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ObjectiveTo determine whether multifactorial falls prevention interventions are effective in preventing falls, fall injuries, emergency department (ED) re-presentations and hospital admissions in older adults presenting to the ED with a fall.DesignSystematic review and meta-analyses of randomised controlled trials (RCTs).Data sourcesFour health-related electronic databases (Ovid MEDLINE, CINAHL, EMBASE, PEDro and The Cochrane Central Register of Controlled Trials) were searched (inception to June 2018).Study selectionRCTs of multifactorial falls prevention interventions targeting community-dwelling older adults ( ≥ 60 years) presenting to the ED with a fall with quantitative data on at least one review outcome.Data extractionTwo independent reviewers determined inclusion, assessed study quality and undertook data extraction, discrepancies resolved by a third.Data synthesis12 studies involving 3986 participants, from six countries, were eligible for inclusion. Studies were of variable methodological quality. Multifactorial interventions were heterogeneous, though the majority included education, referral to healthcare services, home modifications, exercise and medication changes. Meta-analyses demonstrated no reduction in falls (rate ratio = 0.78; 95% CI: 0.58 to 1.05), number of fallers (risk ratio = 1.02; 95% CI: 0.88 to 1.18), rate of fractured neck of femur (risk ratio = 0.82; 95% CI: 0.53 to 1.25), fall-related ED presentations (rate ratio = 0.99; 95% CI: 0.84 to 1.16) or hospitalisations (rate ratio = 1.14; 95% CI: 0.69 to 1.89) with multifactorial falls prevention programmes.ConclusionsThere is insufficient evidence to support the use of multifactorial interventions to prevent falls or hospital utilisation in older people presenting to ED following a fall. Further research targeting this population group is required.

After evaluating a safety signal regarding pancreatitis and pancreatic cancer in patients using incretin-based drugs, the Food and Drug Administration and the European Medicines Agency conclude that assertions of a causal association are inconsistent with the data. With approximately 25.8 million diabetic patients in the United States and 33 million in the European Union alone, the growing prevalence of diabetes worldwide poses a major public health challenge. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are committed to ensuring the safety of drug products marketed for the treatment of diabetes, and postmarketing reports of pancreatitis and pancreatic cancer in patients taking certain antidiabetic medications have been of concern to both agencies. Working in parallel, the agencies have reviewed nonclinical toxicology studies, clinical trial data, and epidemiologic data pertaining to blood glucose-lowering ...

SUMMARYObjectiveThe evolutionary history of human malaria parasites (genusPlasmodium) has long been a subject of speculation and controversy. The complete genome sequences of the two most widespread human malaria parasites,P. falciparumandP. vivax, and of the monkey parasiteP. knowlesiare now available, together with the draft genomes of the chimpanzee parasiteP. reichenowi, three rodent parasites,P. yoelii yoelli, P. bergheiandP. chabaudi chabaudi, and one avian parasite,P. gallinaceum.MethodsWe present here an analysis of 45 orthologous gene sequences across the eight species that resolves the relationships of majorPlasmodiumlineages, and provides the first comprehensive dating of the age of those groups.ResultsOur analyses support the hypothesis that the last common ancestor ofP. falciparumand the chimpanzee parasiteP. reichenowioccurred around the time of the human-chimpanzee divergence.P. falciparuminfections of African apes are most likely derived from humans and not the other way around. On the other hand,P. vivax, split from the monkey parasiteP. knowlesiin the much more distant past, during the time that encompasses the separation of the Great Apes and Old World Monkeys.ConclusionThe results support an ancient association between malaria parasites and their primate hosts, including humans.

We have sequenced the genome of a second Drosophila species, Drosophila pseudoobscura, and compared this to the genome sequence of Drosophila melanogaster, a primary model organism. Throughout evolution the vast majority of Drosophila genes have remained on the same chromosome arm, but within each arm gene order has been extensively reshuffled, leading to a minimum of 921 syntenic blocks shared between the species. A repetitive sequence is found in the D. pseudoobscura genome at many junctions between adjacent syntenic blocks. Analysis of this novel repetitive element family suggests that recombination between offset elements may have given rise to many paracentric inversions, thereby contributing to the shuffling of gene order in the D. pseudoobscura lineage. Based on sequence similarity and synteny, 10,516 putative orthologs have been identified as a core gene set conserved over 25–55 million years (Myr) since the pseudoobscura/melanogaster divergence. Genes expressed in the testes had higher amino acid sequence divergence than the genome-wide average, consistent with the rapid evolution of sex-specific proteins. Cis-regulatory sequences are more conserved than random and nearby sequences between the species—but the difference is slight, suggesting that the evolution of cis-regulatory elements is flexible. Overall, a pattern of repeat-mediated chromosomal rearrangement, and high coadaptation of both male genes and cis-regulatory sequences emerges as important themes of genome divergence between these species of Drosophila.

After weighing the risks and benefits, the FDA recently approved two new drugs as adjuncts to a reduced-calorie diet and increased physical activity for chronic weight management in obese or overweight adults with at least one weight-related coexisting condition.

Having reviewed the data on the risk of myopathy, the FDA recommends that the 80-mg dose of simvastatin be used only in patients who have been taking this dose for an extended period without signs or symptoms of clinically significant muscle toxicity.

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production. Fil: Bovine Genome Sequencing and Analysis Consortium. Bovine Genome Sequencing And Analysis Consortium; Estados Unidos Fil: Amadio, Ariel Fernando. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria Rafaela; Argentina Fil: Poli, Mario Andres. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Genética; Argentina

Background The availability of complete genomic sequences for hundreds of organisms promises to make obtaining genome-wide estimates of substitution rates, selective constraints and other molecular evolution variables of interest an increasingly important approach to addressing broad evolutionary questions. Two of the programs most widely used for this purpose are codeml and baseml, parts of the PAML (Phylogenetic Analysis by Maximum Likelihood) suite. A significant drawback of these programs is their lack of a graphical user interface, which can limit their user base and considerably reduce their efficiency. Results We have developed IDEA (Interactive Display for Evolutionary Analyses), an intuitive graphical input and output interface which interacts with PHYLIP for phylogeny reconstruction and with codeml and baseml for molecular evolution analyses. IDEA's graphical input and visualization interfaces eliminate the need to edit and parse text input and output files, reducing the likelihood of errors and improving processing time. Further, its interactive output display gives the user immediate access to results. Finally, IDEA can process data in parallel on a local machine or computing grid, allowing genome-wide analyses to be completed quickly. Conclusion IDEA provides a graphical user interface that allows the user to follow a codeml or baseml analysis from parameter input through to the exploration of results. Novel options streamline the analysis process, and post-analysis visualization of phylogenies, evolutionary rates and selective constraint along protein sequences simplifies the interpretation of results. The integration of these functions into a single tool eliminates the need for lengthy data handling and parsing, significantly expediting access to global patterns in the data.

