Describing interruptions, multi-tasking and task-switching in the community pharmacy: A qualitative study in England

Background: There is growing evidence base around interruptions and distractions in the community pharmacy setting. There is also evidence to suggest these practices may be associated with dispensing errors. Up to date, qualitative research on this subject is limited. Objective: To explore interruptions and distractions in the community setting; utilising an ethnographic approach to be able to provide a detailed description of the circumstances surrounding such practices. Setting: Community pharmacies in England, July to October 2011. Method: An ethnographic approach was taken. Non participant, unstructured observations were utilised to make records of pharmacists’ every activities. Case studies were formed by combining field notes with detailed information on pharmacists and their respective pharmacy businesses. Content analysis was undertaken both manually and electronically, utilising NVivo 10. Results: Response rate was 12% (n=11). Over fifteen days, a total of 123 hours and 58 minutes of observations were recorded in 11 separate pharmacies of 11 individual pharmacists. The sample was evenly split by gender (female n=6; male n=5) and pharmacy ownership (independent n=5; multiple n=6). Employment statuses included employee pharmacists (n=6), owners (n=4) and a locum (n=1). Average period of registration as a pharmacist was 19 years (range 5-39 years). Average prescriptions busyness of pharmacies ranged from 2,600 – 24,000 items dispensed per month. Two key themes were: “Interruptions and task-switching” and “distractions and multi-tasking.” All observed pharmacists’ work was dominated by interruptions, task-switches, distractions and multi-tasking, often to manage a barrage of conflicting demands. These practices were observed to be part of a deep-rooted culture in the community setting. Directional work maps illustrated the extent and direction of task switching employed by pharmacists. Conclusions: In this study pharmacists’ working practices were permeated by interruptions and multi-tasking. These practices are inefficient and potentially reduce patient safety in terms of dispensing accuracy

Ischemia and Infarction in STEMI Patients With Multivessel Disease : Insights From the CvLPRIT Nuclear Substudy

The CvLPRIT (Complete versus Lesion-only PRimary PCI Trial) trial was undertaken in 7 UK centers (1,2). Patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary stenoses were randomized to primary percutaneous coronary intervention (PPCI) to the infarct-related artery (IRA) only, or complete revascularization. At 12-month follow-up, the rate of the combined primary endpoint (all-cause mortality, recurrent MI, heart failure, ischemia-driven revascularization) was lower after complete revascularization. All surviving patients were asked to undergo myocardial perfusion scintigraphy (MPS) 6 to 8 weeks post-admission. It was expected that this a priori nuclear substudy would provide mechanistic insights into the outcome of the main trial, and help to define the clinical role of MPS in the PPCI era

Power and Authority in Eastern Christian Experience: Papers of the Sophia Institute Academic Conference New York, December 2010

The essays in this volume were delivered at the Third Annual Conference of the Sophia Institute in December 2010 at Union Theological Seminary in New York City. The theme of that conference, “Power and Authority in Eastern Christian Experience,” brought forth a diverse group of scholars who contributed their perspectives on the ways the Eastern Orthodox Church, in its broadest sense, has negotiated the notions of power, authority, (dis)obedience, and resistance over time and space. These insightful essays promise to draw the Orthodox world into a dynamic and productive discourse

Tumor Endothelial Cells with Distinct Patterns of TGF -Driven Endothelial-to-Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGFβ stimulation. Whereas some TEC strikingly up-regulate alpha smooth muscle actin (SMA), a principal marker of EndMT and activated myofibroblasts, counterpart normal mammary gland endothelial cells (NEC) showed little change in SMA expression after TGFβ treatment. Compared with NEC, SMA+ TEC were 40 % less motile in wound healing assays and formed more stable vascular-like networks in vitro when challenged with TGFβ. Lineage tracing using ZsGreenCdh5-Cre reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA+ TEC, suggesting that not all endothelial cells (EC) respond identically to TGFβ in vivo. Indeed, examination of 84 TGFβ-regulated target genes revealed entirely different genetic signatures in TGFβ-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGFβ-regulated genes but operates in tandem with TGFβ to up-regulate others. EC challenged with TGFβ secrete bFGF which blocks SMA expression in secondary cultures suggesting a cell-autonomous or lateral-inhibitory mechanism for impeding mesenchymal differentiation. Together, our results suggest that TGFβ-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

In Vivo Expression Pattern of MICA and MICB and Its Relevance to Auto-Immunity and Cancer

