French Clinical Research Infrastructure Network

Data are needed on the effect of oxygen delivered through a high-flow nasal cannula, as compared with standard oxygen therapy, on intubation and mortality in patients with acute hypoxemic respiratory failure. In this multicenter, open-label trial, we randomly assigned patients who had acute hypoxemic respiratory failure to receive high-flow-oxygen or standard-oxygen therapy. All the patients had a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 or less, a respiratory rate of more than 25 breaths per minute, and pulmonary infiltrate on chest imaging. The primary outcome was death by day 28. A total of 1116 patients underwent randomization. Of these patients, 1110 (556 in the high-flow-oxygen group and 554 in the standard-oxygen group) were included in the analysis. Mortality at day 28 was 14.6% (in 81 of 556 patients) in the high-flow-oxygen group and 14.6% (in 81 of 554 patients) in the standard-oxygen group (difference, -0.05 percentage points; 95% confidence interval [CI], -4.21 to 4.10; P = 0.98). The incidence of intubation by day 28 was 42.4% (in 236 of 556 patients) in the high-flow-oxygen group and 48.4% (in 268 of 554 patients) in the standard-oxygen group (difference, -5.93 percentage points; 95% CI, -11.78 to -0.08). Serious adverse events (cardiac arrest or pneumothorax) occurred during spontaneous breathing in 13 patients (2.3%) in the high-flow-oxygen group and in 6 patients (1.1%) in the standard-oxygen group. Among patients with acute hypoxemic respiratory failure, the use of oxygen delivered through a high-flow nasal cannula did not significantly reduce mortality at day 28. (Funded by the French Ministry of Health and Fisher and Paykel Healthcare; SOHO ClinicalTrials.gov number, NCT04468126.).

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Renal angiomyolipomas (AMLs) drive substantial morbidity in tuberous sclerosis complex (TSC) through haemorrhage and repeated invasive procedures. While mammalian target of rapamycin inhibitors (mTORis) reduce AML volume, long-term real-world data on clinically meaningful bleeding and procedure outcomes remain limited, particularly in cohorts enriched for high-risk imaging phenotypes. We conducted a multicentre observational study (2004-2020) in three French tertiary centres. Among 103 included patients, the 96 with TSC constituted the primary analysis set. We assessed AML-related haemorrhage and selective arterial embolization (SAE). For patients initiating mTORi, follow-up was split into pre- and post-initiation periods and incidence rate ratios (IRRs) were estimated using Poisson regression with patient-time offsets and patient-clustered robust standard errors; generalized estimating equation Poisson and negative binomial models were used as sensitivity analyses. Total follow-up was 694.3 patient-years. Thirty-nine patients (40.6%) initiated an mTORi (everolimus 94.9%). Haemorrhage rates decreased from 0.061 to 0.007 events per patient-year after mTORi initiation {IRR 0.11 [95% confidence interval (CI) 0.02-0.62]} and SAE rates decreased from 0.197 to 0.020 sessions per patient-year [IRR 0.10 (95% CI 0.04-0.29)]. Therapeutic inertia remained substantial: among 57 never-treated patients, high-risk imaging features and active complications were frequent at the last assessment. In this long-term real-world cohort of TSC-associated renal AMLs, mTORi initiation was associated with markedly lower rates of AML haemorrhage and SAE. Despite these benefits, many high-risk patients remained untreated in routine care, supporting earlier nephrology referral, systematic risk stratification and timely treatment initiation to reduce preventable AML-related morbidity.

Acute kidney injury (AKI) is a frequent and severe complication among critically ill patients. Circulating dipeptidyl peptidase 3 (cDPP3), an enzyme released upon cellular injury, has been implicated in hemodynamic instability and organ dysfunction. Its role in severe AKI remains poorly defined. We aimed to assess the prognostic significance of cDPP3 in critically ill patients with severe AKI. In this post hoc analysis of the AKIKI 2 study, we included ICU patients with severe AKI (KDIGO stage 3) who were receiving (or had received) invasive mechanical ventilation and/or vasopressor support and had available blood samples at inclusion. Patients were stratified according to cDPP3 concentration using a predefined cutoff of 40 ng/mL. The primary outcome was 28-day mortality; secondary outcomes were organ support-free days. Among 287 included patients, 143 (49.8%) had cDPP3 concentrations above 40 ng/mL. High cDPP3 was associated with increased 28-day mortality (hazard ratio 1.95; 95% confidence interval 1.37-2.87, p < 0.001). Furthermore, high cDPP3 was associated with fewer days alive without vasopressors (mean difference - 5.59; 95% CI - 8.29 to - 2.78, p < 0.001), invasive mechanical ventilation (mean difference - 6.23; 95% CI - 8.89 to - 3.36, p < 0.001), or renal replacement therapy (mean difference - 6.35; 95% CI - 9.14 to - 3.26, p < 0.001). After adjustment for baseline markers of severity, both the associations with 28-day mortality and organ support-free days remained significant. In critically ill patients with severe AKI, a high cDPP3 concentration at diagnosis is associated with increased short-term mortality and prolonged dependence on organ support.