We present the genome sequences of a new clinical isolate of the important human pathogen, Aspergillus fumigatus, A1163, and two closely related but rarely pathogenic species, Neosartorya fischeri NRRL181 and Aspergillus clavatus NRRL1. Comparative genomic analysis of A1163 with the recently sequenced A. fumigatus isolate Af293 has identified core, variable and up to 2% unique genes in each genome. While the core genes are 99.8% identical at the nucleotide level, identity for variable genes can be as low 40%. The most divergent loci appear to contain heterokaryon incompatibility (het) genes associated with fungal programmed cell death such as developmental regulator rosA. Cross-species comparison has revealed that 8.5%, 13.5% and 12.6%, respectively, of A. fumigatus, N. fischeri and A. clavatus genes are species-specific. These genes are significantly smaller in size than core genes, contain fewer exons and exhibit a subtelomeric bias. Most of them cluster together in 13 chromosomal islands, which are enriched for pseudogenes, transposons and other repetitive elements. At least 20% of A. fumigatus-specific genes appear to be functional and involved in carbohydrate and chitin catabolism, transport, detoxification, secondary metabolism and other functions that may facilitate the adaptation to heterogeneous environments such as soil or a mammalian host. Contrary to what was suggested previously, their origin cannot be attributed to horizontal gene transfer (HGT), but instead is likely to involve duplication, diversification and differential gene loss (DDL). The role of duplication in the origin of lineage-specific genes is further underlined by the discovery of genomic islands that seem to function as designated “gene dumps” and, perhaps, simultaneously, as “gene factories”., Author Summary Aspergillus is an extremely diverse genus of filamentous ascomycetous fungi (molds) found ubiquitously in soil and decomposing vegetation. Being supreme opportunists, aspergilli have adapted to overcome various chemical, physical, and biological stresses found in heterogeneous environments. While most species in the genus are saprophytes, a surprising number are able to infect wounded plants and animals. Remarkably, the allergic human host also responds abnormally to the aspergilli with lung and sinus disease. The advent of immunosuppressive agents and other medical advances have created a large worldwide pool of human hosts susceptible to some Aspergillus species, including the world's most harmful mold and the causative agent of invasive aspergillosis, Aspergillus fumigatus. In this study, we have used the power of comparative genomics to gain insight into genetic mechanisms that may contribute to the metabolic versatility and pathogenicity of this important human pathogen. Comparison of the genomes of two A. fumigatus clinical isolates and two closely related, but rarely pathogenic species showed that their genomes contain several large isolate- and species-specific chromosomal islands. The metabolic capabilities encoded by these highly labile regions are likely to contribute to their rapid adaptation to heterogeneous environments such as soil or a living host.

Background: High gene numbers in plant genomes reflect polyploidy and major gene duplication events. Oryza sativa, cultivated rice, is a diploid monocotyledonous species with a ~390 Mb genome that has undergone segmental duplication of a substantial portion of its genome. This, coupled with other genetic events such as tandem duplications, has resulted in a substantial number of its genes, and resulting proteins, occurring in paralogous families. Results: Using a computational pipeline that utilizes Pfam and novel protein domains, we characterized paralogous families in rice and compared these with paralogous families in the model dicotyledonous diploid species, Arabidopsis thaliana. Arabidopsis, which has undergone genome duplication as well, has a substantially smaller genome (~120 Mb) and gene complement compared to rice. Overall, 53% and 68% of the non-transposable element-related rice and Arabidopsis proteins could be classified into paralogous protein families, respectively. Singleton and paralogous family genes differed substantially in their likelihood of encoding a protein of known or putative function; 26% and 66% of singleton genes compared to 73% and 96% of the paralogous family genes encode a known or putative protein in rice and Arabidopsis, respectively. Furthermore, a major skew in the distribution of specific gene function was observed; a total of 17 Gene Ontology categories in both rice and Arabidopsis were statistically significant in their differential distribution between paralogous family and singleton proteins. In contrast to mammalian organisms, we found that duplicated genes in rice and Arabidopsis tend to have more alternative splice forms. Using data from Massively Parallel Signature Sequencing, we show that a significant portion of the duplicated genes in rice show divergent expression although a correlation between sequence divergence and correlation of expression could be seen in very young genes. Conclusion: Collectively, these data suggest that while co-regulation and conserved function are present in some paralogous protein family members, evolutionary pressures have resulted in functional divergence with differential expression patterns., National Science Foundation (U.S.). Plant Genome Research Program (DBI-0321538), National Science Foundation (U.S.) (DBI-0321437)

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.

Atlas is a suite of programs developed for assembly of genomes by a “combined approach” that uses DNA sequence reads from both BACs and whole-genome shotgun (WGS) libraries. The BAC clones afford advantages of localized assembly with reduced computational load, and provide a robust method for dealing with repeated sequences. Inclusion of WGS sequences facilitates use of different clone insert sizes and reduces data production costs. A core function of Atlas software is recruitment of WGS sequences into appropriate BACs based on sequence overlaps. Because construction of consensus sequences is from local assembly of these reads, only small (overlapper and split-scaffold are also being used in pure WGS projects.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.