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Background: This study aimed to determine whether implementing a rapid response system (RRS) is associated with improved short‐term outcomes in critically ill patients with haematological malignancies. Methods: Our monocentric pre‐ versus post‐intervention study was conducted between January 2012 and April 2020. RRS was activated at early signs of haemodynamic or respiratory failure. The primary outcome was the reduction in Sequential Organ Failure Assessment (SOFA) score on Day 3 after intensive care unit (ICU) admission. Secondary outcomes included time to ICU admission and mortality. Results: A total of 209 patients with a median age of 59 years were enrolled (108 in the pre‐intervention period and 101 in the post‐intervention period). 22% of them had received an allogeneic transplant. The post‐intervention period was associated with a shorter time to ICU admission (195 vs. 390 min, p <.001), a more frequent favourable trend in SOFA score (57% vs. 42%, adjusted odds ratio, 2.02, 95% confidence interval, 1.09 to 3.76), no significant changes in ICU (22% vs. 26%, p =.48) and 1‐year (62% vs. 58%, p =.62) mortality rates. Conclusion: Detection of early organ failure and activation of an RRS was associated with faster ICU admission and lower SOFA scores on Day 3 of admission in critically ill patients with haematological malignancies. [ABSTRACT FROM AUTHOR]

We report meningitis with diffuse neuralgic pain or polyradiculoneuropathy associated with PCR-documented acute hepatitis E in 2 adults. These observations suggest that diagnostic testing for hepatitis E virus should be conducted for patients who have neurologic symptoms and liver cytolysis. [ABSTRACT FROM AUTHOR]

In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to transfuse red blood cells (RBC) in the donor's Rh phenotype from the day of transplantation, leading to a risk of allo-immunization, either of donor or recipient origin. In this single-center retrospective study, the incidence of donor/recipient Rh incompatibility was 7.1% over an 8-year period including 1012 alloHSCT. Six of 58 evaluable patients (10.3%) developed alloantibodies to RBC antigens within one year of alloHSCT. None of these allo-immunizations were directed against the donor-mismatched Rh antigens and none could have been prevented by the transfusion of recipient and donor Rh-compatible RBC units. None of these allo-immunizations led to immune-mediated hemolytic anemia. We observed a statistically significant higher incidence of chronic GVHD among patients with anti-RBC allo-immunization. In the context of donor/recipient Rh incompatibility, the transfusion of packed RBC units in the donor's Rh phenotype from the day of alloHSCT is feasible and not associated with a high risk of allo-immunization. The generalization of this strategy could be discussed even when donor and recipient Rh phenotypes could be respected, to allow the preservation of units of infrequent phenotypes for other indications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: A hypometabolic profile involving the limbic areas, brainstem and cerebellum has been identified in long COVID patients using [ 18 F]fluorodeoxyglucose (FDG)-PET. This study was conducted to evaluate possible recovery of brain metabolism during the follow-up of patients with prolonged symptoms., Methods: Fifty-six adults with long COVID who underwent two brain [ 18 F]FDG-PET scans in our department between May 2020 and October 2022 were retrospectively analysed, and compared to 51 healthy subjects. On average, PET1 was performed 7 months (range 3-17) after acute COVID-19 infection, and PET2 was performed 16 months (range 8-32) after acute infection, because of persistent severe or disabling symptoms, without significant clinical recovery. Whole-brain voxel-based analysis compared PET1 and PET2 from long COVID patients to scans from healthy subjects (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected) and PET1 to PET2 (with the same threshold, and secondarily with a less constrained threshold of p-voxel < 0.005 uncorrected, p-cluster < 0.05 uncorrected). Additionally, a region-of-interest (ROI) semiquantitative anatomical approach was performed for the same comparisons (p < 0.05, corrected)., Results: PET1 and PET2 revealed voxel-based hypometabolisms consistent with the previously reported profile in the literature. This between-group analysis comparing PET1 and PET2 showed minor improvements in the pons and cerebellum (8.4 and 5.2%, respectively, only significant under the less constrained uncorrected p-threshold); for the pons, this improvement was correlated with the PET1-PET2 interval (r = 0.21, p < 0.05). Of the 14,068 hypometabolic voxels identified on PET1, 6,503 were also hypometabolic on PET2 (46%). Of the 7,732 hypometabolic voxels identified on PET2, 6,094 were also hypometabolic on PET1 (78%). The anatomical ROI analysis confirmed the brain hypometabolism involving limbic region, the pons and cerebellum at PET1 and PET2, without significant changes between PET1 and PET2., Conclusion: Subjects with persistent symptoms of long COVID exhibit durable deficits in brain metabolism, without progressive worsening., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Immunization against the Yellow fever virus (YFV) with the 17D live-attenuated vaccine is the most effective way to prevent the disease. However, unexpected severe adverse events can occur. They consist in a neurological impairment - neurological disease (YEL-AND), a YF-like illness - viscerotropic disease (YEL-AVD) or anaphylaxis. In this article, we describe the epidemiology, clinical and biological features of YEL-AND and YEL-AVD cases reported to the French National Reference Center for Arboviruses (NRCA) in the past 10 years., Methods: We conducted a national, retrospective study using the database of the NRCA from June 2012 to June 2022. All patients whose biological samples were sent to the NRCA for detection of YFV by serology and/or RT-qPCR for a suspected vaccine-associated adverse event were included. We collected data by reading medical records and conducted complementary neuro-immunological analysis, followed by a search for autoimmunity against type-1-interferon when samples were available at the NRCA., Results: There were 10 cases of YEL-AND and 2 cases of YEL-AVD reported to the NRCA in the past 10 years, which represented an overall incidence of 0.6 for 100 000 doses. A total of 6/12 cases were previously healthy patients (50%, mean age 31 years), and 4/12 cases had cardiovascular co-morbidities (42%, mean age 56 years). The majority of YEL-AND had a favourable outcome at 6 months of follow up. One YEL-AVD patient passed. In secondary analyses, we evidenced a significant blood cerebrospinal fluid (CSF) barrier dysfunction, without intrathecal synthesis of immunoglobulin and without argument for a neuron damage. We further detected a significant rate of anti-type-1alpha interferon antibodies in 3/10 tested patients (2 YEL-AND and 1 YEL-AVD)., Conclusion: YEL-AND and YEL-AVD are rare events that can underlie defect in the innate immunity of apparently healthy or mild co-morbid subjects. Outcome was generally favourable in the YEL-AND cases of our series, but still life-threatening or even fatal in the YEL-AVD cases., (© International Society of Travel Medicine 2023. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low-dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real-life conditions., Method: This retrospective, real-life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy., Result: Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03-16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second-line/beyond, median progression-free survival was 4.0 months (95% confidence interval [CI] 2.7-12.8) with venetoclax-HMA and 3.4 months (1.3-8.9) with venetoclax-LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax-based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Biallelic rare variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes ranging from severe neurodegenerative disorders to isolated mitochondrial myopathy or deafness. To date, only a small number of patients with NARS2 variants have been reported, and possible genotype-phenotype correlations are still lacking. Here, we present three siblings who had an early-onset hearing loss, while one developed severe symptoms in adulthood associated with early intellectual impairment, refractory seizures, moderate axonal sensorimotor neuropathy, and atypical psychiatric symptoms. Biochemical analysis revealed impairment of the activity and assembly of the respiratory chain complexes in this patient's muscle and fibroblasts. Whole Exome Sequencing allowed identification of a heterozygous variant NM&#95;024678.5(NARS2):c.822G > C (p.Gln274His) that is known to be pathogenic and to affect splicing of the NARS2 gene, but was unable to detect a second variant in this gene. Coverage analysis and Sanger sequencing led to identification of a novel intronic deletion NM&#95;024678.5(NARS2):c.922-21&#95;922-19del in the three siblings in trans with the c.822G > C. Functional analysis by RT-PCR showed that this deletion was causing aberrant splicing and led to exon 9 skipping in NARS2 mRNA in patient fibroblasts. Our work expands the phenotype and genotype spectrum of NARS2-related disorders. We provide evidence of the pathogenic effect of a novel intronic deletion in the NARS2 gene and report on additional adult patients with a large intrafamilial variability associated with splice variants in this gene. More specifically, we detail the phenotype of the oldest living patient to date with NARS2 variants and, for the first time, we report the psychiatric symptoms associated with this gene. Our work confirms the complexity of genotype-phenotype correlation in patients with pathogenic NARS2 variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Autoimmune conditions in B-cell lymphomas are frequent. Steroids are standard of care, but many patients require other immunosuppressive agents. Ibrutinib is a Bruton Tyrosine Kinase inhibitor that is approved for B-cell indolent lymphoma