Involvement of Pharmacists in the Emergency Department to Correct Errors in the Medication History and the Impact on Adverse Drug Event Detection.

(1) Incomplete or wrong medication histories can lead to missed diagnoses of Adverse Drug Effects (ADEs). We aimed to evaluate pharmacist-identified ED errors in the medication histories obtained by physicians, and their consequences for ADE detection. (2) This prospective monocentric study was carried out in an ED of a university hospital. We included adult patients presenting with an ADE detected in the ED. The best possible medication histories collected by pharmacists were used to identify errors in the medication histories obtained by physicians. We described these errors, and identified those related to medications involved in ADEs. We also identified the ADEs that could not have been detected without the pharmacists' interventions. (3) Of 735 patients presenting with an ADE, 93.1% had at least one error on the medication list obtained by physicians. Of the 1047 medications involved in ADEs, 51.3% were associated with an error in the medication history. In total, 23.1% of the medications involved in ADEs were missing in the physicians' medication histories and were corrected by the pharmacists. (4) Medication histories obtained by ED physicians were often incomplete, and half the medications involved in ADEs were not identified, or were incorrectly characterized in the physicians' medication histories.

Heterogeneous distribution of sex ratio distorters in natural populations of the isopod Armadillidium vulgare.

In the isopod Armadillidium vulgare, many females produce progenies with female-biased sex ratios, owing to two feminizing sex ratio distorters (SRD): Wolbachia endosymbionts and the f element. We investigated the distribution and population dynamics of these SRD and mitochondrial DNA variation in 16 populations from Europe and Japan. Confirming and extending results from the 1990s, we found that the SRD are present at variable frequencies in populations and that the f element is overall more frequent than Wolbachia. The two SRD never co-occur at high frequency in any population, suggesting an apparent mutual exclusion. We also detected Wolbachia or the f element in some males, which probably reflects insufficient titer to induce feminization or presence of masculinizing alleles. Our results are consistent with a single integration event of a Wolbachia genome in the A. vulgare genome at the origin of the f element, which contradicts an earlier hypothesis of frequent losses and gains. We identified strong linkage between Wolbachia strains and mitochondrial haplotypes, but no association between the f element and mitochondrial background. Our results open new perspectives on SRD evolutionary dynamics in A. vulgare, the evolution of genetic conflicts and their impact on the variability of sex determination systems.

Frequency, Characteristics, and Predictive Factors of Adverse Drug Events in an Adult Emergency Department according to Age: A Cross-Sectional Study.

Adverse drug events (ADEs) are a major public health concern, given their consequences in terms of morbi-mortality and associated healthcare costs. Many studies have focused on the elderly, who are considered particularly vulnerable in this respect. We aimed to determine and compare the frequency, characteristics, and predictive factors of ADEs according to age in an adult population. A prospective seven-year cross-sectional study was conducted in a university hospital emergency department. Structured medication reviews and ADE detection were performed. Patient data and ADE characteristics were collected. Descriptive statistics and logistic regression were performed in two age groups: Group 1 (age < 65 years) and 2 (age ≥ 65 years). Among the 13,653 patients included, 18.4% in Group 1 and 22.6% in Group 2 experienced an ADE. Differences were identified in terms of the ADE type (more ADEs due to noncompliance in Group 1) and ADE symptoms (greater bleeding in Group 2). In the multivariable analysis, several specific predictive factors were identified, including kidney failure and antidiabetic drug use in Group 1 and inappropriate prescription and antithrombotic treatment in Group 2. Analysis by age provided a more refined vision of ADEs as we identified distinct profiles of iatrogenesis. These results will lead to a better detection of ADEs.

A new set of microsatellite markers for Phoxinus lumaireul senso lato, Phoxinus marsilii and Phoxinus krkae for population and molecular taxonomic studies.