Non-conventional MHC class I MIC molecules interact not with the TCR, but with NKG2D, a C-type lectin activatory receptor present on most NK, γδ and CD8+ αβ T cells. While this interaction is critical in triggering/calibrating the cytotoxic activity of these cells, the actual extent of its in vivo involvement, in man, in infection, cancer or autoimmunity, needs further assessment. The latter has gained momentum along with the reported expansion of peripheral CD4+CD28−NKG2D+ T cells in rheumatoid arthritis (RA). We first initiated to extend this report to a larger cohort of not only RA patients, but also those affected by systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In RA and SS, this initial observation was further tested in target tissues: the joint and the salivary glands, respectively. In conclusion and despite occasional and indiscriminate expansion of the previously incriminated T cell subpopulation, no correlation could be observed between the CD4+CD28−NKG2D+ and auto-immunity. Moreover, in situ, the presence of NKG2D matched that of CD8+, but not that of CD4+ T cells. In parallel, a total body tissue scan of both MICA and MICB transcription clearly shows that despite original presumptions, and with the exception of the central nervous system, both genes are widely transcribed and therefore possibly translated and membrane-bound. Extending this analysis to a number of human tumors did not reveal a coherent pattern of expression vs. normal tissues. Collectively these data question previous assumptions, correlating a tissue-specific expression/induction of MIC in relevance to auto-immune or tumor processes

Impaired RNA incorporation and dimerization in live attenuated leader-variants of SIV(mac239)

BACKGROUND: The 5' untranslated region (UTR) or leader sequence of simian immunodeficiency virus (SIV(mac239)) is multifunctional and harbors the regulatory elements for viral replication, persistence, gene translation, expression, and the packaging and dimerization of viral genomic RNA (vRNA). We have constructed a series of deletions in the SIV(mac239 )leader sequence in order to determine the involvement of this region in both the packaging and dimerization of viral genomic RNA. We also assessed the impact of these deletions upon viral infectiousness, replication kinetics and gene expression in cell lines and monkey peripheral blood mononuclear cells (PBMC). RESULTS: Regions on both sides of the major splice donor (SD) were found to be necessary for the efficiency and specificity of viral genome packaging. However, stem-loop1 is critical for both RNA encapsidation and dimerization. Downstream elements between the splice donor and the initiation site of SIV-Gag have additive effects on RNA packaging and contribute to a lesser degree to RNA dimerization. The targeted disruption of structures on both sides of the SD also severely impacts viral infectiousness, gene expression and replication in both CEMx174 cells and rhesus PBMC. CONCLUSION: In the leader region of SIV(mac239), stem-loop1 functions as the primary determinant for both RNA encapsidation and dimerization. Downstream elements between the splice donor and the translational initiation site of SIV-Gag are classified as secondary determinants and play a role in dimerization. Collectively, these data signify a linkage between the primary encapsidation determinant of SIV(mac239 )and RNA dimerization

Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.

Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin

Reference values for wrist-worn accelerometer physical activity metrics in England children and adolescents

Background: Over the last decade use of raw acceleration metrics to assess physical activity has increased. Metrics such as Euclidean Norm Minus One (ENMO), and Mean Amplitude Deviation (MAD) can be used to generate metrics which describe physical activity volume (average acceleration), intensity distribution (intensity gradient), and intensity of the most active periods (MX metrics) of the day. Presently, relatively little comparative data for these metrics exists in youth. To address this need, this study presents age- and sex-specific reference percentile values in England youth and compares physical activity volume and intensity profiles by age and sex. Methods: Wrist-worn accelerometer data from 10 studies involving youth aged 5 to 15 y were pooled. Weekday and weekend waking hours were first calculated for youth in school Years (Y) 1&2, Y4&5, Y6&7, and Y8&9 to determine waking hours durations by age-groups and day types. A valid waking hours day was defined as accelerometer wear for ≥ 600 min·d−1 and participants with ≥ 3 valid weekdays and ≥ 1 valid weekend day were included. Mean ENMO- and MAD-generated average acceleration, intensity gradient, and MX metrics were calculated and summarised as weighted week averages. Sex-specific smoothed percentile curves were generated for each metric using Generalized Additive Models for Location Scale and Shape. Linear mixed models examined age and sex differences. Results: The analytical sample included 1250 participants. Physical activity peaked between ages 6.5–10.5 y, depending on metric. For all metrics the highest activity levels occurred in less active participants (3rd-50th percentile) and girls, 0.5 to 1.5 y earlier than more active peers, and boys, respectively. Irrespective of metric, boys were more active than girls (p < .001) and physical activity was lowest in the Y8&9 group, particularly when compared to the Y1&2 group (p < .001). Conclusions: Percentile reference values for average acceleration, intensity gradient, and MX metrics have utility in describing age- and sex-specific values for physical activity volume and intensity in youth. There is a need to generate nationally-representative wrist-acceleration population-referenced norms for these metrics to further facilitate health-related physical activity research and promotion

Precision and accuracy of single-molecule FRET measurements - a multi-laboratory benchmark study

Single-molecule Förster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods