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•Patients purchasing at least one antidiabetic drug per month increased over the study period.•Defined daily dose per thousand inhabitants per day increased over the past decade.•The defined daily dose per thousand diabetic patients has decreased throughout the study period.•Biguanides are the most sold antidiabetic drug followed by insulin, sulfonylureas, and DPP4 inhibitors.•GLP-1 analogs and SGLT2 inhibitors have shown the fastest growth in consumption.•GLP-1 analogs became the leading expenditure item in 2022. The prevalence of type 2 diabetes has increased in France over the past decade, with changes in available pharmacologic treatments. This study aimed to assess trends in the sales of antidiabetic drugs in France over the last decade. This retrospective cohort study used data from French national health insurance databases. Defined daily doses per 1000 inhabitants per day (DDD/TID), expenditures associated, and the proportion of the population receiving treatment were analyzed from January 2013 to December 2022. Between 2013 and 2022, the proportion of patients purchasing at least one antidiabetic drug per month increased from 3.07% to 4.12%, with average monthly consumption rising from 82.62 to 101.68 DDD/TID. Biguanides were the most sold antidiabetic drug, followed by sulfonylureas and insulin. The greatest increases in consumption and expenditures were observed for GLP-1 analogs and SGLT2 inhibitors. The consumption and cost of antidiabetic drugs increased with the diabetes prevalence. GLP-1 analogs and SGLT2 inhibitors accounted for the main growth, reflecting their growing clinical adoption and evidence of efficacy, while sales of sulfonylureas and DPP4 inhibitors remained substantial despite concerns regarding their benefit-risk profiles. In 2022, expenditures for GLP-1 analogs surpassed insulin. These findings have implications for healthcare policy and resource allocation planning.

BackgroundMyosin heavy chain 7 (MYH7)-related myopathies (MYH7-RMs) are a group of muscle disorders linked to pathogenic variants in the MYH7 gene, encoding the slow/beta-cardiac myosin heavy chain, which is highly expressed in skeletal muscle and heart. The phenotype is heterogeneous including distal, predominantly axial or scapuloperoneal myopathies with variable cardiac involvement.MethodsWe retrospectively analysed the clinical, muscle MRI, genetic and myopathological features of 57 MYH7 patients. Patients received a thorough neurological (n=57, 100%), cardiac (n=51, 89%) and respiratory (n=45, 79%) assessment. Muscle imaging findings and muscle biopsies were reappraised in 19 (33%) and 27 (47%) patients, respectively.ResultsWe identified three phenotypes with varying degrees of overlap: distal myopathy (70%), scapuloperoneal (23%) and axial with peculiar cervical spine rigidity called the ‘sphinx’ phenotype (7%). 14% of patients had either dilated cardiomyopathy, hypertrophic cardiomyopathy or left ventricular non-compaction cardiomyopathy. 31% of patients had prominent respiratory involvement, including all patients with the ‘sphinx’ phenotype. Muscle MRI showed involvement of tibialis anterior, followed by quadriceps, and erector spinae in patients with axial phenotype. Cores represented the most common myopathological lesion. We report 26 pathogenic variants of MYH7 gene, 9 of which are novel.Conclusions MYH7-RMs have a large phenotypic spectrum, including distal, scapuloperoneal or axial weakness, and variable cardiac and respiratory involvement. Tibialis anterior is constantly and precociously affected both clinically and on muscle imaging. Cores represent the most common myopathological lesion. Our detailed description of MYH7-RMs should improve their recognition and management.

Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems do not recapitulate the histoarchitecture and cellular composition of respiratory tissues. To address this, we developed an innovative ex vivo model of whole human lung infection with SARS-CoV-2, leveraging a lung transplantation technique. Through single-cell RNA-seq, we identified that alveolar and monocyte-derived macrophages (AMs and MoMacs) were initial targets of the virus. Exposure of isolated lung AMs, MoMacs, classical monocytes and non-classical monocytes (ncMos) to SARS-CoV-2 variants revealed that while all subsets responded, MoMacs produced higher levels of inflammatory cytokines than AMs, and ncMos contributed the least. A Wuhan lineage appeared to be more potent than a D614G virus, in a dose-dependent manner. Amidst the ambiguity in the literature regarding the initial SARS-CoV-2 cell target, our study reveals that AMs and MoMacs are dominant primary entry points for the virus, and suggests that their responses may conduct subsequent injury, depending on their abundance, the viral strain and dose. Interfering on virus interaction with lung macrophages should be considered in prophylactic strategies.

Azoospermia (the complete absence of spermatozoa in the semen) is a common cause of male infertility. The etiology of azoospermia is poorly understood. Whole-genome analysis of azoospermic men has identified a number of candidate genes, such as the X-linked testis-expressed 11 (TEX11) gene. Using a comparative genomic hybridization array, an exonic deletion (exons 10-12) of TEX11 had previously been identified in two non-apparent azoospermic patients. However, the putative impact of this genetic alteration on spermatogenesis and the azoospermia phenotype had not been validated functionally. We therefore used a CRISPR/Cas9 system to generate a mouse model (Tex11 Ex9-11del/Y ) with a partial TEX11 deletion that mimicked the human mutation. Surprisingly, the mutant male Tex11 Ex9- 11del/Y mice were fertile. The sperm concentration, motility, and morphology were normal. Similarly, the mutant mouse line's testis transcriptome was normal, and the expression of spermatogenesis genes was not altered. These results suggest that the mouse equivalent of the partial deletion observed in two infertile male with azoospermia has no impact on spermatogenesis or fertility in mice, at least of a FVB/N genetic background and until 10 months of age. Mimicking a human mutation does not necessarily lead to the same human phenotype in mice, highlighting significant differences species.

Background Home-based postnatal care after hospital discharge has become an integral part of postnatal care. This study aimed to determine the factors relating either to individuals or the healthcare system that affect enrollment and full participation (adherence) in the French home-based postnatal coordinated care program (PRADO). Methods All admitted women for delivery in a French district over one year and eligible for this home-based midwifery support after hospital discharge were included ( N  = 4189). Both a simple probit model and a probit Heckman selection model were used. The control variables were the characteristics of the women, the municipalities, and the hospitals. Results Approximately 68% of the eligible women chose to enroll in the PRADO program, of who nearly 60% fully participated in this program. Enrollment in the program was influenced mostly by the family context, such as the woman’s age at the time of her pregnancy and the number of children in the household, the woman’s level of prenatal education and information about postnatal care, as well as some hospital variables such as the characteristics and organization of the maternity units. Full participation in the program was influenced by the accessibility to health professionals, particularly midwives. Furthermore, the women’s level of prenatal education and information about postnatal care, as well as their accessibility to health professionals, correlated with the socioeconomic environment. Conclusion While individual factors impacted enrollment in the PRADO program, only healthcare system-related factors influenced full participation in the program. A public health policy promoting home-based postnatal care could increase the women’s participation by improving their level of prenatal education and information about postnatal care. In addition, reducing regional inequality is likely to have a positive impact, as the availability of health professionals is a key factor for participation in home-based postnatal coordinated care.

Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.

Background Persons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated. Methods In this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc. Results Three major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80–82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc. Conclusion High resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.

Recent data suggest a temporal trend in decline in functional limitations in older adults but whether this trend extends to the period after the 8th decade of life remains unclear. We examined change in prevalence of limitations in activities and instrumental activities of daily living (ADL and IADL) between 2008 and 2015 among adults of 60–94 years and the role of age, sex, multimorbidity; we also examined changes in severity of limitations. Data were drawn from two nationally representative surveys in 2008 (n = 13,593) and 2015 (n = 13,267). The 6-item scales of ADL and IADL were each categorized first as ≥ 1 limitations, and then to examine severity as 0, 1–2, and ≥ 3 limitations. Weighted logistic and multinomial regressions were used to estimate prevalence of limitations; the difference between surveys were extracted every 5 years between 60 and 90 years. The prevalence of ≥ 1 ADL declined between 2008 and 2015, from age 75 (− 1.2%; 95%CI = − 2.0, − 0.4%) to age 90 (− 8.8%; 95%CI = − 12.7, − 5.0%). This decline was more pronounced in men than women (p-value for interaction = 0.05) and observed primarily in those with multimorbidity (p-value for interaction = 0.06). Up to 2 ADL limitations declined from age 75 (− 1.0; 95%CI = − 1.7, − 0.3) to 90 (− 6.7; 95%CI = − 9.9, − 3.6) and from age 80 (− 0.6; 95%CI = − 1.1, 0.1) to 85 (− 1.2; 95%CI = − 2.2, − 0.1) for ≥ 3 ADL limitations. There was no substantial change in IADL limitations. These data from a high-income country with universal health care show improvement in ADL even after the 8th decade of life despite increase in multimorbidity.

Anorexia nervosa is a complex psychiatric disorder that can lead to specific somatic complications. Malnutrition is frequent and can involve a decrease of mobility, up to functional impotence, in individuals with extremely severe cases. The aim of this pilot study was to examine muscle strength and peak expiratory flow (PEF) in severely undernourished patients with anorexia nervosa at admission and after 5 wk of renutrition by tube feeding, and to find the clinical and biological correlates of muscle-strength impairment. A prospective observational study was conducted over 6 mo. Manual muscle testing, measures of PEF, and clinical and biologic assessments were performed at baseline and after 5 wk of renutrition. Twenty-three extremely malnourished female participants (mean body mass index: 11.4 ± 1.3 kg/m2) were included. All participants had global impairment in muscle strength (manual muscle testing: 37.7 ± 7.7) and PEF (253.3 ± 60 mL/min) at admission. Muscle weakness was higher in axial than peripheral muscle groups (P < 0.01), with no significant difference between proximal and distal muscles (P > 0.05). Muscle strength at admission was significantly associated with severity of undernourishment (body mass index and albumin) and transaminitis (P < 0.05). At follow-up, musculoskeletal strength and PEF were significantly improved after partial weight recovery (P < 0.01). Extremely undernourished people with anorexia nervosa present a decrease of PEF and musculoskeletal strength predominant on axial muscles. Both are associated with severity of malnutrition and liver damage. Partial recovery was observed after 5 wk of enteral nutrition. •Malnutrition in anorexia nervosa can lead to a loss of muscle strength and peak expiratory flow.•Muscle weakness is predominant in axial muscles in anorexia nervosa.•Muscle strength is correlated with severity of malnutrition and transaminitis in anorexia nervosa.•Muscle weakness can improve after partial weight recovery.

Mycolactone is a diffusible lipid secreted by the human pathogen Mycobacterium ulcerans, which induces the formation of open skin lesions referred to as Buruli ulcers. Here, we show that mycolactone operates by hijacking the Wiskott-Aldrich syndrome protein (WASP) family of actin-nucleating factors. By disrupting WASP autoinhibition, mycolactone leads to uncontrolled activation of ARP2/3-mediated assembly of actin in the cytoplasm. In epithelial cells, mycolactone-induced stimulation of ARP2/3 concentrated in the perinuclear region, resulting in defective cell adhesion and directional migration. In vivo injection of mycolactone into mouse ears consistently altered the junctional organization and stratification of keratinocytes, leading to epidermal thinning, followed by rupture. This degradation process was efficiently suppressed by coadministration of the N-WASP inhibitor wiskostatin. These results elucidate the molecular basis of mycolactone activity and provide a mechanism for Buruli ulcer pathogenesis. Our findings should allow for the rationale design of competitive inhibitors of mycolactone binding to N-WASP, with anti-Buruli ulcer therapeutic potential.