Minnows of the genus Phoxinus are common and an often highly abundant fish species in Palearctic freshwater habitats. Phoxinus species have a complex evolutionary history, phylogenetic relationships are not well understood and there are a number of unresolved taxonomic problems. There are currently 23 different mitochondrial genetic lineages identified in the genus Phoxinus, 13 of which are recognized as valid species. The taxonomic status of these lineages requires resolution, including the degree to which they can interbreed. Suitable nuclear molecular markers for studies of population divergence and interbreeding between morphotypes and mitochondrial lineages are lacking for Phoxinus species. Therefore, the authors developed a set of microsatellite markers using genomic information from Phoxinus lumaireul and tested their suitability for this and two related species, Phoxinus krkae and Phoxinus marsilii. Out of 16 microsatellite candidate loci isolated, 12 were found to be in Hardy-Weinberg equilibrium when tested on two P. lumaireul senso lato populations. Seven loci amplified across the three species, enabling the study of intraspecific genetic diversity and population structure within P. marsilii and P. krkae. The markers were able to clearly resolve differences among the three tested species, including the recently described P. krkae, and are therefore suitable for the detection of introgression and hybridization among populations consisting of mixtures of two or more of P. lumaireul s. l., P. marsilii and P. krkae.

Evolutionary transition to XY sex chromosomes associated with Y-linked duplication of a male hormone gene in a terrestrial isopod.

Sex chromosomes are highly variable in some taxonomic groups, but the evolutionary mechanisms underlying this diversity are not well understood. In terrestrial isopod crustaceans, evolutionary turnovers in sex chromosomes are frequent, possibly caused by Wolbachia, a vertically-transmitted endosymbiont causing male-to-female sex reversal. Here, we use surgical manipulations and genetic crosses, plus genome sequencing, to examine sex chromosomes in the terrestrial isopod Trachelipus rathkei. Although an earlier cytogenetics study suggested a ZZ/ZW sex chromosome system in this species, we surprisingly find multiple lines of evidence that in our study population, sex is determined by an XX/XY system. Consistent with a recent evolutionary origin for this XX/XY system, the putative male-specific region of the genome is small. The genome shows evidence of Y-linked duplications of the gene encoding the androgenic gland hormone, a major component of male sexual differentiation in isopods. Our analyses also uncover sequences horizontally acquired from past Wolbachia infections, consistent with the hypothesis that Wolbachia may have interfered with the evolution of sex determination in T. rathkei. Overall, these results provide evidence for the co-occurrence of multiple sex chromosome systems within T. rathkei, further highlighting the relevance of terrestrial isopods as models for the study of sex chromosome evolution.

Characterization of a Sex-Determining Region and Its Genomic Context via Statistical Estimates of Haplotype Frequencies in Daughters and Sons Sequenced in Pools.

Sex chromosomes are generally derived from a pair of autosomes that have acquired a locus controlling sex. Sex chromosomes may evolve reduced recombination around this locus and undergo a long process of molecular divergence. At that point, the original loci controlling sex may be difficult to pinpoint. This difficulty has affected many model species from mammals to birds to flies, which present highly diverged sex chromosomes. Identifying sex-controlling loci is easier in species with molecularly similar sex chromosomes. Here we aimed at pinpointing the sex-determining region (SDR) of Armadillidium vulgare, a terrestrial isopod with female heterogamety (ZW females and ZZ males) and whose sex chromosomes appear to show low genetic divergence. To locate the SDR, we assessed single-nucleotide polymorphism (SNP) allele frequencies in F1 daughters and sons sequenced in pools (pool-seq) in several families. We developed a Bayesian method that uses the SNP genotypes of individually sequenced parents and pool-seq data from F1 siblings to estimate the genetic distance between a given genomic region (contig) and the SDR. This allowed us to assign more than 43 Mb of contigs to sex chromosomes, and to demonstrate extensive recombination and very low divergence between these chromosomes. By taking advantage of multiple F1 families, we delineated a very short genomic region (∼65 kb) that presented no evidence of recombination with the SDR. In this short genomic region, the comparison of sequencing depths between sexes highlighted female-specific genes that have undergone recent duplication, and which may be involved in sex determination in A. vulgare.

Impact of medication characteristics and adverse drug events on hospital admission after an emergency department visit: Prospective cohort study.

