Identification and weighting of the most critical "real-life” drug-drug interactions with acenocoumarol in a tertiary care hospital

Purpose: The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. Methods: We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. Results: One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. Conclusion: Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drug

Using ERA-Interim reanalysis for creating datasets of energy-relevant climate variables

The construction of a bias-adjusted dataset of climate variables at the near surface using ERA-Interim reanalysis is presented. A number of different, variable-dependent, bias-adjustment approaches have been proposed. Here we modify the parameters of different distributions (depending on the variable), adjusting ERA-Interim based on gridded station or direct station observations. The variables are air temperature, dewpoint temperature, precipitation (daily only), solar radiation, wind speed, and relative humidity. These are available on either 3 or 6 h timescales over the period 1979–2016. The resulting bias-adjusted dataset is available through the Climate Data Store (CDS) of the Copernicus Climate Change Data Store (C3S) and can be accessed at present from ftp://ecem.climate.copernicus.eu. The benefit of performing bias adjustment is demonstrated by comparinginitial and bias-adjusted ERA-Interim data against gridded observational fields

Identification and weighting of the most critical "real-life” drug-drug interactions with acenocoumarol in a tertiary care hospital

Purpose: The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. Methods: We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. Results: One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. Conclusion: Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drug

How Advanced Change Patterns Impact the Process of Process Modeling

Process model quality has been an area of considerable research efforts. In this context, correctness-by-construction as enabled by change patterns provides promising perspectives. While the process of process modeling (PPM) based on change primitives has been thoroughly investigated, only little is known about the PPM based on change patterns. In particular, it is unclear what set of change patterns should be provided and how the available change pattern set impacts the PPM. To obtain a better understanding of the latter as well as the (subjective) perceptions of process modelers, the arising challenges, and the pros and cons of different change pattern sets we conduct a controlled experiment. Our results indicate that process modelers face similar challenges irrespective of the used change pattern set (core pattern set versus extended pattern set, which adds two advanced change patterns to the core patterns set). An extended change pattern set, however, is perceived as more difficult to use, yielding a higher mental effort. Moreover, our results indicate that more advanced patterns were only used to a limited extent and frequently applied incorrectly, thus, lowering the potential benefits of an extended pattern set

HER2 testing in breast cancer: Opportunities and challenges

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-25% of breast cancers, usually as a result of HER2 gene amplification. Positive HER2 status is considered to be an adverse prognostic factor. Recognition of the role of HER2 in breast cancer growth has led to the development of anti-HER2 directed therapy, with the humanized monoclonal antibody trastuzumab (Herceptin (R)) having been approved for the therapy of HER2-positive metastatic breast cancer. Clinical studies have further suggested that HER2 status can provide important information regarding success or failure of certain hormonal therapies or chemotherapies. As a result of these developments, there has been increasing demand to perform HER2 testing on current and archived breast cancer specimens. This article reviews the molecular background of HER2 function, activation and inhibition as well as current opinions concerning its role in chemosensitivity and interaction with estrogen receptor biology. The different tissue-based assays used to detect HER2 amplification and overexpression are discussed with respect to their advantages and disadvantages, when to test (at initial diagnosis or pre-treatment), where to test (locally or centralized) and the need for quality assurance to ensure accurate and valid testing results

Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis work was supported by a research grant from the Ludwig-Maximilians University of Munich (Förderprogramm für Forschung und Lehre [FöFoLe], grant number 865/829)

Dancing in time: feasibility and acceptability of a contemporary dance programme to modify risk factors for falling in community dwelling older adults

Background: Falls are a common cause of injury in older adults, with the prevention of falls being a priority for public health departments around the world. This study investigated the feasibility, and impact of an 8 week contemporary dance programme on modifiable physical (physical activity status, mobility, sedentary behaviour patterns) and psychosocial (depressive state, fear of falling) risk factors for falls. Methods: An uncontrolled ‘pre-post’ intervention design was used. Three groups of older (60 yrs.+) adults were recruited from local community groups to participate in a 3 separate, 8 week dance programmes. Each programme comprised two, 90 min dance classes per week. Quantitative measures of physical activity, sedentary behaviour, depression, mobility and fear of falling were measured at baseline (T1) and after 8 weeks of dance (T2). Weekly attendance was noted, and post-study qualitative work was conducted with participants in 3 separate focus groups. A combined thematic analysis of these data was conducted. Results: Of the 38 (Mean Age = 77.3 ± 8.4 yrs., 37 females) who attended the dance sessions, 22 (21 females; 1 male; mean age = 74.8, ±8.44) consented to be part of the study. Mean attendance was 14.6 (±2.6) sessions, and mean adherence was 84.3% (±17). Significant increases in moderate and vigorous physical activity were noted, with a significant decrease in sitting time over the weekdays (p < 0.05). Statistically significant decreases in the mean Geriatric Depression Scale (p < 0.05) and fear of falling (p < 0.005) score were noted, and the time taken to complete the TUG test decreased significantly from 10.1 s to 7.7 s over the 8 weeks (p < 0.005). Themes from the focus groups included the dance programme as a means of being active, health Benefits, and dance-related barriers and facilitators. Conclusions: The recruitment of older adults, good adherence and favourability across all three sites indicate that a dance programme is feasible as an intervention, but this may be limited to females only. Contemporary dance has the potential to positively affect the physical activity, sitting behaviour, falls related efficacy, mobility and incidence of depression in older females which could reduce their incidence of falls. An adequately powered study with control groups are required to test this intervention further

Inter-phylum circulation of a beta-lactamase-encoding gene: a rare but observable event.

Beta-lactamase-mediated degradation of beta-lactams is the most common mechanism of beta-lactam resistance in Gram-negative bacteria. Beta-lactamase-encoding genes can be transferred between closely related bacteria, but spontaneous inter-phylum transfers (between distantly related bacteria) have never been reported. Here, we describe an extended-spectrum beta-lactamase (ESBL)-encoding gene (bla &lt;sub&gt;MUN-1&lt;/sub&gt; ) shared between the Pseudomonadota and Bacteroidota phyla. An Escherichia coli strain was isolated from a patient in Münster (Germany). Its genome was sequenced. The ESBL-encoding gene (named bla &lt;sub&gt;MUN-1&lt;/sub&gt; ) was cloned, and the corresponding enzyme was characterized. The distribution of the gene among bacteria was investigated using the RefSeq Genomes database. The frequency and relative abundance of its closest homolog in the global microbial gene catalog (GMGC) were analyzed. The E. coli strain exhibited two distinct morphotypes. Each morphotype possessed two chromosomal copies of the bla &lt;sub&gt;MUN-1&lt;/sub&gt; gene, with one morphotype having two additional copies located on a phage-plasmid p0111. Each copy was located within a 7.6-kb genomic island associated with mobility. bla &lt;sub&gt;MUN-1&lt;/sub&gt; encoded for an extended-spectrum Ambler subclass A2 beta-lactamase with 43.0% amino acid identity to TLA-1. bla &lt;sub&gt;MUN-1&lt;/sub&gt; was found in species among the Bacteroidales order and in Sutterella wadsworthensis (Pseudomonadota). Its closest homolog in GMGC was detected frequently in human fecal samples. This is, to our knowledge, the first reported instance of inter-phylum transfer of an ESBL-encoding gene, between the Bacteroidota and Pseudomonadota phyla. Although the gene was frequently detected in the human gut, inter-phylum transfer was rare, indicating that inter-phylum barriers are effective in impeding the spread of ESBL-encoding genes, but not entirely impenetrable

What is the Role of Acid-Acid Interactions in Asymmetric Phosphoric Acid Organocatalysis? A Detailed Mechanistic Study using Interlocked and Non-Interlocked Catalysts

Organocatalysis has revolutionized asymmetric synthesis. However, the supramolecular interactions of organocatalysts in solution are often neglected, although the formation of catalyst aggregates can have a strong impact on the catalytic reaction. For phosphoric acid based organocatalysts, we have now established that catalyst-catalyst interactions can be suppressed by using macrocyclic catalysts, which react predominantly in a monomeric fashion, while they can be favored by integration into a bifunctional catenane, which react mainly as phosphoric acid dimers. For acyclic phosphoric acids, we found a strongly concentration dependent behavior, involving both monomeric and dimeric catalytic pathways. Based on a detailed experimental analysis, DFT-calculations and a direct NMR-based observation of the catalyst aggregates, we could demonstrate that intermolecular acid-acid interactions have a drastic influence on the reaction rate and stereoselectivity of the asymmetric transfer-hydrogenation catalyzed by chiral phosphoric acids

ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer

Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.POCI/CVT/62940/2004 and by the PhD grants (SFRH/BD/23406/2005 and SFRH/BD/31754/2006, of the Science and Technology Foundation (FCT) from Portugal