The Rx for Change database: a first-in-class tool for optimal prescribing and medicines use

<p>Abstract</p> <p>Background</p> <p>Globally, suboptimal prescribing practices and medication errors are common. Guidance to health professionals and consumers alone is not sufficient to optimise behaviours, therefore strategies to promote evidence-based decision making and practice, such as decision support tools or reminders, are important. The literature in this area is growing, but is of variable quality and dispersed across sources, which makes it difficult to identify, access, and assess. To overcome these problems, by synthesizing and evaluating the data from systematic reviews, we have developed <it>Rx for Change </it>to provide a comprehensive, online database of the evidence for strategies to improve drug prescribing and use.</p> <p>Methods</p> <p>We use reliable and valid methods to search and screen the literature, and to appraise and analyse the evidence from relevant systematic reviews. We then present the findings in an online format which allows users to easily access pertinent information related to prescribing and medicines use. The database is a result of the collaboration between the Canadian Agency for Drugs and Technologies in Health (CADTH) and two Cochrane review groups.</p> <p>Results</p> <p>To capture the body of evidence on interventions to improve prescribing and medicines use, we conduct comprehensive and regular searches in multiple databases, and hand-searches of relevant journals. We screen articles to identify relevant systematic reviews, and include them if they are of moderate or high methodological quality. Two researchers screen, assess quality, and extract data on demographic details, intervention characteristics, and outcome data. We report the results of our analysis of each systematic review using a standardised quantitative and qualitative format. <it>Rx for Change </it>currently contains over 200 summarised reviews, structured in a multi-level format. The reviews included in the database are diverse, covering various settings, conditions, or diseases and targeting a range of professional and consumer behaviors.</p> <p>Conclusions</p> <p><it>Rx for Change </it>is a novel database that synthesizes current research evidence about the effects of interventions to improve drug prescribing practices and medicines use.</p

Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension.</p> <p>Case presentation</p> <p>We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy.</p> <p>Conclusion</p> <p>We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.</p

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial EMG (n = 3 CIP participants and n = 8 healthy controls) we have found that these patients also have abnormalities in the encoding of affective touch which is mediated by the specialised afferents; C-low threshold mechanoreceptors (C-LTMRs). In the mouse we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch

Taking Ecological Function Seriously: Soil Microbial Communities Can Obviate Allelopathic Effects of Released Metabolites

Allelopathy (negative, plant-plant chemical interactions) has been largely studied as an autecological process, often assuming simplistic associations between pairs of isolated species. The growth inhibition of a species in filter paper bioassay enriched with a single chemical is commonly interpreted as evidence of an allelopathic interaction, but for some of these putative examples of allelopathy, the results have not been verifiable in more natural settings with plants growing in soil.On the basis of filter paper bioassay, a recent study established allelopathic effects of m-tyrosine, a component of root exudates of Festuca rubra ssp. commutata. We re-examined the allelopathic effects of m-tyrosine to understand its dynamics in soil environment. Allelopathic potential of m-tyrosine with filter paper and soil (non-sterile or sterile) bioassays was studied using Lactuca sativa, Phalaris minor and Bambusa arundinacea as assay species. Experimental application of m-tyrosine to non-sterile and sterile soil revealed the impact of soil microbial communities in determining the soil concentration of m-tyrosine and growth responses.Here, we show that the allelopathic effects of m-tyrosine, which could be seen in sterilized soil with particular plant species were significantly diminished when non-sterile soil was used, which points to an important role for rhizosphere-specific and bulk soil microbial activity in determining the outcome of this allelopathic interaction. Our data show that the amounts of m-tyrosine required for root growth inhibition were higher than what would normally be found in F. rubra ssp. commutata rhizosphere. We hope that our study will motivate researchers to integrate the role of soil microbial communities in bioassays in allelopathic research so that its importance in plant-plant competitive interactions can be thoroughly evaluated

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

A comparative evaluation of the effect of internet-based CME delivery format on satisfaction, knowledge and confidence

<p>Abstract</p> <p>Background</p> <p>Internet-based instruction in continuing medical education (CME) has been associated with favorable outcomes. However, more direct comparative studies of different Internet-based interventions, instructional methods, presentation formats, and approaches to implementation are needed. The purpose of this study was to conduct a comparative evaluation of two Internet-based CME delivery formats and the effect on satisfaction, knowledge and confidence outcomes.</p> <p>Methods</p> <p>Evaluative outcomes of two differing formats of an Internet-based CME course with identical subject matter were compared. A Scheduled Group Learning format involved case-based asynchronous discussions with peers and a facilitator over a scheduled 3-week delivery period. An eCME On Demand format did not include facilitated discussion and was not based on a schedule; participants could start and finish at any time. A retrospective, pre-post evaluation study design comparing identical satisfaction, knowledge and confidence outcome measures was conducted.</p> <p>Results</p> <p>Participants in the Scheduled Group Learning format reported significantly higher mean satisfaction ratings in some areas, performed significantly higher on a post-knowledge assessment and reported significantly higher post-confidence scores than participants in the eCME On Demand format that was not scheduled and did not include facilitated discussion activity.</p> <p>Conclusions</p> <p>The findings support the instructional benefits of a scheduled delivery format and facilitated asynchronous discussion in Internet-based CME.</p

Varying Herbivore Population Structure Correlates with Lack of Local Adaptation in a Geographic Variable Plant-Herbivore Interaction