OBJECTIVES: Emergency department (ED) overcrowding is a problem for the delivery of adequate and timely emergency care. To improve patient flow and the admission process, the quick prediction of a patient's need for admission is crucial. We aimed to investigate the variables associated with hospitalisation after an ED visit, with a particular focus on the variables related to medication. METHODS: This prospective study was conducted from 2011 to 2018 in subacute medical ED of a French University Hospital. Specialised EDs (paediatric, gynaecologic, head and neck and psychiatric) and the outpatient unit of the ED were not included. Participation in this study was proposed to all adult patients who underwent a medication history interview with a pharmacist. Pharmacists conducted structured interviews for the completion of the medication history and the detection of adverse drug events (ADE). Relations between patient characteristics and hospitalisation were analysed using logistic regression. RESULTS: Among the 14 511 included patients, 5972 (41.2%) were hospitalised including 69 deaths. In total, 7458 patients (51.4%) took more than 5 medications and 2846 patients (19.6%) had an ADE detected during the ED visit. In hospitalised patients, bleeding (32.2%) and metabolic disorders (16.8%) were the most observed ADE symptoms. Variables associated with increased hospital admission included 2 demographic variables (age, male gender), 4 clinical variables (renal and hepatic failures, alcohol addiction, ED visit for respiratory reason) and 6 medication-related variables (medications >5, use of blood, systemic anti-infective, metabolism and antineoplastic/immunomodulating medications and ADE). CONCLUSION: We identified variables associated with hospitalisation including drug-related variables. These results point out the importance and the relevance of collecting medication data in a subacute medical ED (study registered on ClinicalTrials.gov, NCT03442010).

Draft Genome Sequences of Thelohania contejeani and Cucumispora dikerogammari, Pathogenic Microsporidia of Freshwater Crustaceans.

We announce the draft genome sequences of two pathogenic microsporidia of European freshwater crustaceans, Thelohania contejeani (the causative agent of porcelain disease) and Cucumispora dikerogammari Both species are implicated in mass mortalities in natural populations of their crayfish and amphipod hosts, respectively.

Comparative Genomics of Strictly Vertically Transmitted, Feminizing Microsporidia Endosymbionts of Amphipod Crustaceans.

Microsporidia are obligate intracellular eukaryotic parasites of vertebrates and invertebrates. Microsporidia are usually pathogenic and undergo horizontal transmission or a mix of horizontal and vertical transmission. However, cases of nonpathogenic microsporidia, strictly vertically transmitted from mother to offspring, have been reported in amphipod crustaceans. Some of them further evolved the ability to feminize their nontransmitting male hosts into transmitting females. However, our understanding of the evolution of feminization in microsporidia is hindered by a lack of genomic resources. We report the sequencing and analysis of three strictly vertically transmitted microsporidia species for which feminization induction has been demonstrated (Nosema granulosis) or is strongly suspected (Dictyocoela muelleri and Dictyocoela roeselum), along with a draft genome assembly of their host Gammarus roeselii. Contrary to horizontally transmitted microsporidia that form environmental spores that can be purified, feminizing microsporidia cannot be easily isolated from their host cells. Therefore, we cosequenced symbiont and host genomic DNA and devised a computational strategy to obtain genome assemblies for the different partners. Genomic comparison with feminizing Wolbachia bacterial endosymbionts of isopod crustaceans indicated independent evolution of feminization in microsporidia and Wolbachia at the molecular genetic level. Feminization thus represents a remarkable evolutionary convergence of eukaryotic and prokaryotic microorganisms. Furthermore, a comparative genomics analysis of microsporidia allowed us to identify several candidate genes for feminization, involving functions such as DNA binding and membrane fusion. The genomic resources we generated contribute to establish Gammarus roeselii and its microsporidia symbionts as a new model to study the evolution of symbiont-mediated feminization.

Adverse Drug Events Detected by Clinical Pharmacists in an Emergency Department: A Prospective Monocentric Observational Study.