treatment. We evaluated the use of ibrutinib in previously treated hematologic immune manifestations associated with B-cell lymphomas., Results: We conducted a retrospective multicentric observational study. Patients presenting with active, relapsed/refractory B-cell lymphoma associated hematological immune manifestation (autoimmune cytopenia, acquired immune-mediated bleeding disorders) were included. Twenty-five patients were identified. Median age at ibrutinib introduction was 69 years (range 44-84) and median number of previous treatment lines before ibrutinib was 2 (1-7). Twenty-two patients (88%) were on concomitant stable treatment at inclusion. Within a median exposure of 8 months (2-35), overall response rate to ibrutinib on immune manifestations was 76% (95% CI, 54.9-90.6); complete response rate 44%. Fourteen patients (63%) were able to be weaned from concomitant treatments. Fourteen patients (56%) presented treatment-related adverse events, mostly Grade 1 or 2., Conclusions: Ibrutinib in this setting provides good efficacy and safety profile. Clinical trials are needed to define subgroups of patients who will benefit from this strategy and establish its place in the therapeutic arsenal., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Prognosis of herpetic encephalitis remains severe, with a high proportion of deaths and sequelae. Its treatment is based on acyclovir, but the precise and most effective modalities of this treatment are not established. The objective of this study was to determine them., Methods: For this, we carried out a descriptive, retrospective, monocentric study, using the current coding database at Marseille University Hospitals. Cohort was intended to be exhaustive for the disease, from January 2000 to June 2019, including patients hospitalized in intensive care and conventional hospitalization sector. Patients (n = 76) included were at least 16 years of age and had a clinical presentation, cerebral Magnetic Resonance Imaging, and/or electroencephalogram abnormalities consistent with herpetic encephalitis confirmed by a positive HSV-PCR in the CSF. Clinical data and treatment, including the doses actually administered to the patient, were compared according to patient's outcome., Results: The mortality rate was 12%, whereas 49% had complete recovery and 39% sequelae impeding independence. Poor outcome was statistically associated with persistence of confusion, aphasia, and impaired consciousness lasting more than 5 days, superinfection, status epilepticus, and length of stay in intensive care unit. A statistical decision tree, constructed using the Classification And Regression Tree model, to prioritize treatment management, showed two main factors that influence the outcome: the patient's weight, and the average daily acyclovir dose actually administered., Conclusion: These results suggest to modify acyclovir management in herpetic encephalitis, for low-weight patients (< 79 kg) with a minimum dosage of 2550 mg/day (850 mg/ 8 h), when possible., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: The aim of this [ 18 F]-FDG PET study was to determine the diagnostic value of the cortex/striatum metabolic ratio in a large cohort of patients suffering from autoimmune encephalitis (AE) and to search for correlations with the course of the disease., Methods: We retrospectively collected clinical and paraclinical data of patients with AE, including brain 18 F-FDG PET/CT. Whole-brain statistical analysis was performed using SPM8 software after activity parametrization to the striatum in comparison to healthy subjects. The discriminative performance of this metabolic ratio was evaluated in patients with AE using receiver operating characteristic curves against 44 healthy subjects and a control group of 688 patients with MCI. Relationship between cortex/striatum metabolic ratios and clinical/paraclinical data was assessed using univariate and multivariate analysis in patients with AE., Results: Fifty-six patients with AE were included. In comparison to healthy subjects, voxel-based statistical analysis identified one large cluster (p-cluster < 0.05, FWE corrected) of widespread decreased cortex/striatum ratio in patients with AE. The mean metabolic ratio was significantly lower for AE patients (1.16 ± 0.13) than that for healthy subjects (1.39 ± 0.08; p < 0.001) and than that for MCI patients (1.32 ± 0.11; p < 0.001). A ratio threshold of 1.23 allowed to detect AE patients with a sensitivity of 71% and a specificity of 82% against MCI patients, and 98% against healthy subjects. A lower cortex/striatum metabolic ratio had a trend towards shorter delay before 18 F-FDG PET/CT (p = 0.07) in multivariate analysis., Conclusion: The decrease in the cortex/striatal metabolic ratio has a good early diagnostic performance for the differentiation of AE patients from controls., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families., Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines., Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation., Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)