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/)

Bloc interscalénique échoguidé (importance des variations anatomiques en clinique)

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome

International audienceAn autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G\textgreaterA missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G\textgreaterA variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G\textgreaterA missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk

In Vivo Myoblasts Tracking Using the Sodium Iodide Symporter Gene Expression in Dogs

Stem cell-based therapies are a promising approach for the treatment of degenerative muscular diseases; however, clinical trials have shown inconclusive and even disappointing results so far. Noninvasive cell monitoring by medicine imaging could improve the understanding of the survival and biodistribution of cells following injection. In this study, we assessed the canine sodium iodide symporter (cNIS) reporter gene as an imaging tool to track by single-photon emission computed tomography (SPECT/CT) transduced canine myoblasts after intramuscular (IM) administrations in dogs. cNIS-expressing cells kept their myogenic capacities and showed strong 99 mTc-pertechnetate (99 mTcO4-) uptake efficiency both in vitro and in vivo. cNIS expression allowed visualization of cells by SPECT/CT along time: 4 h, 48 h, 7 days, and 30 days after IM injection; biopsies collected 30 days post administration showed myofiber's membranes expressing cNIS. This study demonstrates that NIS can be used as a reporter to track cells in vivo in the skeletal muscle of large animals. Our results set a proof of concept of the benefits NIS-tracking tool may bring to the already challenging cell-based therapies arena in myopathies and pave the way to a more efficient translation to the clinical setting from more accurate pre-clinical results.status: publishe

Genotypes for chromosome C2 candidate region.

<p>SNP genotypes for each cat were manually inspected in Excel to identify homozygous regions shared by the two affected cats. Only one region from chromosome C2 spanning from position 137108027 bp to position 140984522 bp (according to the updated felCat5 SNP manifest for the Illumina Feline 63k SNP genotyping array, [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137019#pone.0137019.ref020" target="_blank">20</a>]) was consistent with the highly-probable heterozygous status of the sire and dam, the non-homozygously mutated status of the proband’s healthy littermate and the inferred heterozygous status of the paternal grandmother. This region encompassed 3.9 Mb. Homozygosity for the allele shared by the affected sib-pair is shown in light green. Heterozygosity or homozygosity for the opposite allele is shown in yellow. Missing genotypes are noticed 0. Chr: chromosome. bp: base pairs.</p

In Vivo Myoblasts Tracking Using the Sodium Iodide Symporter Gene Expression in Dogs

International audienc

Congenital neuromuscular disorder in a Sphynx kitten.

<p>Picture of the four-month-old Sphynx female kitten presented at the Neurology clinics located at the Alfort School of Veterinary Medicine campus, in Maisons-Alfort, France. The kitten displayed a peculiar gait while walking, with ventroflexion of her neck. Note the marked dorsal protrusion of scapulae. No significant muscle atrophy was noticed.</p

Histological and histochemical features of the disease.

<p>Cryosections (6 μm) of cervical muscle from a four-month-old affected Sphynx kitten (A-C) and from her healthy littermate (D-F). Haematoxylin-eosin staining (A, D) showed a wide range of fibre size with more rounded fibres surrounded by a thicker endomysium in the affected kitten (A) compared to the healthy control (D). No internal nuclei were present on both sections. Myosin adenosine triphosphatase isoforms (ATPase activity at pH 9.4, B and E) showed a slight increase in pale type-1 fibres in the affected kitten (B) compared to the healthy control (E) but no fibre-type aggregation. Motor end-plates were labelled with alpha-bungarotoxin (for acetylcholine receptors AchR; C and F insets; green) and esterase activity (for AchE; C, F; brown stain). Muscle nuclei were stained with Dapi (C and F insets; blue). Sections from the healthy littermate (F) showed a perfect colocalization of compacted AchR (green) and AchE (brown). In contrast, sections from the affected cat showed a faint, abnormally dispersed AchE staining in myofibres with normal clusters of AchR (C).</p

Genotypes for the c.1190G>A variant in affected cats and unaffected relatives.

<p>Genotypes for the c.1190G>A variant in affected cats and unaffected relatives.</p