OBJECTIVES: Adverse drug events (ADEs) are a major public health issue in hospitals. They are difficult to detect because of incomplete or unavailable medication history. In this study, we aimed to assess the rate and characteristics of ADEs identified by pharmacists in an emergency department (ED) to identify factors associated with ADEs. METHODS: In this prospective observational study, we included consecutive adult patients presenting to the ED of a French 2600-bed tertiary care university hospital from November 2011 to April 2015. Clinical pharmacists conducted structured interviews and collected the medication history to detect ADEs (i.e., injuries resulting directly or indirectly from adverse drug reactions and noncompliance to medication prescriptions). Unsure ADE cases were reviewed by an expert committee. Relations between patient characteristics, type of ED visit, and ADE risk were analyzed using logistic regression. RESULTS: Among the 8275 included patients, 1299 (15.7%) presented to the ED with an ADE. The major ADE symptoms were bleeding, endocrine problems, and neurologic disorders. Moreover, ADEs led to the ED visit, hospitalization, and death in 87%, 49.3%, and 2.2% of cases, respectively. Adverse drug event risk was independently associated with male sex, ED visit for neurological symptoms, visit to the ED critical care unit, or ED short stay hospitalization unit, use of blood, anti-infective, antineoplastic, and immunomodulating drugs. CONCLUSIONS: This study improves the knowledge about ADE characteristics and on the patients at risk of ADE. This could help ED teams to better identify and manage ADEs and to improve treatment quality and safety.

Characterization of a new case of XMLV (Bxv1) contamination in the human cell line Hep2 (clone 2B).

The use of misidentified cell lines contaminated by other cell lines and/or microorganisms has generated much confusion in the scientific literature. Detailed characterization of such contaminations is therefore crucial to avoid misinterpretation and ensure robustness and reproducibility of research. Here we use DNA-seq data produced in our lab to first confirm that the Hep2 (clone 2B) cell line (Sigma-Aldrich catalog number: 85011412-1VL) is indistinguishable from the HeLa cell line by mapping integrations of the human papillomavirus 18 (HPV18) at their expected loci on chromosome 8. We then show that the cell line is also contaminated by a xenotropic murine leukemia virus (XMLV) that is nearly identical to the mouse Bxv1 provirus and we characterize one Bxv1 provirus, located in the second intron of the pseudouridylate synthase 1 (PUS1) gene. Using an RNA-seq dataset, we confirm the high expression of the E6 and E7 HPV18 oncogenes, show that the entire Bxv1 genome is moderately expressed, and retrieve a Bxv1 splicing event favouring expression of the env gene. Hep2 (clone 2B) is the fourth human cell line so far known to be contaminated by the Bxv1 XMLV. This contamination has to be taken into account when using the cell line in future experiments.

Dataset for sequencing and de novo assembly of the European endangered white-clawed crayfish (Austropotamobius pallipes) abdominal muscle transcriptome.

The white-clawed crayfish (Austropotamobius pallipes) is an endangered species in Europe with limited genomic information. Despite its conservation status there is no transcriptomic data available for A. pallipes in public databases. The data here represents the first transcriptome profile of the white-clawed crayfish generated using Illumina stranded RNA sequencing. Pair-end reads were assembled de novo with three separate transcriptome assemblers (Trinity, RNABloom, and RNASpades) followed by transcript assembly reduction and gene reconstruction using the EvidentialGene pipeline. The transcriptome was functionally annotated using InterProScan and genes coding for carbohydrate-active enzymes were identified through the dbCAN2 server. Raw fastq reads and the final version of the transcriptome assembly have been deposited in the NCBI-SRA (SRR10549898) and NCBI-TSA (GICG01) databases.

Sex chromosomes control vertical transmission of feminizing Wolbachia symbionts in an isopod.

Microbial endosymbiosis is widespread in animals, with major ecological and evolutionary implications. Successful symbiosis relies on efficient vertical transmission through host generations. However, when symbionts negatively affect host fitness, hosts are expected to evolve suppression of symbiont effects or transmission. Here, we show that sex chromosomes control vertical transmission of feminizing Wolbachia endosymbionts in the isopod Armadillidium nasatum. Theory predicts that the invasion of an XY/XX species by cytoplasmic sex ratio distorters is unlikely because it leads to fixation of the unusual (and often lethal or infertile) YY genotype. We demonstrate that A. nasatum X and Y sex chromosomes are genetically highly similar and that YY individuals are viable and fertile, thereby enabling Wolbachia spread in this XY-XX species. Nevertheless, we show that Wolbachia cannot drive fixation of YY individuals, because infected YY females do not transmit Wolbachia to their offspring, unlike XX and XY females. The genetic basis fits the model of a Y-linked recessive allele (associated with an X-linked dominant allele), in which the homozygous state suppresses Wolbachia transmission. Moreover, production of all-male progenies by infected YY females restores a balanced sex ratio at the host population level. This suggests that blocking of Wolbachia transmission by YY females may have evolved to suppress feminization, thereby offering a whole new perspective on the evolutionary interplay between microbial symbionts and host sex chromosomes.

