Evaluation of Elastic Venous Compression Device dispensation in pregnant and post-partum women using the French National Health Insurance Claims Database: The ProFIL retrospective cohort study.

OBJECTIVES: To describe the real-world use of Elastic Venous Compression Devices (EVCDs) during pregnancy and post-partum using data from a representative subset of the French National Health Insurance Claims Database (the Echantillon Généraliste des Bénéficiaires, EGB). STUDY DESIGN: Women aged 15-49 who were pregnant between 1st July 2017 and 15th June 2018 were identified in the EGB using pregnancy-specific acts (certain prenatal examinations or deliveries). Subgroups were defined by age, presence of Venous Thrombo-Embolism (VTE) risk factors, history of VTE, delivery type and time period. EVCD dispensations (format, prescriber, and date) were identified among those for "standard orthotics" using their unique reimbursement tariffs. Dispensation rates were computed for all subgroups, overall and by format and were compared. RESULTS: 15,528 pregnant women were included: 7,252 [46.7 %] deliveries (5,796 vaginal [79.9 %], 482 planned cesarean sections (C-sections) [6.7 %] and 974 unplanned C-Sections [13.4 %]), 2,734 (17.6 %) terminations and 5,542 (35.7 %) unknown outcomes. Overall, 4,919 (31.7 %) women were dispensed at least one EVCD. Ante-partum dispensation occurred in 43.1 % (n = 3,122) of women whose pregnancy led to a delivery. Dispensation rates were 17.3 % (n = 1,005), 46.7 % (n = 225) and 44.1 % (n = 430) after vaginal delivery, planned C-sections or unplanned C-sections, respectively. Overall, dispensation rates significantly increased with age, the presence of VTE risk factors, and a history of VTE (p < 0.01). EVCD dispensation was most frequent (17.0 %) during the 5th month of pregnancy. Among pregnant women who were dispensed at least one EVCD during ante- or post-partum, 69.0 % had one or two units of compression (27.1 % [one unit], 41.9 % [two units]). Stockings (48.6 %, n = 6,038) were dispensed significantly more frequently than socks (36.9 %, n = 4,586) and tights (14.5 %, n = 1,806) (p < 0.01). The main contributors to mechanical VTE prophylaxis were gynecologists (26.3 % of dispensations, n = 2,280), general practitioners (20.2 %, n = 1,749) and midwives (15.1 %, n = 1,314). CONCLUSIONS: Low observed dispensation rates highlight a discrepancy between the French National Authority for Health (Haute Autorité de Santé, HAS), recommending EVCDs use during pregnancy and after delivery, and the real-life use of EVCD. Prescription sensitization combined with targeted information campaigns for pregnant women would be beneficial to contribute to the prevention of VTE, a health problem for pregnant women.

HuR Mediates Changes in the Stability of AChR ß-Subunit mRNAs after Skeletal Muscle Denervation.

Acetylcholine receptors (AChRs) are heteromeric membrane proteins essential for neurotransmission at the neuromuscular junction. Previous work showed that muscle denervation increases expression of AChR mRNAs due to transcriptional activation of AChR subunit genes. However, it remains possible that post-transcriptional mechanisms are also involved in controlling the levels of AChR mRNAs following denervation. We examined whether post-transcriptional events indeed regulate AChR ß-subunit mRNAs in response to denervation. First, in vitro stability assays revealed that the half-life of AChR ß-subunit mRNAs was increased in the presence of denervated muscle protein extracts. A bioinformatics analysis revealed the existence of a conserved AU-rich element (ARE) in the 3'-untranslated region (UTR) of AChR ß-subunit mRNA. Furthermore, denervation of mouse muscle injected with a luciferase reporter construct containing the AChR ß-subunit 3'UTR, caused an increase in luciferase activity. By contrast, mutation of this ARE prevented this increase. We also observed that denervation increased expression of the RNA-binding protein human antigen R (HuR) and induced its translocation to the cytoplasm. Importantly, HuR binds to endogenous AChR ß-subunit transcripts in cultured myotubes and in vivo, and this binding is increased in denervated versus innervated muscles. Finally, p38 MAPK, a pathway known to activate HuR, was induced following denervation as a result of MKK3/6 activation and a decrease in MKP-1 expression, thereby leading to an increase in the stability of AChR ß-subunit transcripts. Together, these results demonstrate the important contribution of post-transcriptional events in regulating AChR ß-subunit mRNAs and point toward a central role for HuR in mediating synaptic gene expression. SIGNIFICANCE STATEMENT: Muscle denervation is a convenient model to examine expression of genes encoding proteins of the neuromuscular junction, especially acetylcholine receptors (AChRs). Despite the accepted model of AChR regulation, which implicates transcriptional mechanisms, it remains plausible that such events cannot fully account for changes in AChR expression following denervation. We show that denervation increases expression of the RNA-binding protein HuR, which in turn, causes an increase in the stability of AChR ß-subunit mRNAs in denervated muscle. Our findings demonstrate for the first time the contribution of post-transcriptional events in controlling AChR expression in skeletal muscle, and points toward a central role for HuR in mediating synaptic development while also paving the way for developing RNA-based therapeutics for neuromuscular diseases.

Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in response to formoterol administration in rat skeletal muscle.

Administration of ß2-agonists triggers skeletal muscle anabolism and hypertrophy. We investigated the time course of the molecular events responsible for rat skeletal muscle hypertrophy in response to 1, 3 and 10 days of formoterol administration (i.p. 2000µg/kg/day). A marked hypertrophy of rat tibialis anterior muscle culminated at day 10. Phosphorylation of Akt, ribosomal protein S6, 4E-BP1 and ERK1/2 was increased at day 3, but returned to control level at day 10. This could lead to a transient increase in protein translation and could explain previous studies that reported increase in protein synthesis following ß2-agonist administration. Formoterol administration was also associated with a significant reduction in MAFbx/atrogin-1 mRNA level (day 3), suggesting that formoterol can also affect protein degradation of MAFbx/atrogin1 targeted substrates, including MyoD and eukaryotic initiation factor-3f (eIF3-f). Surprisingly, mRNA level of autophagy-related genes, light chain 3 beta (LC3b) and gamma-aminobutyric acid receptor-associated protein-like 1 (Gabarapl1), as well as lysosomal hydrolases, cathepsin B and cathepsin L, was significantly and transiently increased after 1 and/or 3 days, suggesting that autophagosome formation would be increased in response to formoterol administration. However, this has to be relativized since the mRNA level of Unc-51-like kinase1 (Ulk1), BCL2/adenovirus E1B interacting protein3 (Bnip3), and transcription factor EB (TFEB), as well as the protein content of Ulk1, Atg13, Atg5-Atg12 complex and p62/Sqstm1 remained unchanged or was even decreased in response to formoterol administration. These results demonstrate that the effects of formoterol are mediated, in part, through the activation of Akt-mTOR pathway and that other signaling pathways become more important in the regulation of skeletal muscle mass with chronic administration of ß2-agonists.

ß2-Adrenergic agonists and the treatment of skeletal muscle wasting disorders.

ß2-Agonists are traditionally used for the treatment of bronchospasm associated with asthma and the treatment of symptomatic patients with COPD. However, ß2-agonists are also powerful anabolic agents that trigger skeletal muscle hypertrophy. Investigating the effects of ß2-agonists in skeletal muscle over the past 30 years in different animal models has led to the identification of potential therapeutic applications in several muscle wasting disorders, including neuromuscular diseases, cancer cachexia, sepsis or thermal injury. In these conditions, numerous studies indicate that ß2-agonists can attenuate and/or reverse the decrease in skeletal muscle mass and associated weakness in animal models of muscle wasting but also in human patients. The purpose of this review is to present the biological and clinical significance of ß2-agonists for the treatment of skeletal muscle wasting. After the description of the molecular mechanisms involved in the hypertrophy and anti-atrophy effect of ß2-agonists, we will review the anti-atrophy effects of ß2-agonist administration in several animal models and human pathologies associated with or leading to skeletal muscle wasting. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.