Fatal Enterovirus-related Myocarditis in a Patient with Devic’s Syndrome Treated with Rituximab

Enteroviruses are a frequent source of infection and among the most common central nervous system viral pathogens. Enteroviruses – in particular, the Coxsackie B viruses – are a known cause of myocarditis. Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. Many reports in the literature suggest a higher risk of infection following repeated rituximab therapy, including viral infection. However, observations of enterovirus-related myocarditis in the context of rituximab treatment are scarce. The authors describe the case of a patient with neuromyelitis optica spectrum disorder who developed severe and fatal enterovirus-related myocarditis after rituximab therapy with a difficult differential diagnosis of autoimmune or giant-cell myocarditis. This case highlights the importance of complete diagnostic workup in difficult cases of myocarditis, including endomyocardial biopsies

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The pharmacokinetic challenge of treating invasive aspergillosis complicating severe influenzae assisted by extracorporeal membrane oxygenation

International audienc

Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder

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Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

International audienceFragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G > A (family 2) and a maternally inherited c.420-8A > G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up

Oxygenation management during veno-arterial ECMO support for cardiogenic shock: a multicentric retrospective cohort study

International audienceBackgound Hyperoxemia is common and associated with poor outcome during veno-arterial extracorporeal membrane oxygenation (VA ECMO) support for cardiogenic shock. However, little is known about practical daily management of oxygenation. Then, we aim to describe sweep gas oxygen fraction (F S O 2 ), postoxygenator oxygen partial pressure (P POST O 2 ), inspired oxygen fraction (F I O 2 ), and right radial arterial oxygen partial pressure (P a O 2 ) between day 1 and day 7 of peripheral VA ECMO support. We also aim to evaluate the association between oxygenation parameters and outcome. In this retrospective multicentric study, each participating center had to report data on the last 10 eligible patients for whom the ICU stay was terminated. Patients with extracorporeal cardiopulmonary resuscitation were excluded. Primary endpoint was individual mean F S O 2 during the seven first days of ECMO support (F S O 2 mean (day 1−7) ). Results Between August 2019 and March 2022, 139 patients were enrolled in 14 ECMO centers in France, and one in Switzerland. Among them, the median value for F S O 2 mean (day 1−7) was 70 [57; 79] % but varied according to center case volume. Compared to high volume centers, centers with less than 30 VA-ECMO runs per year were more likely to maintain F S O 2 ≥ 70% (OR 5.04, CI 95% [1.39; 20.4], p = 0.017). Median value for right radial P a O 2 mean (day 1−7) was 114 [92; 145] mmHg, and decreased from 125 [86; 207] mmHg at day 1, to 97 [81; 133] mmHg at day 3 ( p < 0.01). Severe hyperoxemia (i.e. right radial P a O 2 ≥ 300 mmHg) occurred in 16 patients (12%). P POST O 2 , a surrogate of the lower body oxygenation, was measured in only 39 patients (28%) among four centers. The median value of P POST O 2 mean (day 1−7) value was 198 [169; 231] mmHg. By multivariate analysis, age (OR 1.07, CI95% [1.03–1.11], p < 0.001), F S O 2 mean (day 1−3) (OR 1.03 [1.00-1.06], p = 0.039), and right radial P a O 2 mean (day 1−3) (OR 1.03, CI95% [1.00-1.02], p = 0.023) were associated with in-ICU mortality. Conclusion In a multicentric cohort of cardiogenic shock supported by VA ECMO, the median value for F S O 2 mean (day 1−7) was 70 [57; 79] %. P POST O 2 monitoring was infrequent and revealed significant hyperoxemia. Higher F S O 2 mean (day 1−3) and right radial P a O 2 mean (day 1−3) were independently associated with in-ICU mortality