The Genome of Armadillidium vulgare (Crustacea, Isopoda) Provides Insights into Sex Chromosome Evolution in the Context of Cytoplasmic Sex Determination.

The terrestrial isopod Armadillidium vulgare is an original model to study the evolution of sex determination and symbiosis in animals. Its sex can be determined by ZW sex chromosomes, or by feminizing Wolbachia bacterial endosymbionts. Here, we report the sequence and analysis of the ZW female genome of A. vulgare. A distinguishing feature of the 1.72 gigabase assembly is the abundance of repeats (68% of the genome). We show that the Z and W sex chromosomes are essentially undifferentiated at the molecular level and the W-specific region is extremely small (at most several hundreds of kilobases). Our results suggest that recombination suppression has not spread very far from the sex-determining locus, if at all. This is consistent with A. vulgare possessing evolutionarily young sex chromosomes. We characterized multiple Wolbachia nuclear inserts in the A. vulgare genome, none of which is associated with the W-specific region. We also identified several candidate genes that may be involved in the sex determination or sexual differentiation pathways. The A. vulgare genome serves as a resource for studying the biology and evolution of crustaceans, one of the most speciose and emblematic metazoan groups.

[Involvement of addictovigilance in emergency department for the detection of abuse and dependence cases: 3 years of experience]. / Implication de l'addictovigilance dans un service d'urgence pour la détection et le recueil des cas d'abus et de dépendance : bilan de 3 ans d'expérience.

INTRODUCTION: Due to the increase of hospitalization at emergency department (ED) related to psychoactive substances use (PSU), the addictovigilance center of Montpellier has been integrated into the URGEIM program for the detection of iatrogenic events at the ED. The objective of the present work was to analyze spontaneous reports (SR) collected via the URGEIM program. METHODS: Analysis of spontaneous reports related to PSU at the ED of the Montpellier University Hospital, collected through the URGEIM program, between January 2014 and December 2016. RESULTS: During the study period, 160 SR were collected through the URGEIM program on 1118 SR collected by the Addictovigilance center over the period: 40SR/342 in 2014, 46 SR/303 in 2015 and 74 SR/473 in 2016. Most patients were male (70%) and the mean age at admission was 33 years old. A total of 240 psychoactive substances were identified with 160 illicit substances (66.6%) [cocaine 38.1%, cannabis 30.6%] and 80 medications (33.3%) [buprenorphine 22.5%, benzodiazepines 20% and methadone 18.8%]. Mental and behavioral disorders (20.0%), general health problems associated with substance use (17.5%), cardiovascular diseases (13.1%) and infectious diseases (12.5%) were the main reported effects. The duration of emergency stay was inferior to 12hours in 63.1% of cases and greater than 24hours in 12.5% of cases. In 69.4% of cases, the event was considered as serious. The outcome was unknown for 6.9% of patients. CONCLUSION: The number of SR from ED has increased over the study period, with the notification of serious and worrying cases, and the possibility of setting up actions. The deployment of addictovigilance within clinical services is a significant factor for notification and quality of care.

Investigating the Molecular Genetic Basis of Cytoplasmic Sex Determination Caused by Wolbachia Endosymbionts in Terrestrial Isopods.

In animals, sexual differences between males and females are usually determined by sex chromosomes. Alternatively, sex may also be determined by vertically transmitted intracellular microbial endosymbionts. The best known cytoplasmic sex manipulative endosymbiont is Wolbachia which can, for instance, feminize genetic males into phenotypic females in the terrestrial isopod Armadillidium vulgare. However, the molecular genetic basis of cytoplasmic sex determination is unknown. To identify candidate genes of feminization induced by Wolbachia strain wVulC from A. vulgare, we sequenced the genome of Wolbachia strain wCon from Cylisticus convexus, the most closely related known Wolbachia strain to wVulC that does not induce feminization, and compared it to the wVulC genome. Then, we performed gene expression profiling of the 216 resulting wVulC candidate genes throughout host developmental stages in A. vulgare and the heterologous host C. convexus. We identified a set of 35 feminization candidate genes showing differential expression during host sexual development. Interestingly, 27 of the 35 genes are present in the f element, which is a piece of a feminizing Wolbachia genome horizontally transferred into the nuclear genome of A. vulgare and involved in female sex determination. Assuming that the molecular genetic basis of feminization by Wolbachia and the f element is the same, the 27 genes are candidates for acting as master sex determination genes in A. vulgare females carrying the f element.