Local adaptation of parasites to their hosts due to coevolution is a central prediction of many theories in evolutionary biology. However, empirical studies looking for parasite local adaptation show great variation in outcomes, and the reasons for such variation are largely unknown. In a previous study, we showed adaptive differentiation in the arctiid moth Utetheisa ornatrix to its host plant, the pyrrolizidine alkaloid-bearing legume Crotalaria pallida, at the continental scale, but found no differentiation at the regional scale. In the present study, we sampled the same sites to investigate factors that may contribute to the lack of differentiation at the regional scale. We performed field observations that show that specialist and non-specialist polyphagous herbivore incidence varies among populations at both scales. With a series of common-garden experiments we show that some plant traits that may affect herbivory (pyrrolizidine alkaloids and extrafloral nectaries) vary at the regional scale, while other traits (trichomes and nitrogen content) just vary at the continental scale. These results, combined with our previous evidence for plant population differentiation based on larval performance on fresh fruits, suggest that U. ornatrix is subjected to divergent selection even at the regional scale. Finally, with a microsatellite study we investigated population structure of U. ornatrix. We found that population structure is not stable over time: we found population differentiation at the regional scale in the first year of sampling, but not in the second year. Unstable population structure of the herbivore is the most likely cause of the lack of regional adaptation

Genetic Traces of Recent Long-Distance Dispersal in a Predominantly Self-Recruiting Coral

Understanding of the magnitude and direction of the exchange of individuals among geographically separated subpopulations that comprise a metapopulation (connectivity) can lead to an improved ability to forecast how fast coral reef organisms are likely to recover from disturbance events that cause extensive mortality. Reef corals that brood their larvae internally and release mature larvae are believed to show little exchange of larvae over ecological times scales and are therefore expected to recover extremely slowly from large-scale perturbations.Using analysis of ten DNA microsatellite loci, we show that although Great Barrier Reef (GBR) populations of the brooding coral, Seriatopora hystrix, are mostly self-seeded and some populations are highly isolated, a considerable amount of sexual larvae (up to approximately 4%) has been exchanged among several reefs 10 s to 100 s km apart over the past few generations. Our results further indicate that S. hystrix is capable of producing asexual propagules with similar long-distance dispersal abilities (approximately 1.4% of the sampled colonies had a multilocus genotype that also occurred at another sampling location), which may aid in recovery from environmental disturbances.Patterns of connectivity in this and probably other GBR corals are complex and need to be resolved in greater detail through genetic characterisation of different cohorts and linkage of genetic data with fine-scale hydrodynamic models

Human Population Differentiation Is Strongly Correlated with Local Recombination Rate

Allele frequency differences across populations can provide valuable information both for studying population structure and for identifying loci that have been targets of natural selection. Here, we examine the relationship between recombination rate and population differentiation in humans by analyzing two uniformly-ascertained, whole-genome data sets. We find that population differentiation as assessed by inter-continental FST shows negative correlation with recombination rate, with FST reduced by 10% in the tenth of the genome with the highest recombination rate compared with the tenth of the genome with the lowest recombination rate (P≪10−12). This pattern cannot be explained by the mutagenic properties of recombination and instead must reflect the impact of selection in the last 100,000 years since human continental populations split. The correlation between recombination rate and FST has a qualitatively different relationship for FST between African and non-African populations and for FST between European and East Asian populations, suggesting varying levels or types of selection in different epochs of human history

Population genetic structure of Aedes polynesiensis in the Society Islands of French Polynesia: implications for control using a Wolbachia-based autocidal strategy

Abstract Background Aedes polynesiensis is the primary vector of Wuchereria bancrofti in the South Pacific and an important vector of dengue virus. An improved understanding of the mosquito population genetics is needed for insight into the population dynamics and dispersal, which can aid in understanding the epidemiology of disease transmission and control of the vector. In light of the potential release of a Wolbachia infected strain for vector control, our objectives were to investigate the microgeographical and temporal population genetic structure of A. polynesiensis within the Society Islands of French Polynesia, and to compare the genetic background of a laboratory strain intended for release into its population of origin. Methods A panel of eight microsatellite loci were used to genotype A. polynesiensis samples collected in French Polynesia from 2005-2008 and introgressed A. polynesiensis and Aedes riversi laboratory strains. Examination of genetic differentiation was performed using F-statistics, STRUCTURE, and an AMOVA. BAYESASS was used to estimate direction and rates of mosquito movement. Results FST values, AMOVA, and STRUCTURE analyses suggest low levels of intra-island differentiation from multiple collection sites on Tahiti, Raiatea, and Maupiti. Significant pair-wise FST values translate to relatively minor levels of inter-island genetic differentiation between more isolated islands and little differentiation between islands with greater commercial traffic (i.e., Tahiti, Raiatea, and Moorea). STRUCTURE analyses also indicate two population groups across the Society Islands, and the genetic makeup of Wolbachia infected strains intended for release is similar to that of wild-type populations from its island of origin, and unlike that of A. riversi. Conclusions The observed panmictic population on Tahiti, Raiatea, and Moorea is consistent with hypothesized gene flow occurring between islands that have relatively high levels of air and maritime traffic, compared to that of the more isolated Maupiti and Tahaa. Gene flow and potential mosquito movement is discussed in relation to trials of applied autocidal strategies.</p