An unfolding signifier: London's Baltic Exchange in Tallinn

In the summer of 2007 an unusual cargo arrived at Muuga and Paldiski harbors outside Tallinn. It consisted of nearly 50 containers holding over 1,000 tons of building material ranging from marble columns, staircases and fireplaces, to sculpted allegorical figures, wooden paneling and old-fashioned telephone booths. They were once part of the Baltic Exchange in the City of London. Soon they will become facets of the landscape of Tallinn. The following article charts this remarkable story and deploys this fragmented monument to analyze three issues relating to the Estonian capital: the relocation of the ‘Bronze Soldier’, the demolition of the Sakala Culture Center, and Tallinn’s future role as European Cultural Capital in 2011

Inappropriate prescribing and adverse drug events in older people

Inappropriate prescribing (IP) in older patients is highly prevalent and is associated with an increased risk of adverse drug events (ADEs), morbidity, mortality and healthcare utilisation. Consequently, IP is a major safety concern and with changing population demographics, it is likely to become even more prevalent in the future. IP can be detected using explicit or implicit prescribing indicators. Theoretically, the routine clinical application of these IP criteria could represent an inexpensive and time efficient method to optimise prescribing practice. However, IP criteria must be sensitive, specific, have good inter-rater reliability and incorporate those medications most commonly associated with ADEs in older people. To be clinically relevant, use of prescribing appropriateness tools must translate into positive patient outcomes, such as reduced rates of ADEs. To accurately measure these outcomes, a reliable method of assessing the relationship between the administration of a drug and an adverse clinical event is required. The Naranjo criteria are the most widely used tool for assessing ADE causality, however, they are often difficult to interpret in the context of older patients. ADE causality criteria that allow for the multiple co-morbidities and prescribed medications in older people are required. Ultimately, the current high prevalence of IP and ADEs is unacceptable. IP screening criteria need to be tested as an intervention to assess their impact on the incidence of ADEs in vulnerable older patients. There is a role for IP screening tools in everyday clinical practice. These should enhance, not replace good clinical judgement, which in turn should be based on sound pharmacogeriatric training

Novel features of ARS selection in budding yeast Lachancea kluyveri

<p>Abstract</p> <p>Background</p> <p>The characterization of DNA replication origins in yeast has shed much light on the mechanisms of initiation of DNA replication. However, very little is known about the evolution of origins or the evolution of mechanisms through which origins are recognized by the initiation machinery. This lack of understanding is largely due to the vast evolutionary distances between model organisms in which origins have been examined.</p> <p>Results</p> <p>In this study we have isolated and characterized autonomously replicating sequences (ARSs) in <it>Lachancea kluyveri </it>- a pre-whole genome duplication (WGD) budding yeast. Through a combination of experimental work and rigorous computational analysis, we show that <it>L. kluyveri </it>ARSs require a sequence that is similar but much longer than the ARS Consensus Sequence well defined in <it>Saccharomyces cerevisiae</it>. Moreover, compared with <it>S. cerevisiae </it>and <it>K. lactis</it>, the replication licensing machinery in <it>L. kluyveri </it>seems more tolerant to variations in the ARS sequence composition. It is able to initiate replication from almost all <it>S. cerevisiae </it>ARSs tested and most <it>Kluyveromyces lactis </it>ARSs. In contrast, only about half of the <it>L. kluyveri </it>ARSs function in <it>S. cerevisiae </it>and less than 10% function in <it>K. lactis</it>.</p> <p>Conclusions</p> <p>Our findings demonstrate a replication initiation system with novel features and underscore the functional diversity within the budding yeasts. Furthermore, we have developed new approaches for analyzing biologically functional DNA sequences with ill-defined motifs.</p

Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes

Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6–15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries:interrupted time series regression analysis

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings

Targeting the epigenome: effects of epigenetic treatment strategies on genomic stability in healthy human cells

Epigenetic treatment concepts have long been ascribed as being tumour-selective. Over the last decade, it has become evident that epigenetic mechanisms are essential for a wide range of intracellular functions in healthy cells as well. Evaluation of possible side-effects and their underlying mechanisms in healthy human cells is necessary in order to improve not only patient safety, but also to support future drug development. Since epigenetic regulation directly interacts with genomic and chromosomal packaging density, increasing genomic instability may be a result subsequent to drug-induced epigenetic modifications. This review highlights past and current research efforts on the influence of epigenetic modification on genomic stability in healthy human cells

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial

Background Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. Objectives To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. Methods We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2–16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg–1 daily) or MTX (0.4 mg kg–1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. Results In total, 103 participants were randomized (May 2016–February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD –5.69, 97.5% confidence interval (CI) –10.81 to –0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23–5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13–0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42–6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. Conclusions Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation