HAL Portal Chu Clermont-Ferrand
Not a member yet
7589 research outputs found
Sort by
Cardiogenic shock in patients with active onco-hematological malignancies: A multicenter retrospective study
No full textInternational audienceOnco-hematological (OH) patients face significant cardiovascular risks due to malignancy and drug toxicity. Data are limited on the characteristics and outcomes of OH patients with cardiogenic shock (CS) in intensive care units (ICUs)
A Risk Stratification Tool for Relapse After Intravenous-to-Subcutaneous Switching of Infliximab in Patients with Inflammatory Bowel Diseases
No full textInternational audienceObjectives: A subcutaneous formulation of infliximab was recently approved for maintenance therapy of inflammatory bowel disease (IBD). However, limited clinical experience, particularly with patients on escalated intravenous infliximab regimens, poses challenges for the transition to subcutaneous therapy. We investigated the pharmacokinetics and pharmacodynamics of subcutaneous infliximab to identify early predictors of relapse upon switching. Methods: We repurposed data from a prospective, multicenter trial involving patients with IBD switching from intravenous to subcutaneous infliximab. We estimated each patient’s infliximab clearance using Bayesian forecasting from a pre-switch sample and a population pharmacokinetics model. We performed pharmacodynamics modeling to evaluate pre-switch predictors of post-switch relapse. Relapse was defined as clinical recurrence (partial Mayo score >2 or Harvey–Bradshaw Index >4 leading to therapeutic escalation) or an increase in fecal calprotectin ≥150 μg/g upon switching. Results: Using data from 98 patients with IBD, we identified infliximab clearance and fecal calprotectin as independent predictors of relapse. A two-item risk score stratified patients into low-risk (<19% probability of relapse; 75/98; 77%) and high-risk (≥19% probability of relapse; 23/98; 23%) groups (sensitivity 0.52 [95%CI 0.31−0.73], specificity 0.95 [95%CI 0.87−0.99], positive predictive value 75% [95%CI 48−93%], negative predictive value 87% [95%CI 77−93%]). Our pharmacokinetics–pharmacodynamics model classified patients with and without relapse ( p <0.0001) with an area under the receiver operating characteristic curve of 0.83 (95%CI 0.71−0.93). Conclusions: Pre-switch infliximab clearance and fecal calprotectin are accurate predictors of relapse after switching to subcutaneous infliximab. An interactive risk stratification tool facilitates confirmation of a stratified medicine approach to improve infliximab therapy in IBD
MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights
No full textInternational audienceBackground: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.Methods: We analyzed a whole-exome sequencing database comprising 470 ALS patients and explored the pathogenicity of the identified variants through familial, clinical, neuropathological, and cellular studies.Results: We identified two missense variants in the Tau repeat domains: the novel p.I308T variant, in a patient with earlyonset ALS, and the p.P364S mutation in three families with spinal-or respiratory-onset ALS. Segregation of this mutation with disease could be confirmed in two affected cousins. The observation of p.P364S patient's tissue showed accumulations of hyperphosphorylated Tau in various brain regions, prominent in the motor cortex with Lewy body-like inclusions, along with a C-terminal cleaved form of Tau in muscle. In NSC-34 motor neuron cells expressing p.I308T or p.P364S mutants, Tau was discontinuous along the neurites, with clusters of mitochondria resulting from impaired mitochondrial motility.Conclusion These findings expand the molecular understanding of ALS to include MAPT mutations. MAPT analysis should be incorporated into ALS genetic screening, particularly in patients with a familial history of the disease. Recognizing the full spectrum of MAPT-linked neurodegenerative diseases is of considerable interest, given the ongoing efforts to develop MAPT-targeted therapies
P0704 A Multicenter Study Evaluating the Persistence, Effectiveness, and Safety of Methotrexate in Patients with Inflammatory Bowel Disease: The MICI-METHO Study
No full textInternational audienceBackground Methotrexate has demonstrated efficacy in Crohn’s disease (CD) as monotherapy and is increasingly used in combination therapy. There is no consensus regarding its use in clinical practice, and it remains underused. The aims of this study were to describe the use of methotrexate in patients with inflammatory bowel disease (IBD) in France, and assess its persistence and safety. Methods This was an observational, retrospective, multicenter study involving adult patients with IBD treated with methotrexate in monotherapy or combination therapy between January 2015 and December 2022. All patients were followed for at least 6 months after the initiation of treatment. Results A total of 1115 patients were included from 15 French centers. Among them, 510 were men (45.7%). The median age at diagnosis was 24 [17.9–36.4] years, and the median age at initiation of methotrexate was 35.6 [24.8–50.3] years. The majority of patients had CD (77%), and 378 (34.5%) patients had at least one extra-intestinal manifestation (EIM). Regarding prior treatments, 45.8% of patients had been exposed to azathioprine and 78.2% to anti-TNF agents. The median treatment duration was 12.3 [5.9–29.9] months. The primary indication for methotrexate was IBD (81.5%), followed by EIM (rheumatological (11.9%) or dermatological (3.9%)). The most frequently used induction doses were 15 mg/week (47.5%) and 25 mg/week (31%), while the most common maintenance dose was 15 mg/week (51.1%). The treatment was mainly administered by subcutaneous injection (57.8%) or orally (38%). Methotrexate was prescribed in combination therapy in 90.6% of cases. The persistence rate of methotrexate was 27.7 months in CD and 22.4 months in ulcerative colitis (UC). For CD, factors associated with persistence were female sex (Hazard Ratio (HR) 1.258; 95% Confidence Interval (CI) 1.051–1.506) and the presence of EIM (HR 0.709; 95% CI 0.583–0.862). In UC, the presence of EIM (HR 0.629; 95% CI 0.420–0.944) was associated with treatment persistence. The main reasons for discontinuation of methotrexate were inefficacy (32.5%), intolerance (29.6%), and cessation of combination therapy (20.4%). A total of 344 (31.7%) patients experienced an adverse event related to methotrexate, and 9 patients experienced a serious adverse event. After discontinuation of methotrexate, 53.8% of patients continued treatment as monotherapy, 40% required another treatment, and 6.1% underwent surgical intervention. Conclusion The French multicenter MICI-METHO study is the first to provide a comprehensive overview of the real-world use, effectiveness, and safety of methotrexate in patients with IBD. A better understanding of this treatment could improve its use in IBD management
Association between education level and disability progression in patients with multiple sclerosis in France
No full textInternational audienceBackground: Studies have reported an association between socioeconomic status and disability progression in multiple sclerosis (MS), but findings using the pre-MS individual socioeconomic status are missing. Objective: The objective was to investigate the association between education level and disability progression. Methods: All Observatoire Français de la Sclérose en Plaques (OFSEP) patients with MS clinical onset over 1960–2014, and aged ⩾25 years at MS onset were included. Education level was classified into four categories from low (primary/secondary school) to very high (master/doctoral degree). Time from MS onset to EDSS 4.0 was studied using flexible parametric survival models adjusted for age, period, and center, and stratified by phenotype (relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS)) and sex. Results: A total of 11,586 patients were included (women/men ratio = 2.5; age = 36.7 ± 8.6 years; follow-up duration 16.7 ± 9.3 years; 86.4% RMS). For women with RMS, the risk of reaching the outcome at 5 years was inversely associated with the education level (Hazard Ratio medium: 0.74 (0.63–0.87), high: 0.51 (0.43–0.62), very high: 0.39 (0.30–0.50) vs low). Results were similar for men. In PPMS, the risk was significantly different between the extreme groups (very high vs low) for women (0.45 (0.28–0.75)) and men (0.54 (0.32–0.91)), but no gradient was evident. Conclusion: Our study showed a strong association between education level and disability progression, regardless of sex and phenotype
Top-down infliximab plus azathioprine versus azathioprine alone in patients with acute severe ulcerative colitis responsive to intravenous steroids: a parallel, open-label randomised controlled trial, the ACTIVE trial
No full textInternational audienceBackground: It is unknown which maintenance therapy is the most effective option for patients admitted for an acute severe ulcerative colitis (ASUC) episode responding to intravenous steroids.Methods: We conducted a multicentre, parallel-group, open-label randomised controlled trial among 23 French centres in thiopurine and biologics-naïve adults admitted for ASUC responding to intravenous steroids. Eligible patients were randomly assigned to receive infliximab (IFX) and azathioprine (AZA) with a 7-day steroid tapering scheme (IFX+AZA arm) or AZA and conventional standardised steroid tapering regimen (AZA arm). The primary composite endpoint was treatment failure at week 52, defined as the absence of steroid-free clinical remission, the absence of endoscopic response, the use of a prohibited treatment for relapse, severe adverse event leading to treatment interruption, colectomy or death. Multiple imputation for missing data was performed.Findings: Among the 64 patients randomised (Lichtiger score 13.5±2.0; median age of 34.5 (P25-P75 26.3-50.3) years, median C reactive protein of 29.0 (12.8-96.8) mg/L at baseline): 32 were assigned to the IFX+AZA arm and 32 to the AZA arm. In the ITT population, treatment failure at week 52 was observed in 22/27 (81.5%) in the AZA arm and 16/30 (53.3%) in the IFX+AZA arm (risk ratio 3.85, 95% CI (1.15 to 12.88), p=0.03). 29 adverse events were severe, including 13 disease exacerbations, 6 severe infections without any difference between both arms.Interpretation: Combination therapy with IFX+AZA was more effective at 1 year than AZA alone to avoid treatment failure in patients with ASUC responding to intravenous steroids.Trial registration number: NCT02425852
Screening for Frailty According to Rural and Suburban Health Areas in the Context of Adapted Integrated Care for Older People Approach: The FRAGING Study
No full textInternational audienceABSTRACT Background The integrated care for older people (ICOPE) program, developed by the World Health Organization, serves as a public health initiative to maintain older adults’ functional abilities and promote healthier aging. Here, we adapted the ICOPE approach to assess overall prevalence of frailty in rural and semi‐urban areas. We also investigated health‐related quality of life and physical activity and sedentary behavior in older people. Methods The FRAGING multicenter cohort study was performed on screening days dedicated to older adults (≥65 years) without chronic disease in a rural area (RU) and in a semi‐urban area (SU). Results The study included a total of 105 participants: 98.4% of participants were frail, with a mean of 4.3 [SD: 2.5] frailties per participant. RU participants had higher number of frailties ( p = 0.02) and a higher percentage of frail participants in the dimensions of health‐related quality of life ( p < 0.0001), socioeconomical level ( p = 0.008), colorectal cancer screening ( p = 0.022), and tetanus booster doses ( p = 0.008). Globally, women were less sedentary than men ( p = 0.02) and engaged more in low physical activity (LPA) than men ( p = 0.01). RU participants engaged more in LPA than SU participants ( p = 0.03). Conclusions The prevalence of frailty is alarmingly underestimated in older adults without chronic disease. This study demonstrated the need to propose appropriate, validated screening tests that consider territorial issues and organization of care delivery. The ICOPE framework serves as a good startpoint for reorganizing person‐centered healthcare pathways
Efficacy and tolerance of dupilumab in patients with moderate‐to‐severe atopic dermatitis and obesity
No full textInternational audienc
Do prospective randomized controlled trials comply with filed protocols? Spin study of 206 trials from 2010 to 2023
No full textInternational audienceIntroductionProspective randomized controlled trials (RCT) have a robust methodology, but some distortions may occur during the course of study. Some protocols may not be available at the time an article is reading. Some authors may change the methodology between the time the protocol was submitted and when the trial results are actually published. Others may distort results to favor more attractive findings and draw conclusions that support prior hypotheses. This has rarely been investigated and none explored the RCTs published in the Journal of Bone and Joint Surgery (JBJS). Therefore, we did a retrospective investigation aiming to determine: (1) the proportion of trials with a protocol deposited and accessible to the reader, (2) whether the trials scrupulously followed the filed protocols.HypothesisProtocols were available in over 80% of cases, and these protocols were followed in over 80% of trials for the primary endpoint.Patients and methodsThis was a retrospective study of articles published in the JBJS between January 2010 and November 2023. Differences in primary and secondary endpoints between protocols and articles were sought.ResultsOf the 206 RCT articles studied, 113 (54.9%) described clear and identifiable endpoints, and 93 (45.1%) were not identifiable and were inferred in the results; 184 (89.3%) articles identified a trial protocol. For the 184 articles (89.3%) declaring a trial protocol in the text, 23 (11.1%) protocols were not accessible. In all, 45 articles (21.8%) thus had no protocol available on the Internet (i.e., not available to the reader either because it was not cited in the text or because it was not accessible) so we analyzed 161 articles. The primary endpoint remained unchanged in 97 articles (60.2%) out of the 161 studied, was changed in 64 articles (39.8%), and was lacking (protocol not accessible) in 45 articles (21.8% of all articles). The secondary endpoints of the articles were unchanged in 61 articles (37.9%) out of the 161 studied.DiscussionLike other leading journals, JBJS publishes RCT articles containing a significant proportion of inconsistencies between preoperative trial protocols and the methods actually used in the research.Level of evidenceIII; retrospective comparative study non randomize
Evaluation of imipenem-relebactam, meropenem-vaborbactam, aztreonam-avibactam and cefepime-zidebactam activities on a wide collection of French clinical Enterobacterales isolates
No full textInternational audienceIn recent years, novel (3-lactam-inhibitor combinations (imipenem-relebactam (I/R), meropenem-vaborbactam (M/V), aztreonam-avibactam (A/A)) have been commercialized and some are not yet on the market (cefepime-zidebactam (C/Z)). The objective of this study was to evaluate the efficacy of these (3-lactam-(3-lactamase inhibitors (BL/BLIs) combinations against a wide collection of French clinical multiresistant Enterobacterales isolates and to assess the performance of the E-test MIC method for I/R and M/V. BL/BLIs MICs were determined by broth microdilution on a collection of 200 ESBL-producing and 414 carbapenem-resistant clinical Enterobacterales (K. pneumoniae (271), E. coli (245), E. cloacae complex (48), other species (50)) including 292 carbapenemase-producing isolates. E-test method was evaluated for the determination of I/R and M/V MICs using 131 isolates from this collection. All the combinations were active against most ESBL-producing isolates (99-100 %), but C/Z and A/A MIC90 were lower than that of I/R and M/V (2mg/L and 2mg/L versus 8mg/L and 8mg/L). The M/V and I/R E-tests performances were close to those required by the FDA recommendations: Categorical agreement (CA) and Essential agreement (EA) > 90 %, Major discrepancy (MD) and Very major discrepancy (VMD) <3 %): 96.9 % (CA), 92.4 % (EA), 1.2 % (MD), 6.1 % (VMD) for I/R and 94.7 % (CA), 96.9 % (EA), 4.1 % (MD), 8.8 % (VMD) for M/V. This work confirmed the interest of C/Z and A/A combinations against carbapenem-resistant Enterobacterales isolates compared with M/V and I/R. Additionally, the findings indicate that the E-test method can be used for the determination of M/V and I/R MIC for E. coli and K. pneumoniae strains