Author Correction: Diversity and evolution of sex determination systems in terrestrial isopods.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

A Survey of Virus Recombination Uncovers Canonical Features of Artificial Chimeras Generated During Deep Sequencing Library Preparation.

Chimeric reads can be generated by in vitro recombination during the preparation of high-throughput sequencing libraries. Our attempt to detect biological recombination between the genomes of dengue virus (DENV; +ssRNA genome) and its mosquito host using the Illumina Nextera sequencing library preparation kit revealed that most, if not all, detected host-virus chimeras were artificial. Indeed, these chimeras were not more frequent than with control RNA from another species (a pillbug), which was never in contact with DENV RNA prior to the library preparation. The proportion of chimera types merely reflected those of the three species among sequencing reads. Chimeras were frequently characterized by the presence of 1-20 bp microhomology between recombining fragments. Within-species chimeras mostly involved fragments in opposite orientations and located less than 100 bp from each other in the parental genome. We found similar features in published datasets using two other viruses: Ebola virus (EBOV; -ssRNA genome) and a herpesvirus (dsDNA genome), both produced with the Illumina Nextera protocol. These canonical features suggest that artificial chimeras are generated by intra-molecular template switching of the DNA polymerase during the PCR step of the Nextera protocol. Finally, a published Illumina dataset using the Flock House virus (FHV; +ssRNA genome) generated with a protocol preventing artificial recombination revealed the presence of 1-10 bp microhomology motifs in FHV-FHV chimeras, but very few recombining fragments were in opposite orientations. Our analysis uncovered sequence features characterizing recombination breakpoints in short-read sequencing datasets, which can be helpful to evaluate the presence and extent of artificial recombination.

Pan-arthropod analysis reveals somatic piRNAs as an ancestral defence against transposable elements.

In animals, small RNA molecules termed PIWI-interacting RNAs (piRNAs) silence transposable elements (TEs), protecting the germline from genomic instability and mutation. piRNAs have been detected in the soma in a few animals, but these are believed to be specific adaptations of individual species. Here, we report that somatic piRNAs were probably present in the ancestral arthropod more than 500 million years ago. Analysis of 20 species across the arthropod phylum suggests that somatic piRNAs targeting TEs and messenger RNAs are common among arthropods. The presence of an RNA-dependent RNA polymerase in chelicerates (horseshoe crabs, spiders and scorpions) suggests that arthropods originally used a plant-like RNA interference mechanism to silence TEs. Our results call into question the view that the ancestral role of the piRNA pathway was to protect the germline and demonstrate that small RNA silencing pathways have been repurposed for both somatic and germline functions throughout arthropod evolution.

Diversity and evolution of sex determination systems in terrestrial isopods.

Sex determination systems are highly variable in many taxa, sometimes even between closely related species. Yet the number and direction of transitions between these systems have seldom been characterized, and the underlying mechanisms are still poorly understood. Here we generated transcriptomes for 19 species of terrestrial isopod crustaceans, many of which are infected by Wolbachia bacterial endosymbionts. Using 88 single-copy orthologous genes, we reconstructed a fully resolved and dated phylogeny of terrestrial isopods. An original approach involving crossings of sex-reversed individuals allowed us to characterize the heterogametic systems of five species (one XY/XX and four ZW/ZZ). Mapping of these and previously known heterogametic systems onto the terrestrial isopod phylogeny revealed between 3 and 13 transitions of sex determination systems during the evolution of these taxa, most frequently from female to male heterogamety. Our results support that WW individuals are viable in many species, suggesting sex chromosomes are at an incipient stage of their evolution. Together, these data are consistent with the hypothesis that nucleo-cytoplasmic conflicts generated by Wolbachia endosymbionts triggered recurrent turnovers of sex determination systems in terrestrial isopods. They further establish terrestrial isopods as a model to study evolutionary transitions in sex determination systems and pave the way to molecularly characterize these systems.