Does the availability of positron emission tomography modify diagnostic strategies for solitary pulmonary nodules? An observational study in France

International audienceBACKGROUND: Previous studies showed that at the individual level, positron emission tomography (PET) has some benefits for patients and physicians in terms of cancer management and staging. We aimed to describe the benefits of (PET) in the management of solitary pulmonary nodules (SPNs) in a population level, in terms of the number of diagnostic and invasive tests performed, time to diagnosis and factors determining PET utilization. METHODS: In an observational study, we examined reports of computed tomography (CT) performed and mentioning "spherical lesion", "nodule" or synonymous terms. We found 11,515 reports in a before-PET period, 2002-2003, and 20,075 in an after-PET period, 2004-2005. Patients were followed through their physician, who was responsible for diagnostic management. RESULTS: We had complete data for 112 patients (73.7%) with new cases of SPN in the before-PET period and 250 (81.4%) in the after-PET period. Patients did not differ in mean age (64.9 vs. 64.8 years). The before-PET patients underwent a mean of 4 tests as compared with 3 tests for the after-PET patients (p = 0.08). Patients in the before-PET period had to wait 41.4 days, on average, before receiving a diagnosis as compared with 24.0 days, on average, for patients in the after-PET period who did not undergo PET (p < 0.001). In the after-PET period, 11% of patients underwent PET during the diagnostic process. A spiculated nodule was more likely to determine prescription for PET (p < 0.001). Multivariate analysis revealed that patients in both periods underwent fewer tests when PET was prescribed by general practitioners (p < 0.001) and if the nodule was not spiculated (p < 0.001). The proportion of unnecessary invasive approaches prescribed (47% vs. 49%) did not differ between the groups. CONCLUSION: In our study, 1 year after the availability of PET, the technology was not the first choice for diagnostic management of SPN. Even though we observed a tendency for reduced number of tests and mean time to diagnosis with PET, these phenomena did not fully relate to PET availability in health communities. In addition, the availability of PET in the management of SPN diagnosis did not reduce the overall rate of unnecessary invasive approaches

Opportunities, barriers, and recommendations in down syndrome research

Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy

DNA methylation in childhood asthma : an epigenome-wide meta-analysis

Background DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p Interpretation Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.Peer reviewe

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

The G2-to-M transition from a phosphatase perspective: a new vision of the meiotic division

International audienceCell division is orchestrated by the phosphorylation and dephosphorylation of thousands of proteins. These post-translational modifications underlie the molecular cascades converging to the activation of the universal mitotic kinase, Cdk1, and entry into cell division. They also govern the structural events that sustain the mechanics of cell division. While the role of protein kinases in mitosis has been well documented by decades of investigations, little was known regarding the control of protein phosphatases until the recent years. However, the regulation of phos-phatase activities is as essential as kinases in controlling the activation of Cdk1 to enter M-phase. The regulation and the function of phosphatases result from post-translational modifications but also from the combinatorial association between conserved catalytic subunits and regulatory subunits that drive their substrate specificity, their cellular localization and their activity. It now appears that sequential dephosphorylations orchestrated by a network of phosphatase activities trigger Cdk1 activation and then order the structural events necessary for the timely execution of cell division. This review discusses a series of recent works describing the important roles played by protein phos-phatases for the proper regulation of meiotic division. Many breakthroughs in the field of cell cycle research came from studies on oocyte meiotic divisions. Indeed, the meiotic division shares most of the molecular regulators with mitosis. The natural arrests of oocytes in G2 and in M-phase, the giant size of these cells, the variety of model species allowing either biochemical or imaging as well as genetics approaches explain why the process of meiosis has served as an historical model to decipher signalling pathways involved in the G2-to-M transition. The review especially highlights how the phosphatase PP2A-B55δ critically orchestrates the timing of meiosis resumption in amphibian oocytes. By opposing the kinase PKA, PP2A-B55δ controls the release of the G2 arrest through the dephosphorylation of their substrate, Arpp19. Few hours later, the inhibition of PP2A-B55δ by Arpp19 releases its opposing kinase, Cdk1, and triggers M-phase. In coordination with a variety of phosphatases and kinases, the PP2A-B55δ/Arpp19 duo therefore emerges as the key effector of the G2-to-M transition

Trends in Antibiotic-Resistant Bacteria Isolated from Screening Clinical Samples in a Tertiary Care Hospital over the 2018–2022 Period

