR 9-23], and were mostly located to the lungs (79%, 65/82). Mold NAFI were breakthrough in 59% of patients (35/59), and 24% were receiving immunosuppressive treatments (13/54, mostly high-dose corticosteroids, n = 11). Lung surgical biopsies yielded the highest diagnostic rate (39/39) compared to less invasive methods (BAL 8/18 and transthoracic punctures 8/12). Nine patients with mold NAFI, including 3 refractory cases, were cured after Hematopoietic Stem Cell Transplantation (HSCT). Overall mortality for mold NAFI was 25% (20/81). Yeast infections occurred at a median age of 5 years [IQR 0-13], and 36% were receiving immunosuppressive treatments (5/14, mostly anti-TNF agents, n = 4). Infections were frequently located to lymph nodes or lungs, and 64% (21/33) were disseminated. Two yeast NAFI were cured after HSCT. Mortality was 26% (7/27).Conclusion: NAFI in CGD patients are frequently severe, often occur despite prophylaxis and under additional immunosuppression, commonly require invasive procedures for diagnosis, and may be effectively managed with HSCT
Evaluation of the effects of metformin on gut functions and microbiota and their contribution to improving glucose tolerance in diabetic mice
No full textInternational audienceObjectivesAlthough the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, increasing evidence points to a pivotal role of the gut. Aiming to clarify whether metformin-induced changes in the intestinal tract directly contribute to metabolic improvement, we evaluated the effects of escalating doses (from 50 to 200 mg/kg/day) of metformin orally administered for 4 weeks in mice made glucose intolerant by ten weeks of high fat high sucrose diet.MethodsSeveral intestinal parameters were studied, including caecal microbiota composition and bile acids profile, ileal FXR signaling, abundance of GLP1-producing cells and goblet cells and blood metabolome.ResultsMetformin restored glucose tolerance, fasting insulinemia and HOMA-IR index in a dose-dependent manner. Only a subset of gut-related effects, including mucus production and GLP-1 expression, exhibited a parallel dose–response relationship, suggesting a possible contribution to the observed metabolic improvements. In contrast, other changes, including ileal Fxr-Fgf15 inhibition and hepatic ceramide reduction did not scale with dose, suggesting they are not the main drivers of metformin dose-dependent effects on glycemic control. We also pointed out marked differential sensitivity of gut bacteria to metformin supporting complex interactions of the drug with the microbial ecosystem.ConclusionFinally, metformin enhanced the proliferation of intestinal epithelium, resulting in increased length of ileal villi. Altogether, this study offers new insights into the metformin mechanism of action and revealed potential novel microbial biomarkers and targets for enhancing its therapeutic efficacy
Clinical Characteristics, Symptoms, and Long-Term Outcomes in Gitelman Syndrome
No full textInternational audienceIntroduction: Gitelman syndrome (GS) is a rare inherited salt-losing tubulopathy with limited clinical data.Methods: Surveys were conducted with GS physicians in Europe and patients with GS in the Netherlands to compare findings with the general population.Results: Data from 587 patients (25% pediatric) across 13 countries showed 93% were genotyped, with 94% having variants in SLC12A3. Children with GS were shorter and lighter than the general population, with lower bodyweight persisting into adulthood. The sex distribution was uneven, with more males in childhood and more females in adulthood. Patients with GS had the expected electrolyte disorders as well as significantly lower blood phosphate levels. Positive correlations were found between blood magnesium and potassium, and potassium and aldosterone. Physicians reported muscle cramps, salt craving, and muscle weakness as most common GS symptoms. Patients with GS scored worse than the general population in fatigue, physical, and cognitive function; and ranked salt craving and polydipsia-polyuria as the most severe symptoms. Symptom burden was higher in adult females and patients with lower blood magnesium. Treatment mainly consisted of potassium (94%) and magnesium (50%) supplementation. Potassium-sparing medication (used in 33%) slightly increased blood potassium levels (3.2 vs. 3.1 mmol/l). Adult patients with GS had a high prevalence of chondrocalcinosis (15%) and elevated blood cell counts (26%). Compared with the general population, adult patients with GS had lower rates of chronic kidney disease (CKD) and hypertension, a similar rate of diabetes, but a higher rate of albuminuria or proteinuria (28%).Conclusions: These findings provide new insights into GS, highlight disease burden, and suggest areas for future research
Outcome after relapse in older patients with Philadelphia Chromosome–Negative B-cell ALL treated with inotuzumab ozogamicin and low-dose chemotherapy in first-line therapy: A graall study
No full textInternational audienceBackground: With the advent of immunotherapy, the prognosis of older patients with Philadelphia-negative (Ph-neg) B-cell acute lymphoblastic leukemia (B-ALL) has significantly improved these recent years. Overall survival (OS) is now around 50% at 2 years, with the consequence that is it now possible to consider the outcome of relapsing patients (pts) after a first-line therapy. Here we studied the outcome of pts who relapsed after receiving a frontline immuno-chemotherapy with inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, as part of the EWALL-INO study (NCT03249870, JCO 2024). Methods The RELAPSINO study aimed to retrospectively describe post-relapse outcome in pts included in the single arm phase 2 prospective multicenterEWALL-INO study. In this former study, InO was associated with low dose chemotherapy for 2 induction cycles. In case of complete response (CR), pts then received 6 consolidation cycles and an 18-month (m) POMP maintenance or an allogeneic stem cell transplantation (allo-SCT). At diagnosis, all pts were aged ≥ 55 years and had a newly diagnosed CD22+ Ph-neg B-ALL. A total of 131 pts were included between December, 2017, and March, 2022, and 49 relapses (incidence 38% at 2 years) were documented at last follow-up in May, 2023, including 45 in France, 2 in Finland and 2 in Czech Republic. The RELAPSINO study was approved by the Groupe Nantais d'Ethique dans le domaine de la Santé (GNEDS, reference 24-79-07-100, July 2024). For administrative reason, only French pts were included in this new study. Data regarding pts were updated until May, 2025, and analyses were performed in June, 2025. Results Since the last follow-up, 6 additional relapses have been documented among French pts. Among the 45 previous relapsed French pts, we excluded 3 pts who presented concomitant therapy-related myelodysplastic syndrome. In total, 48 French relapsed pts (male n=25, female n=23) were included in this updated analysis, of whom 60% had a high-risk cytogenetics at diagnosis. None had received an allo-SCT in CR1. At relapse, median age was 70 years (IQR, 67-74; range, 55-86) and median duration of CR1 was 15.2m (IQR 5.3-22.9). Site of relapse was bone marrow (BM) in 38 (79%) pts, extra-medullary in 4 pts (CNS n=2, testis n=1, vertebra bone n=1) and combined in 3 pts (BM + skin n=1, BM + ocular n=1, BM + CNS n=1) (missing n=3). Although none of the patients received the CD19-CD3 bi-specific T-cell engager blinatumomab before relapse, CD19 and CD22 expressions were negative at relapse in 5/41 (12%) and 9/40 (23%) of evaluable pts, respectively. A large majority of pts were re-treated (n=41, 85%) and 29/41 (71%) received blinatumomab as salvage regimen, either alone (n=14) or after low-dose (n=9) or intensive (n=6) chemotherapy. Twelve pts received chemotherapy only (low dose n=3, intensive n=9). No patient was re-treated with InO or received CAR-T cells as salvage regimen. Half of the pts (n=20/41, 49%) achieved CR2. One was consolidated with CAR-T cells and 4 with an allo-SCT. By multivariate analysis (MA), a CR1 duration > 12m (but not >15m or 18m) was the only significant factor associated with CR2 achievement (p=0.04). With a median follow-up from relapse of 30.3 months (95%CI, 25.0–NA), median event-free survival (EFS) and OS were 3.2m (95%CI 2.3-5.7) and 4.5m (95%CI 3.8-11.0), respectively. Two-year EFS and OS were respectively 15% and 19%. By MA, salvage regimen with intensive chemotherapy (p=0.01), CR1 duration >18m (but not >12m or 15m) (p=0.04), and CR2 (p<0.001) were significantly associated with better OS. Intensive chemotherapy (p=0.008) and CR1 duration >18m (but not >12m or >15m) (p=0.01) were also associated with significant better EFS. The 2-year cumulative incidence of relapse after CR2 was 53%. No predictive factor for second relapse was identified. Median LFS and OS after CR2 were 13m and 24m, respectively, with 2-year LFS and OS of 36% and 46%. In pts who did not achieve CR2, median OS was 3.8m only. Overall, 38 pts (79%) died, the main cause of death being relapse or progression (n=36, 95%). Two pts died in CR2 of unknown cause.Conclusion: Half of older Ph-neg B-ALL patients relapsing after a front-line Ino-based therapy can achieve a new remission and good survival. These encouraging results support the risk of re-treating patients, especially those with late relapse, even with intensive chemotherapy, which appears the best salvage regimen in this series
Real life study of ivosidenib in either monotherapy or combined with azacytidine for first line mutant IDH1 AML: A study from the french AML intergroup ALFA/filo
No full textInternational audienceBackground: IDH1 mutations are found in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (IVO), an oral mIDH1 inhibitor, is approved for newly diagnosed mIDH1 AML in patients (pts) aged ≥75 years or unfit for intensive chemotherapy as monotherapy (US), based on the results of the AG120-C-001 study (Roboz, Blood, 2020, median overall survival (mOS) 12.6 months) or with azacitidine (AZA) (US and Europe) based on the results of the AGILE study (Montesinos, NEJM, 2022, mOS 29.3 months). However, data available on IVO+/-AZA in real-life are limited. Method: This retrospective study (IVOOBS, NCT06377579)included pts treated in France between 01/2017 and 02/2024 through a compassionate use program with IVO+/-AZA for mIDH1 AML, front-line or at time of relapse or for a refractory disease. Here we focused only on newly diagnosed pts. The primary objective was OS and secondary objectives included response rate (ELN-2022 criteria) and toxicity. Results: 49 pts from 17 centers were included; 16 (33%) received IVO alone (IVO-mono cohort) and 33 (67%) the combination (IVO+AZA cohort). IVO-mono cohort (n=16) : The median age was 72 yo (IQR: 60 - 83.25), 62.5% were male. Most of the pts were unfit (PS > 2 in 92%) with high-risk disease (secondary AML n=14, including 8 pts who have already received AZA for prior hematologic disease; adverse (adv)-risk according to ELN-2022 classification n=7, 43%, intermediate (int)-risk n= 9, 57%). The median white blood count (WBC) was 2.67 Giga/L. The majority of pts started IVO at the recommended dose of 500 mg/day (d) (n=13, 81%), while 3 started at 250 mg/d (concomitant prescription of azole). Median duration of IVO treatment was short (3.25 months, IQR: 1.6-7.07) as 77% % (n=10) of IVO discontinuations occurred within 4 months (3 allo-HCT, 3 progressions, 2 differentiation syndrome (DS), 1 QT prolongation (QTp), 1 death). Any grades of DS and QTp were reported in 25% (n=4) and 7% (n=1) of pts, respectively, while grade 3-4 hepatic, infection and hematologic adverse events (AE) occurred in 0, 4 and 3 pts, respectively. Two deaths were linked to IVO (DS). Mortality at D30 and D60 was 6% and 25%, respectively. Composite complete remission (CCR) (CR/CRh/CRi) rate was 37% (31%/6%/0%), with no MLFS and 44% of non-responders (19% of pts not assessed (NA)). For pts receiving IVO at 500mg/d, CCR was 46% (38%/8%/0%). At 250mg/d, 2 pts did not respond and 1 was NA. Four pts (3 in CR, 1 in no response) received an allo-HCT after IVO. Among responders (n=6), 1 pt relapsed at 10.8 months. With a median follow-up (mFU) of 4.5 months, mOS was 4.5 months (95% CI: 2.07-not reached (NR)) and 2y OS 31.25% (95% CI: 15.11-64.64). IVO+AZA cohort (n=33): The median age was 78 yo (IQR: 75 – 80), 60% were male. The majority of pts were unfit (PS > 2 in 93%) and classified as int-risk (83%) according to ELN-2022 classification (adv-risk 17%). However, according to ELN-2024 classification, most pts had favourable-risk (n=22, 67%) (adv-risk n=2, NA n=9). The median WBC was 2.15 Giga/L. Nine pts (27%) had a secondary AML. The majority of pts started IVO at the dose of 500 mg/d (n=27, 82%), while 6 pts started at 250 mg/d (concomitant prescription of azole (n=5), previous cardiac history (n=1)). Median number of AZA cycles was 6 (range: 1; 28). Median duration of IVO treatment was 13.1 months (IQR: 8.4-18.4) and 26% (n=5) of IVO discontinuations occurred within 4 months (3 progressions, 2 deaths). Mortality at D30 and D60 was 3% and 9%, respectively. DS was reported