We aimed to better understand patient characteristics and pathophysiological mechanisms associated with severe diastolic dysfunction in aortic stenosis patients undergoing transcatheter aortic valve implantation (TAVI). Patients with severe aortic stenosis often have echocardiographic signs of diastolic dysfunction. However, their characteristics and underlying disease mechanisms remain unclear. Untargeted LC–MS lipidomics (1110 lipids) and proteomics (834 proteins) were performed on peri-procedural plasma from 231 TAVI patients. Pre-procedural echocardiography was available in 191 patients. DIABLO (mixOmics, version 6.3.0, R version 4.4.1) was used to integrate lipidomic and proteomic profiles. Median age was 80 years, and 61% were female. In total, 75 (39%) patients had severe diastolic dysfunction. Patients with severe diastolic dysfunction more often had atrial fibrillation, higher plasma NT-proBNP concentrations, and more heart failure hospitalizations and mortality. Multi-omic network analysis identified two major lipid–protein clusters associated with severe diastolic dysfunction. The first showed dysregulation of membrane phospholipids such as cardiolipins (essential for mitochondrial integrity and energy metabolism), and phosphatidylserines (cytoprotective and anti-inflammatory properties). This cluster was associated with cytoskeletal and extracellular matrix remodeling. The second cluster showed high concentrations of acylcarnitines (indicative of metabolic dysfunction), which were associated with extracellular matrix remodeling and inflammatory responses. In patients with aortic stenosis undergoing TAVI, those with severe diastolic dysfunction showed a disrupted balance of membrane phospholipids and acylcarnitines, suggesting that impaired energy metabolism, cellular and extracellular structural remodeling, and inflammatory responses may underlie the development and progression of diastolic dysfunction and heart failure. We investigated clinical features and molecular profiles linked to severe diastolic dysfunction in aortic stenosis patients undergoing TAVI. Untargeted lipidomics (1110 lipids) and proteomics (834 proteins) were performed on peri-procedural plasma from 231 patients. Pre-procedural echocardiography was available in 191 patients. Severe diastolic dysfunction was present in 39% and was associated with atrial fibrillation, higher NT-proBNP, and more heart failure hospitalizations and mortality. Multi-omic integration identified two major lipid-protein clusters. The first was characterized by dysregulated membrane phospholipids, including cardiolipins and phosphatidylserines, linked to cytoskeletal and extracellular matrix remodeling. The other showed elevated acylcarnitines, indicating metabolic dysfunction, and inflammatory activation. These findings suggest that altered energy metabolism, structural remodeling, and inflammation are associated with severe diastolic dysfunction in aortic stenosis. Patients with severe aortic stenosis and severe diastolic dysfunction undergoing TAVI (n = 75 patients with severe diastolic dysfunction, n = 116 patients without severe diastolic dysfunction) show a disrupted balance of membrane phospholipids and acylcarnitines, suggesting that impaired energy metabolism, cellular and extracellular structural remodeling, and inflammatory responses may underlie the development and progression of diastolic dysfunction and heart failure. TAVI = transcatheter aortic valve replacement; LAVI = left atrial volume index; PASP = pulmonary artery systolic pressure; LA = left atrium; GLS = global longitudinal strain; LVMI = left ventricular mass index. • Diastolic dysfunction was linked to more atrial fibrillation and higher NT-proBNP. • Diastolic dysfunction predicted more HF admissions and mortality after TAVI. • Diastolic dysfunction was linked to altered phospholipid and acylcarnitine balance. • Metabolic impairments and inflammation may drive diastolic dysfunction in AS. • These mechanisms mirror those in heart failure with preserved ejection fraction.

Rare diseases (RD) have progressively emerged as public health priority in many countries. Epidemiological data are still lacking and the extraction of data from the public health system remains insufficient. In France, RD database set up in 2013 as Banque Nationale de Données de Maladies Rares (BNDMR). Patients’ information is provided by physician at each consultation and RD are classified according ORPHAcode. The status of each diagnosis can be entered as ‘confirmed’, ‘probable’ or ‘under investigation’, as well as related families. We aimed to test the reliability and quality of data for epidemiology by analyzing the data from a RD caused by autosomal dominant inheritance and with a univocal genetic diagnosis: TNF receptor-associated periodic syndrome (TRAPS). Patients were extracted on January 2023 and genetic files were retrieved from January to march 2023. All patients registered with a diagnosis of TRAPS were included. We identified 132 patients who fulfilled inclusion criteria, among which 31 were excluded (missing data and duplicates). We analyzed 101 patients and their sequences of TNFSRSF1A gene. Pathogenic and likely pathogenic variants were found in 69% of patients, while the remaining 31% may rather represent undetermined systemic autoinflammatory disease. The main pathogenic variant found was T50M (c.236 G > T) while the main VUS was R92Q (c.362 G > A). For the patients entered as ‘confirmed’, only 44% of them had a pathogenic/likely pathogenic variant. We identified eight different families. We therefore estimated the minimum prevalence of TRAPS in France: 1/1 156 711. In the French National Rare Disease Registry, the quality of data remains a challenge, especially in monogenic diseases where the knowledge of the pathogenicity of variants and the number of gene involved is constantly increasing. Our study suggests that the data exported from the BNDMR needs important data correction to allow reliable epidemiologic studies in these diseases.