To assess the putative impact of the COVID-19 pandemic on multidrug-resistant (MDR) bacteria recovered from routine screening samples and, more globally, the trends in time to first positive screening sample and carriage duration of those bacteria in patients admitted to a tertiary hospital, data from laboratory results were retrospectively mined over the 2018–2022 period. No significant differences could be found in the number of positive patients or MDR isolates per year, time to positive screening, or carriage duration. Extended-spectrum beta-lactamase producers were dominant throughout the studied period but their relative proportion decreased over time as well as that of meticillin-resistant Staphylococcus aureus. Meanwhile, carbapenemase-producing enterobacteria (CPE) proportion increased. Among the 212 CPE isolates, Klebsiella pneumoniae and Escherichia coli were the more frequent species but, beginning in 2020, a significant rise in Enterobacter cloacae complex and Citrobacter freundii occurred. OXA48 was identified as the leading carbapenemase and, in 2020, a peak in VIM-producing enterobacteria linked to an outbreak of E. cloacae complex during the COVID-19 pandemic was singled out. Finally, a worrisome rise in isolates producing multiple carbapenemases (NDM/VIM and mostly NDM/OXA48) was highlighted, especially in 2022, which could lead to therapeutic dead-ends if their dissemination is not controlled

Microstructures of bedding-parallel faults under multistage deformation: Examples from the Southeast Basin of France

International audienceWe conducted a microstructural analysis of bedding-parallel faults (BPFs) in Mesozoic clay-rich layers of the Southeast Basin of France. Various microstructures are recognized in thin sections under a petrographic microscope and by cathodoluminescence. The microscale observations are combined with outcrop observations from previous studies to provide insight into the origin of the BPFs and their evolution during successive phases of deformation in a basin that had a polyphase tectonic history. The BPFs slipped while normal faults were formed during the Oligocene extension. Then, another phase of slip occurred later during the basin inversion. These two phases of deformation are expressed by recurrent crack-seal veins, pull-apart veins and stylolites. In addition, calcite veins with an elongate blocky morphology suggest an opening normal to bedding before the reactivation. The BPFs initiated in clay layers that were shallow dipping. Such conditions may appear mechanically unfavourable for an opening normal to bedding or a shearing parallel to bedding. We suggest that the role of rock anisotropy is critical. This study furthermore demonstrates that BPFs can be long-lived brittle structures that may record successive tectonic events

Response to selection on fecal microbiota composition in Large White piglets

International audiencePig gut microbiota displays high inter-individual variability and it remains an open question to determine to what extent its taxonomic composition relies on host genetic determinism and not only on environmental conditions. We carried out a study to demonstrate coevolution of the host and its gut microbiota established one month post-weaning, by directional selection over two generations. The gut microbiota was characterized by sequencing the V3-V4 variable region of the 16S rRNA gene from fecal samples collected on 60-day-old Large White piglets. Amplicon sequence variants were inferred from amplicon data and the microbial community was further studied at the genus level. Based on the stratification of the initial population (generation G0) according to the two major pig enterotypes, characterized by relative overabundance of either Prevotella and Mitsuokella or Ruminococcus and Treponema, we used the relative abundance of these four genera as selection criteria. From the G0 population of 317 piglets, we selected 6 males and 30 females per line and produced two successive generations (G1 and G2) of approximately 130 pigs per line. We consistently confirmed a moderate heritability for each of the selected genera (h²=0.3 to 0.4). We also estimated the heritability values of the relative abundances for 64 additional bacterial genera, which ranged from 0.1 to 0.5. We showed significant differences between the two lines in the relative abundance of the four bacterial genera at G1 (P<0.001, from 0.6 genetic standard deviation for Treponema to 1.3 for Prevotella). In the following generation G2, response to selection was maintained for Prevotella and was even increased for the three other genera. The observed contrasts were in the expected direction for the genera under direct selection, and we extended the analysis to the 64 other bacterial genera with estimated heritabilities higher than 0.1. All these results confirm a significant influence of host genetics on the composition of gut microbiota at 60 days of age in pigs, and a capacity of directional selection over generations that will be further explored together with early and late host traits

The M-phase regulatory phosphatase PP2A-B55δ opposes protein kinase A on Arpp19 to initiate meiotic division

International audienceOocytes are held in meiotic prophase for prolonged periods until hormonal signals trigger meiotic divisions. Key players of M-phase entry are the opposing Cdk1 kinase and PP2A-B55δ phosphatase. In Xenopus, the protein Arpp19, phosphorylated at serine 67 by Greatwall, plays an essential role in inhibiting PP2A-B55δ, promoting Cdk1 activation. Furthermore, Arpp19 has an earlier role in maintaining the prophase arrest through a second serine (S109) phosphorylated by PKA. Prophase release, induced by progesterone, relies on Arpp19 dephosphorylation at S109, owing to an unknown phosphatase. Here, we identified this phosphatase as PP2A-B55δ. In prophase, PKA and PP2A-B55δ are simultaneously active, suggesting the presence of other important targets for both enzymes. The drop in PKA activity induced by progesterone enables PP2A-B55δ to dephosphorylate S109, unlocking the prophase block. Hence, PP2A-B55δ acts critically on Arpp19 on two distinct sites, opposing PKA and Greatwall to orchestrate the prophase release and M-phase entry