in 3 pts (9%) and QTp in 2 (7%), any grades, while grade 3-4 hepatic, infection and hematologic AE occurred in 0, 5 and 8 pts, respectively. No death was linked to IVO. CCR was 73% (55%/12%/6%), 3% showed MLFS, 21% were non-responders and 3% NA. CCR was 78% (56%/15%/7%) and 50% (50%/0%/0%) for those receiving IVO at 500 mg/d and 250mg/d, respectively. Among responders (n=24), only 1 pt was consolidated with an allo-HCT and 8 (33%) relapsed at a median of 11.4 months. At relapse, 4 were treated with AZA+BCL2 inhibitor and 1 obtained CR. With a mFU of 16.6 months, mOS was NR (95% CI: 16.62-NR) and 2y OS 52% (95% CI: 35.55-76.56). Conclusion: This retrospective real-life study shows the reproducibility of the results of the AGILE study (IVO+AZA). Pts receiving IVO mono had poorer outcome compared to those of the AG120-C-001 study, likely because pts were at higher risk. The dose of 500 mg/d should also be preferred questioning the role of azole prophylaxis
Patient-Reported Outcomes of CAR T-Cell Therapy in Non-Hodgkin Lymphoma Patients and Their Impact on Survival
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Evaluation of a pro-recovery training intervention (REFOCUS-RETAFORM) in specialist mental health services across France: stepped-wedge cluster randomised controlled trial protocol
No full textInternational audienceBackground: While recovery orientation is national policy in many countries, evidence remains limited for the effectiveness at a service level. This paper describes the protocol for implementing a pro-recovery training intervention (REFOCUS-RETAFORM) in specialist mental health services across France. The aim is to evaluate whether REFOCUS-RETAFORM plus usual care leads to improved outcomes for adolescent and adult mental health service users compared with usual care alone.Methods: A two-step stepped wedge cluster randomised controlled trial will be conducted, with a nested qualitative sub-study exploring stakeholders' views on changes in staff-user relationships and implementation influences. The REFOCUS-RETAFORM intervention is a training intervention for mental health staff, to develop recovery-promoting relationships and pro-recovery working practices. Clusters are services, which transition sequentially from control to intervention condition in a randomised order. Eight clusters are randomised to deliver REFOCUS-RETAFORM in year one and eight clusters in year two. Each cluster delivers REFOCUS-RETAFORM to two teams from their organisation (32 teams in total). Participants are a) service users aged 13-65 years attending services implementing REFOCUS-RETAFORM, and b) staff receiving the intervention. The primary outcome is the Questionnaire about the Process of Recovery. Secondary outcomes include perceived stigma and coercion, self-stigma and wellbeing for service users, and recovery-orientation for staff. Data will be collected from 540 service users (180 at baseline, 180 at month 12, 180 at month 24) and 220 staff. We will use multilevel mixed-effects models, adjusting for secular trends and thematic analysis for the qualitative interview data.Discussion: Findings will inform the continued transformation of French specialist mental health services toward a recovery orientation.Trial registration: Clinical Trials NCT05824234, registered 21 April 2023
The prefrontal operculum, a human-specific hub for the cognitive control of speech
No full textInternational audienceCurrent theories fail to explain why the ability to control speech is unique to humans. We recently identified one unique feature in the human frontal cortex that may hold the key to this question: the Prefrontal Operculum (PFO). Here we aim to identify 1) its anatomo-functional organization to elucidate its potential function and 2) whether it has a homolog in the macaque brain. Functional connectivity (FC) results in humans, revealed that PFO is subdivided in two regions (aPFO and pPFO), displaying strong interactions but distinct whole brain FC profiles with respectively the language and the cognitive control networks, and thus suggesting an important role of PFO in the cognitive control of speech. Connectivity fingerprint analyses in macaques revealed similarities with pPFO, but we found no macaque homolog of human aPFO. Altogether, this study points toward the emergence of aPFO as an evolutionary advantage in hominids for modern speech abilities