Repeat prescribing of medications: a system-centred risk management model for primary care organisations

Rationale, aims and objectives: Reducing preventable harm from repeat medication prescriptions is a patient safety priority worldwide. In the United Kingdom, repeat prescriptions items issued has doubled in the last 20 years from 5.8 to 13.3 items per patient per annum. This has significant resource implications and consequences for avoidable patient harms. Consequently, we aimed to test a risk management model to identify, measure, and reduce repeat prescribing system risks in primary care. Methods: All 48 general medical practices in National Health Service (NHS) Lambeth Clinical Commissioning Group (an inner city area of south London in England) were recruited. Multiple interventions were implemented, including educational workshops, a web-based risk monitoring system, and external reviews of repeat prescribing system risks by clinicians. Data were collected via documentation reviews and interviews and subject to basic thematic and descriptive statistical analyses. Results: Across the 48 participating general practices, 62 unique repeat prescribing risks were identified on 505 occasions (eg, practices frequently experiencing difficulty interpreting medication changes on hospital discharge summaries), equating to a mean of 8.1 risks per practice (range: 1-33; SD = 7.13). Seven hundred sixty-seven system improvement actions were recommended across 96 categories (eg, alerting hospitals to illegible writing and delays with discharge summaries) with a mean of 15.6 actions per practice (range: 0-34; SD = 8.0). Conclusions: The risk management model tested uncovered important safety concerns and facilitated the development and communication of related improvement recommendations. System-wide information on hazardous repeat prescribing and how this could be mitigated is very limited. The approach reported may have potential to close this gap and improve the reliability of general practice systems and patient safety, which should be of high interest to primary care organisations internationally

Landscape of standing variation for tandem duplications in Drosophila yakuba and Drosophila simulans

We have used whole genome paired-end Illumina sequence data to identify tandem duplications in 20 isofemale lines of D. yakuba, and 20 isofemale lines of D. simulans and performed genome wide validation with PacBio long molecule sequencing. We identify 1,415 tandem duplications that are segregating in D. yakuba as well as 975 duplications in D. simulans, indicating greater variation in D. yakuba. Additionally, we observe high rates of secondary deletions at duplicated sites, with 8% of duplicated sites in D. simulans and 17% of sites in D. yakuba modified with deletions. These secondary deletions are consistent with the action of the large loop mismatch repair system acting to remove polymorphic tandem duplication, resulting in rapid dynamics of gain and loss in duplicated alleles and a richer substrate of genetic novelty than has been previously reported. Most duplications are present in only single strains, suggesting deleterious impacts are common. D. simulans shows larger numbers of whole gene duplications in comparison to larger proportions of gene fragments in D. yakuba. D. simulans displays an excess of high frequency variants on the X chromosome, consistent with adaptive evolution through duplications on the D. simulans X or demographic forces driving duplicates to high frequency. We identify 78 chimeric genes in D. yakuba and 38 chimeric genes in D. simulans, as well as 143 cases of recruited non-coding sequence in D. yakuba and 96 in D. simulans, in agreement with rates of chimeric gene origination in D. melanogaster. Together, these results suggest that tandem duplications often result in complex variation beyond whole gene duplications that offers a rich substrate of standing variation that is likely to contribute both to detrimental phenotypes and disease, as well as to adaptive evolutionary change.Comment: Revised Version- Accepted at Molecular Biology and Evolutio

Climate Change Totems and Discursive Hegemony Over the Arctic

The Arctic and its animals figure prominently as icons of climate change in Western imaginaries. Persuasive storytelling centred on compelling animal icons, like the polar bear, is a powerful strategy to frame environmental challenges, mobilizing collective global efforts to resist environmental degradation and species endangerment. The power of the polar bear in Western climate imagery is in part derived from the perceived "environmental sacredness"of the animal that has gained a totem-like status. In dominant "global"discourses, this connotation often works to the detriment of Indigenous peoples, for whom animals signify complex socio-ecological relations and cultural histories. This Perspective article offers a reflexive analysis on the symbolic power of the polar bear totem and the discursive exclusion of Indigenous peoples, informed by attendance during 2015-2017 at annual global climate change negotiations and research during 2016-2018 in Canada's Nunavut Territory. The polar bear's totem-like status in Western imaginaries exposes three discursive tensions that infuse climate change perception, activism, representation and Indigenous citizenship. The first tension concerns the global climate crisis, and its perceived threat to ecologically significant or sacred species, contrasted with locally lived realities. The second tension concerns a perceived sacred Arctic that is global, pristine, fragile and "contemplated,"but simultaneously local, hazardous, sustaining and lived. The third tension concerns Indigenization, distorted under a global climate gaze that reimagines the role of Indigenous peoples. Current discursive hegemony over the Arctic serves to place Indigenous peoples in stasis and restricts the space for Arctic Indigenous engagement and voice.This research was funded by the University of Calgary, University Research Grants Committee (URGC) Seed Grant 1037188, the Social Sciences and Humanities Research Council of Canada (SSHRC) Insight Development Grant 430-2016-00190, and Canadian High Arctic Research Station – CHARS (Polar Knowledge Canada) NST-1718-0024

Analysis of Gal4-directed transcription activation using Tra1 mutants selectively defective for interaction with Gal4

Promoter-specific transcriptional activators (activators) stimulate transcription through direct interactions with one or more components of the transcription machinery, termed the target. The identification of direct in vivo targets of activators has been a major challenge. Previous studies have provided evidence that the Tra1 subunit of the yeast SAGA (Spt-Ada-Gcn5-acetyltransferase) complex is the target of the yeast activator Gal4. However, several other general transcription factors, in particular the mediator complex, have also been implicated as Gal4 targets. Here we perform a large-scale genetic screen to derive and characterize tra1 alleles that are selectively defective for interaction with Gal4 in vivo [Gal4 interaction defective (GID) mutants]. In contrast to WT Tra1, Tra1 GID mutants are not recruited by Gal4 to the promoter and cannot support Gal4-directed transcription, demonstrating the essentiality of the Gal4-Tra1 interaction. In yeast strains expressing a Tra1 GID mutant, binding of Gal4 to the promoter is unexpectedly also diminished, indicating that Gal4 and Tra1 bind cooperatively. Consistent with cooperative binding, we demonstrate that the Gal4-Tra1 interaction occurs predominantly on the promoter and not off DNA. Finally, we show that although Tra1 is targeted by other activators, these interactions are unaffected by GID mutations, revealing an unanticipated specificity of the Gal4-Tra1 interaction

Creating, Modeling, and Visualizing Metabolic Networks

Metabolic networks combine metabolism and regulation. These complex networks are difficult to understand and create due to the diverse types of information that need to be represented. This chapter describes a suite of interlinked tools for developing, displaying, and modeling metabolic networks. The metabolic network interactions database, MetNetDB, contains information on regulatory and metabolic interactions derived from a combination of web databases and input from biologists in their area of expertise. PathBinderA mines the biological “literaturome” by searching for new interactions or supporting evidence for existing interactions in metabolic networks. Sentences from abstracts are ranked in terms of the likelihood that an interaction is described and combined with evidence provided by other sentences. FCModeler, a publicly available software package, enables the biologist to visualize and model metabolic and regulatory network maps. FCModeler aids in the development and evaluation of hypotheses, and provides a modeling framework for assessing the large amounts of data captured by high-throughput gene expression experiments

Non-canonical TAF complexes regulate active promoters in human embryonic stem cells

The general transcription factor TFIID comprises the TATA-box-binding protein (TBP) and approximately 14 TBP-associated factors (TAFs). Here we find, unexpectedly, that undifferentiated human embryonic stem cells (hESCs) contain only six TAFs (TAFs 2, 3, 5, 6, 7 and 11), whereas following differentiation all TAFs are expressed. Directed and global chromatin immunoprecipitation analyses reveal an unprecedented promoter occupancy pattern: most active genes are bound by only TAFs 3 and 5 along with TBP, whereas the remaining active genes are bound by TBP and all six hESC TAFs. Consistent with these results, hESCs contain a previously undescribed complex comprising TAFs 2, 6, 7, 11 and TBP. Altering the composition of hESC TAFs, either by depleting TAFs that are present or ectopically expressing TAFs that are absent, results in misregulated expression of pluripotency genes and induction of differentiation. Thus, the selective expression and use of TAFs underlies the ability of hESCs to self-renew