Nantes Université

Fostamatinib is available in France since October 2021 for the treatment of adult chronic immune thrombocytopenia (ITP). French health authorities requested a 3-year, prospective, multicenter registry to provide real-world evidence about the effectiveness and safety of fostamatinib. Patients' characteristics, treatment response (ongoing exposure to fostamatinib and a platelet count ≥ 30 × 109/L with no rescue in the previous 4 weeks) after 3, 6, 12, and 24 months (M); bleeding; fostamatinib discontinuation; adverse drug reactions (ADRs) and other events of interest have been analyzed. In total, 164 patients were included (median age: 59 years; 55.5% women; 84.1% had previous bleeding; 30 had secondary ITP; 89.0% had chronic ITP). The median ITP duration was 7.2 years and the median number of previous ITP treatments was 6. The response rate was 44.0% (70/159) at M3, 41.9% (62/148) at M6, 32.4% (44/136) at M12 and 20.0% (21/105) at M24. Concomitant treatment (mostlyTPO-RA) was used in > 60.0% of responders at each endpoint. The cumulative discontinuation rate at each endpointwas, respectively, 27.0%, 44.6%, 55.9%, and 76.2%. Seventy-one (43.3%) patients experienced at least one bleeding duringfostamatinib exposure; none was fatal. One hundred adverse drug reactions (8 serious) were observed in 61 (36.7%)patients, including diarrhea in 28 (17.1%) patients, arterial hypertension in 17 (10.4%). Seven thrombosis (4.3%) and40 infections (12 serious) were reported in 25 patients (15.2%), mostly in patients with known risk factors. In conclusion,fostamatinib in combination with TPO-RA should be considered in difficult-to-treat ITP patients. No new safety signal was observed.

HLA-G encodes an immune checkpoint molecule with restricted expression in immune-privileged tissues and pathological conditions. It exhibits limited coding diversity but substantial regulatory-region variation influencing expression levels. Strong linkage disequilibrium across HLA-G creates a structured genetic architecture in which regulatory and coding variants co-segregate into well-defined haplotypes, enabling the imputation of complete HLA-G haplotypes from partial genomic data. We developed imputation models to predict HLA-G 4-field alleles, promoter, and 3'UTR haplotypes from whole-exome sequencing and SNP array data using HIBAG. Multi-ethnic reference panels were constructed from 5,347 individuals from three diverse cohorts (1000 Genomes, Human Genome Diversity Project, and Brazilian SABE cohort). Models were validated through cross-validation and independent datasets. Exome-based imputation achieved high accuracy (>99%) for common alleles (frequency>1%), with mean posterior probabilities exceeding 0.95. SNP array-based models showed slightly lower but still robust performance (>95% accuracy). Our approach enables simultaneous prediction of coding and regulatory sequences, providing comprehensive functional information from datasets that do not capture the complete HLA-G diversity. These models facilitate HLA-G analysis in widely available genomic datasets lacking introns and regulatory regions (tumor exomes, SNP arrays), enabling investigation of HLA-G's role in immune regulation, transplantation, cancer, and pregnancy complications without full-gene sequencing.

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.).

BackgroundMethemoglobin is formed when the iron in hemoglobin is oxidized from the ferrous to the ferric state, preventing oxygen transport. This potentially life-threatening condition requires prompt diagnosis and treatment.MethodWe report the case of a 30-year-old Senegalese man with newly diagnosed acute leukemia, admitted to the emergency department for suspected leukostasis syndrome. Induction chemotherapy and rasburicase were initiated. Unexpectedly, 24-h later, he developed acute hemolysis and a methemoglobinemia of 17%.ResultsInvestigation suggested rasburicase-induced methemoglobinemia. Rasburicase generates hydrogen peroxide during acid uric metabolism, normally neutralized by glutathione reductase, an enzyme that requires NADPH, which is produced via the pentose phosphate pathway. In this case, the presence of severe hemolytic anemia and marked susceptibility to oxidative stress prompted comprehensive laboratory investigations, including glucose-6-phosphate dehydrogenase deficiency testing, which returned positive. Supportive care, including monitoring, blood transfusions, and oxygen therapy, allowed normalization of methemoglobin levels within 48-h.DiscussionMethemoglobin can serve as a sentinel marker for the detection and monitoring of oxidative stress and related hematologic disorders. This case highlights the laboratory's role in identifying such abnormalities and the importance of clinician-laboratory awareness regarding rasburicase-induced methemoglobinemia. It also suggests the necessity of G6PD screening prior to rasburicase administration whenever possible.

Despite recent advances in operational streamflow forecasting systems, anticipating and forecasting droughts and associated low-flow conditions remain major challenges in hydrology, with substantial impacts on water-dependent sectors such as agriculture and industry. Enhancing sub-seasonal to seasonal streamflow forecasting is therefore critical for improving water resources management. This study investigates the performance of a Handoff forecast Long Short-Term Memory (LSTM) architecture (Nearing et al., 2024) for probabilistic streamflow forecasting at lead times extending up to six months, with a particular emphasis on low-flow conditions.The Handoff forecast LSTM is trained regionally on a subset of 292 basins from the Catchment Attributes and MEteorology for Large-sample Studies - FRance dataset (CAMELS-FR) (Delaigue et al., 2025), after excluding basins affected by unreliable low-flow measurements. Model training relies on basin-averaged hydro-meteorological reanalysis data provided by CAMELS-FR. Evaluation of the model is conducted using ensemble streamflow forecasts generated from historical scenarios and meteorological ensemble predictions from the SEAS5 model from the European Center for Medium-Range Weather Forecasts (ECMWF) (Johnson et al., 2019)The generated ensemble streamflow forecasts are evaluated using a set of probabilistic metrics such as the Continuous Ranked Probability Score (CRPS), the Brier Score, the Area under the ROC curve, and the Talagrand diagram, and using the natural streamflow climatology as a reference. In addition, a sensitivity analysis of static catchment attributes is performed to assess their relative contribution to model performance and to better understand the drivers of predictability across basins.Delaigue, O., Guimarães, G. M., Brigode, P., Génot, B., Perrin, C., Soubeyroux, J.-M., Janet, B., Addor, N., & Andréassian, V. (2025). CAMELS-FR dataset: a large-sample hydroclimatic dataset for France to explore hydrological diversity and support model benchmarking. Earth System Science Data, 17(4), 1461–1479. https://doi.org/10.5194/essd-17-1461-2025Johnson, S. J., Stockdale, T. N., Ferranti, L., Balmaseda, M. A., Molteni, F., Magnusson, L., Tietsche, S., Decremer, D., Weisheimer, A., Balsamo, G., Keeley, S. P. E., Mogensen, K., Zuo, H., & Monge-Sanz, B. M. (2019). SEAS5: The new ECMWF seasonal forecast system. Geoscientific Model Development, 12(3), 1087–1117. https://doi.org/10.5194/gmd-12-1087-2019Nearing, G., Cohen, D., Dube, V., Gauch, M., Gilon, O., Harrigan, S., Hassidim, A., Klotz, D., Kratzert, F., Metzger, A., Nevo, S., Pappenberger, F., Prudhomme, C., Shalev, G., Shenzis, S., Tekalign, T. Y., Weitzner, D., & Matias, Y. (2024). Global prediction of extreme floods in ungauged watersheds. Nature, 627(8004), 559–563. https://doi.org/10.1038/s41586-024-07145-