Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes:insights from the EXSCEL trial

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m(2)/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m(2)/year). Conclusions This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010

Stroke in India: a systematic review of the incidence, prevalence and case fatality

Background: The burden of stroke is increasing in India; stroke is now the fourth leading cause of death and the fifth leading cause of disability. Previous research suggests that the incidence of stroke in India ranges between 105 and 152/100,000 people per year. However, there is a paucity of available data and a lack of uniform methods across published studies. Aim: To identify high-quality prospective studies reporting the epidemiology of stroke in India. Summary of review: A search strategy was modified from the Cochrane Stroke Strategy and adapted for a range of bibliographic databases from January 1997 to August 2020. From 7,717 identified records, nine studies were selected for inclusion; three population-based registries, a further three population-based registries also using community-based ascertainment and three community-based door-to-door surveys. Studies represented the four cities of Mumbai, Trivandrum, Ludhiana, Kolkata, the state of Punjab and 12 villages of Baruipur in the state of West Bengal. The total population denominator was 22,479,509 and 11,654 (mean 1,294 SD 1,710) people were identified with incident stroke. Crude incidence of stroke ranged from 108 to 172/100,000 people per year, crude prevalence from 26 to 757/100,000 people per year and one-month case fatality rates from 18% to 42%. Conclusions: Further high-quality evidence is needed across India to guide stroke policy and inform the development and organisation of stroke services. Future researchers should consider the World Health Organisation STEPwise approach to Surveillance (STEPS) framework, including longitudinal data collection, the inclusion of census population data and a combination of hospital-registry and comprehensive community ascertainment strategies to ensure complete stroke identification

Comparative structural and functional analysis of Bunyavirus and Arenavirus cap-snatching Endonucleases

Segmented negative strand RNA viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mRNA transcription by the cap-snatching mechanism. This involves cleavage of host mRNAs close to their capped 5′ end by an endonuclease (EN) domain located in the N-terminal region of the viral polymerase. We present the structure of the cap-snatching EN of Hantaan virus, a bunyavirus belonging to hantavirus genus. Hantaan EN has an active site configuration, including a metal co-ordinating histidine, and nuclease activity similar to the previously reported La Crosse virus and Influenza virus ENs (orthobunyavirus and orthomyxovirus respectively), but is more active in cleaving a double stranded RNA substrate. In contrast, Lassa arenavirus EN has only acidic metal co-ordinating residues. We present three high resolution structures of Lassa virus EN with different bound ion configurations and show in comparative biophysical and biochemical experiments with Hantaan, La Crosse and influenza ENs that the isolated Lassa EN is essentially inactive. The results are discussed in the light of EN activation mechanisms revealed by recent structures of full-length influenza virus polymerase

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The genome of the extremophile Artemia provides insight into strategies to cope with extreme environments

BACKGROUND : Brine shrimp Artemia have an unequalled ability to endure extreme salinity and complete anoxia. This study aims to elucidate its strategies to cope with these stressors. RESULTS AND DISCUSSION : Here, we present the genome of an inbred A. franciscana Kellogg, 1906. We identified 21,828 genes of which, under high salinity, 674 genes and under anoxia, 900 genes were differentially expressed (42%, respectively 30% were annotated). Under high salinity, relevant stress genes and pathways included several Heat Shock Protein and Leaf Embryogenesis Abundant genes, as well as the trehalose metabolism. In addition, based on differential gene expression analysis, it can be hypothesized that a high oxidative stress response and endocytosis/exocytosis are potential salt management strategies, in addition to the expression of major facilitator superfamily genes responsible for transmembrane ion transport. Under anoxia, genes involved in mitochondrial function, mTOR signalling and autophagy were differentially expressed. Both high salt and anoxia enhanced degradation of erroneous proteins and protein chaperoning. Compared with other branchiopod genomes, Artemia had 0.03% contracted and 6% expanded orthogroups, in which 14% of the genes were differentially expressed under high salinity or anoxia. One phospholipase D gene family, shown to be important in plant stress response, was uniquely present in both extremophiles Artemia and the tardigrade Hypsibius dujardini, yet not differentially expressed under the described experimental conditions. CONCLUSIONS : A relatively complete genome of Artemia was assembled, annotated and analysed, facilitating research on its extremophile features, and providing a reference sequence for crustacean research.Additional file 1. Assembly characteristics of all assembled crustacean genomes. Characteristics listed are: species, whether the species genome is annotated yes or no, N50 of the fragments with the highest assembly hierarchy, number of fragments with the highest assembly hierarchy in the assembly, haploid genome size, assembly size, completeness of the assembly (=haploid GS/assembly size), taxonomic lineage (NCBI taxonomy), reference for the genome paper.Additional file 2. Evolution of Artemia assembly quality metrics throughout the assembly steps. Evolution of the scaffold N50, the number of fragments and the genome completeness (assembly size/ genome size) in the subsequent Artemia assembly stagesAdditional file 3 BUSCO analysis results for the A. franciscana genome assembly and annotation.Additional file 4. BLAST results for mitochondrial genes in the Artemia genome. Listed: Query accession and gene name, presence of a (significant) BLAST hit in the Artemia proteome with the highest bit score, E-value and bit score of the hit, scaffold length of the scaffold on which the hit lies, percentage of mitochondrial genes on this scaffold.Additional file 5. Taxonomic groups of alien genomes identified in the Artemia genome.Additional file 6 Expanded or contracted Artemia orthogroups compared to other Branchiopoda. Listed: Orthogroup ID, number of genes in this orthogroup in A. franciscana, D. pulex, L. arcticus, and E. texana, expanded or contracted status of the orthogroup in Artemia compared to D. pulex, L. arcticus and E. texana, conservation in Branchiopoda (whether this orthogroup contains genes for each branchiopod), comma-separated IPR description of Artemia genes in this orthogroup, Artemia genes in this orthogroup.Additional file 7 GO enrichment of Artemia compared to other Branchiopoda. Listed: GO ID, name and category, false discovery rate (FDR) and P value of the Fisher’s exact test enrichment analysis in Blast2GO, number of Artemia genes from expanded/contracted orthogroups in this GO ID, number of whole Artemia genome genes in this GO category, number of Artemia genes from expanded/contracted orthogroups in this GO ID without GO annotation. The Fisher’s Exact Test is sensitive in the direction of the test: the genes that are present in the test-set and also in the reference genome set will be deleted from the reference, but not from the test set, resulting in zero sequences in the reference set and values above zero in the test set. Significantly enriched GOs (FDR ≤ 0.05, biological process) of Artemia genes in expanded or contracted orthogroups compared to Branchiopoda are given.Additional file 8 Expanded or contracted Artemia and H. dujardini orthogroups compared to other Arthropoda. Listed: Orthogroup ID, number of genes in this orthogroup in A. franciscana and in the other arthropod species, expanded or contracted status of the orthogroup in Artemia compared to the other arthropod species, comma-separated IPR description of Artemia genes in this orthogroup, H. dujardini genes in this orthogroup, Artemia genes in this orthogroup.Additional file 9. STAR mapping statistics for differential expression analysis in Artemia. Listed: sample name, total number of reads for this sample, percentage of uniquely mapped reads, absolute number of uniquely mapped reads, percentage of multi mapped reads, absolute number of multi mapped reads.Additional file 10. Summarization statistics for differential expression analysis in Artemia. Listed: sample name, total counts, percentage of counts assigned to a gene annotation, absolute counts assigned to a gene annotation. * notice that this amount can be more than the sum of uniquely mapped + multi-mapped in the mapping statistics since multimapped reads are considered.Additional file 11 Differentially expressed genes under high salinity (p < 0.05). Listed: functional annotation of the differentially expressed gene, gene ID in the genome annotation and on the ORCAE platform, p value, average log fold change of gene expression under high salinity, gene regulation of the differentially expressed gene (up or down), InterPro description of the gene family to which the gene belongs.Additional file 12 Differentially expressed genes under anoxia (p < 0.05). Listed: functional annotation of the differentially expressed gene, gene ID in the genome annotation and on the ORCAE platform, p value, log fold change of gene expression under anoxia, gene regulation of the differentially expressed gene (up or down), InterPro description of the gene family to which the gene belongs.Additional file 13 GO enrichment in Artemia under high salinity. Significantly Enriched GOs (FDR ≤ 0.05) of Artemia genes differentially expressed under high salinity. Listed: GO ID, name and category, false discovery rate (FDR) and P value of the Fisher’s exact test enrichment analysis in Blast2GO, number of DEG under high salinity in this GO category, number of whole Artemia genome genes in this GO category, number of DEG under high salinity without GO annotation. The Fisher’s Exact Test is sensitive in the direction of the test: the genes that are present in the test-set and also in the reference genome set will be deleted from the reference, but not from the test set, resulting in zero sequences in the reference set and values above zero in the test set.Additional file 14 Pathway enrichment in Artemia under high salinity. Significantly enriched (Fisher’s exact test corrected for multiple testing, FDR ≤ 0.05) pathways of Artemia genes differentially expressed under high salinity. Listed in first worksheet (STRING annotation): gene number, ORCAE gene ID, STRING Daphnia pulex gene ID, BLAST identity and bit score, gene name and gene annotation. Listed in second worksheet (STRING pathway enrichment): KEGG Daphnia pulex pathway name, pathway description, number of DEG under high salinity in this pathway, number of genes in the D. pulex genome that belong to this pathway, enrichment FDR, matching D. pulex gene IDs, matching gene names in pathways shown in figures and additional files, matching D. pulex gene ID labels.Additional file 15. Consolidation of DEG analysis, GO enrichment and pathway enrichment in Artemia under high salinity.Additional file 16. The enriched Carbon metabolism pathway in Artemia under high salinity. Up- and downregulated genes are indicated on the KEGG map dpx01200.Additional file 17. GO enrichment in Artemia under anoxia. Significantly enriched GOs (FDR ≤ 0.05) of Artemia genes differentially expressed under anoxia. Listed: GO ID, name and category, false discovery rate (FDR) and P value of the Fisher’s exact test enrichment analysis in Blast2GO, number of DEG under anoxia in this GO ID, number of whole Artemia genome genes in this GO ID, number of DEG under anoxia without GO annotation. The Fisher’s Exact Test is sensitive in the direction of the test: the genes that are present in the test set and also in the reference genome set will be deleted from the reference, but not from the test set, resulting in zero sequences in the reference set and values above zero in the test set.Additional file 18 Pathway enrichment in Artemia under anoxia. Significantly enriched (Fisher’s exact test corrected for multiple testing, FDR ≤ 0.05) pathways of Artemia genes differentially expressed under anoxia. Listed in first worksheet (STRING annotation): gene number, ORCAE gene ID, STRING Daphnia pulex gene ID, BLAST identity and bit score, gene name and gene annotation. Listed in second worksheet (STRING pathway enrichment): KEGG Daphnia pulex pathway name, pathway description, number of DEG under anoxia in this pathway, number of genes in the D. pulex genome that belong to this pathway, enrichment FDR, matching D. pulex gene IDs, matching gene names in pathways shown in figures and additional files, matching D. pulex gene ID labels.Additional file 19. Consolidation of DEG analysis, GO enrichment and pathway enrichment in Artemia under anoxia.Additional file 20. The enriched N-glycan biosynthesis pathway in Artemia under anoxia. Up- and downregulated genes are indicated on the KEGG map dpx00510.Additional file 21. The enriched Basal transcription factors pathway in Artemia under anoxia. Up- and downregulated genes are indicated on the KEGG map dpx03022.Additional file 22. Augustus custom training files for Artemia. Includes probabilities, parameters and weights used for Augustus training for annotation of the Artemia genome.Additional file 23. EuGene custom parameter file for Artemia. Includes parameters used for EuGene training for annotation of the Artemia genome.Additional file 24. Sequence GC-content profiles for all samples used for differential expression analysis.The Flemish Government Special Research Fund and the Laboratory of Aquaculture & Artemia Reference Center.http://www.biomedcentral.com/bmcgenomicsam2022BiochemistryGeneticsMicrobiology and Plant Patholog

CATALISE: A multinational and multidisciplinary Delphi consensus study. Identifying language impairments in children

Delayed or impaired language development is a common developmental concern, yet thereis little agreement about the criteria used to identify and classify language impairments inchildren. Children's language difficulties are at the interface between education, medicineand the allied professions, who may all adopt different approaches to conceptualising them.Our goal in this study was to use an online Delphi technique to see whether it was possibleto achieve consensus among professionals on appropriate criteria for identifying childrenwho might benefit from specialist services. We recruited a panel of 59 experts representingten disciplines (including education, psychology, speech-language therapy/pathology, paediatricsand child psychiatry) from English-speaking countries (Australia, Canada, Ireland,New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46statements based on articles and commentaries in a special issue of a journal focusing onthis topic. Panel members rated each statement for both relevance and validity on a sevenpointscale, and added free text comments. These responses were synthesised by the firsttwo authors, who then removed, combined or modified items with a view to improving consensus.The resulting set of statements was returned to the panel for a second evaluation(round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percentfor 24 of 27 round 2 statements, though many respondents qualified their responsewith written comments. These were again synthesised by the first two authors. The resultingconsensus statement is reported here, with additional summary of relevant evidence, and aconcluding commentary on residual disagreements and gaps in the evidence base.</p

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR:CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm bound to heat shock proteins. Thus, we have identified third generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC

RNA Interference in Schistosoma mansoni Schistosomula: Selectivity, Sensitivity and Operation for Larger-Scale Screening

RNA interference (RNAi) is a technique to selectively suppress mRNA of individual genes and, consequently, their cognate proteins. RNAi using double-stranded (ds) RNA has been used to interrogate the function of mainly single genes in the flatworm, Schistosoma mansoni, one of a number of schistosome species causing schistosomiasis. In consideration of large-scale screens to identify candidate drug targets, we examined the selectivity and sensitivity (the degree of suppression) of RNAi for 11 genes produced in different tissues of the parasite: the gut, tegument (surface) and otherwise. We used the schistosomulum stage prepared from infective cercariae larvae which are accessible in large numbers and adaptable to automated screening platforms. We found that RNAi suppresses transcripts selectively, however, the sensitivity of suppression varies (40%–>75%). No obvious changes in the parasite occurred post-RNAi, including after targeting the mRNA of genes that had been computationally predicted to be essential for survival. Additionally, we defined operational parameters to facilitate large-scale RNAi, including choice of culture medium, transfection strategy to deliver dsRNA, dose- and time-dependency, and dosing limits. Finally, using fluorescent probes, we show that the developing gut allows rapid entrance of dsRNA into the parasite to initiate RNAi