A systematic review of electronic patient records using the meta-narrative approach: Empirical findings and methodological challenges.

Systematic reviews are central to the enterprise of evidence-based medicine (EBM). However, traditional ‘Cochrane’ reviews have major limitations, especially when dealing with heterogeneous methodologies or an applied setting. The meta-narrative review (see Soc Sci Med 2005; 61: 417-30) is one of several new methods that seek to address pragmatic policy-level questions via broad-based literature reviews. Inspired by Kuhn, meta-narrative review takes a historical and paradigmatic approach to considering different areas of research activity. As an interpretive tool, the approach seeks distinct research traditions, each with its own meta-narrative. We then use these ‘stories of how research unfolded’ as a way of making sense of a diverse literature. Incommensurability between different traditions is seen not as a problem to be lamented or resolved but as a window to higher-order explanations about the nuances of empirical data and what these nuances mean for different applied situations. Having originally developed the meta-narrative method for a study of the diffusion of innovations in healthcare, we are now applying it in a review of the electronic patient record (EPR) in an organizational context. We have collated some 600 papers and books across multiple research traditions including health informatics, information systems research, computer-supported cooperative work (CSCW) and sociology. This very contemporary topic area is raising interesting methodological questions. For example, the EPR literature does not comprise as cleanly delineable traditions for four main reasons: 1. Information and communications technology research is a particularly fast-moving field, so paradigm shifts are relatively common (e.g. the rise of CSCW out of human-computer interaction research). 2. In the electronic age, it is easy for researchers to explore beyond their own discipline and ‘borrow’ theories, ideas and methods from elsewhere. Journal editors may commission overviews from experts in another tradition; authors may explicitly address an audience in another tradition. Research traditions can begin to converge (e.g. papers bringing together CSCW, information systems research and STS). 3. Some researchers are adept ‘boundary spanners’, writing for a number of different academic audiences and adapting their theoretical pedigree to fit (e.g. Marc Berg). 4. Some traditions are characterized not by a single unified paradigm but by active dialogue between competing paradigms (e.g. ‘hard’ versus ‘soft’ perspectives on knowledge management). This work contributes to the STS literature by critically questioning the nature of rigour in secondary research. The EBM movement values ‘Cochrane’ reviews because they meet positivist criteria (e.g. they are rational, objective, replicable, data-led, and transferable across contexts). In contrast, the meta-narrative review is interpretive, reflexive, problem-oriented and work-led, and makes no claim to either replicability or transferability. Rigour is redefined in terms of plausibility, authenticity and usefulness – raising the radical suggestion that the evidence base for key policy decisions can never be set in stone. Systematic reviews are central to the enterprise of evidence-based medicine (EBM). However, traditional ‘Cochrane’ reviews have major limitations, especially when dealing with heterogeneous methodologies or an applied setting. The meta-narrative review (see Soc Sci Med 2005; 61: 417-30) is one of several new methods that seek to address pragmatic policy-level questions via broad-based literature reviews. Inspired by Kuhn, meta-narrative review takes a historical and paradigmatic approach to considering different areas of research activity. As an interpretive tool, the approach seeks distinct research traditions, each with its own meta-narrative. We then use these ‘stories of how research unfolded’ as a way of making sense of a diverse literature. Incommensurability between different traditions is seen not as a problem to be lamented or resolved but as a window to higher-order explanations about the nuances of empirical data and what these nuances mean for different applied situations. Having originally developed the meta-narrative method for a study of the diffusion of innovations in healthcare, we are now applying it in a review of the electronic patient record (EPR) in an organizational context. We have collated some 600 papers and books across multiple research traditions including health informatics, information systems research, computer-supported cooperative work (CSCW) and sociology. This very contemporary topic area is raising interesting methodological questions. For example, the EPR literature does not comprise as cleanly delineable traditions for four main reasons: 1. Information and communications technology research is a particularly fast-moving field, so paradigm shifts are relatively common (e.g. the rise of CSCW out of human-computer interaction research). 2. In the electronic age, it is easy for researchers to explore beyond their own discipline and ‘borrow’ theories, ideas and methods from elsewhere. Journal editors may commission overviews from experts in another tradition; authors may explicitly address an audience in another tradition. Research traditions can begin to converge (e.g. papers bringing together CSCW, information systems research and STS). 3. Some researchers are adept ‘boundary spanners’, writing for a number of different academic audiences and adapting their theoretical pedigree to fit (e.g. Marc Berg). 4. Some traditions are characterized not by a single unified paradigm but by active dialogue between competing paradigms (e.g. ‘hard’ versus ‘soft’ perspectives on knowledge management). This work contributes to the STS literature by critically questioning the nature of rigour in secondary research. The EBM movement values ‘Cochrane’ reviews because they meet positivist criteria (e.g. they are rational, objective, replicable, data-led, and transferable across contexts). In contrast, the meta-narrative review is interpretive, reflexive, problem-oriented and work-led, and makes no claim to either replicability or transferability. Rigour is redefined in terms of plausibility, authenticity and usefulness – raising the radical suggestion that the evidence base for key policy decisions can never be set in stone

Rewritable nanoscale oxide photodetector

Nanophotonic devices seek to generate, guide, and/or detect light using structures whose nanoscale dimensions are closely tied to their functionality. Semiconducting nanowires, grown with tailored optoelectronic properties, have been successfully placed into devices for a variety of applications. However, the integration of photonic nanostructures with electronic circuitry has always been one of the most challenging aspects of device development. Here we report the development of rewritable nanoscale photodetectors created at the interface between LaAlO3 and SrTiO3. Nanowire junctions with characteristic dimensions 2-3 nm are created using a reversible AFM writing technique. These nanoscale devices exhibit a remarkably high gain for their size, in part because of the large electric fields produced in the gap region. The photoconductive response is gate-tunable and spans the visible-to-near-infrared regime. The ability to integrate rewritable nanoscale photodetectors with nanowires and transistors in a single materials platform foreshadows new families of integrated optoelectronic devices and applications.Comment: 5 pages, 5 figures. Supplementary Information 7 pages, 9 figure

Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and cerine residues in the Epstein-Barr Virus lytic switch protein

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with various malignancies, including Burkitt's lymphoma and nasopharyngeal carcinoma. Like all herpesviruses, the EBV life cycle alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and, in the switch to the lytic cycle, this epigenetic silencing is overturned. A key event is the activation of the viral BRLF1 gene by the immediate-early protein Zta. Zta is a bZIP transcription factor that preferentially binds to specific response elements (ZREs) in the BRLF1 promoter (Rp) when these elements are methylated. Zta's ability to trigger lytic cycle activation is severely compromised when a cysteine residue in its bZIP domain is mutated to serine (C189S), but the molecular basis for this effect is unknown. Here we show that the C189S mutant is defective for activating Rp in a Burkitt's lymphoma cell line. The mutant is compromised both in vitro and in vivo for binding two methylated ZREs in Rp (ZRE2 and ZRE3), although the effect is striking only for ZRE3. Molecular modeling of Zta bound to methylated ZRE3, together with biochemical data, indicate that C189 directly contacts one of the two methyl cytosines within a specific CpG motif. The motif's second methyl cytosine (on the complementary DNA strand) is predicted to contact S186, a residue known to regulate methyl-ZRE recognition. Our results suggest that C189 regulates the enhanced interaction of Zta with methylated DNA in overturning the epigenetic control of viral latency. As C189 is conserved in many bZIP proteins, the selectivity of Zta for methylated DNA may be a paradigm for a more general phenomenon

Multi-gap superconductivity in a BaFe1.84Co0.16As2 film from optical measurements at terahertz frequencies

We measured the THz reflectance properties of a high quality epitaxial thin film of the Fe-based superconductor BaFe$_{1.84}$Co$_{0.16}$As$_2$ with T$_c$=22.5 K. The film was grown by pulsed laser deposition on a DyScO$_3$ substrate with an epitaxial SrTiO$_3$ intermediate layer. The measured $R_S/R_N$ spectrum, i.e. the reflectivity ratio between the superconducting and normal state reflectance, provides clear evidence of a superconducting gap $\Delta_A$ close to 15 cm$^{-1}$. A detailed data analysis shows that a two-band, two-gap model is absolutely necessary to obtain a good description of the measured $R_S/R_N$ spectrum. The low-energy $\Delta_A$ gap results to be well determined ($\Delta_A$=15.5$\pm$0.5 cm$^{-1}$), while the value of the high-energy gap $\Delta_B$ is more uncertain ($\Delta_B$=55$\pm$7 cm$^{-1}$). Our results provide evidence of a nodeless isotropic double-gap scenario, with the presence of two optical gaps corresponding to 2$\Delta/kT_c$ values close to 2 and 7.Comment: Published Versio

Possible Conservation of the K -Quantum Number in Excited Rotating Nuclei

The \ensuremath{\gamma} cascades feeding into low-K and high-K bands in ${}^{163}$Er are investigated analyzing variances and covariance of the spectrum fluctuations. From a large data set of 1${0}^{9}$ triple coincidences, \ensuremath{\gamma}-\ensuremath{\gamma} coincidence spectra gated by resolved low-lying rotational bands are analyzed. Low-K bands are found to be fed by a much larger effective number of cascades than high-K bands. The covariance between pairs of gated spectra shows that the cascades feeding low-K bands are different from those feeding the high-K bands. The persistence of the K-selection rules for the excited rotational bands within the angular momentum region 30\ensuremath{\Elzxh}\ensuremath{\le}I\ensuremath{\le}40\ensuremath{\Elzxh} is suggested as explanation

Upregulation of the cell-cycle regulator RGC-32 in Epstein-Barr virus-immortalized cells

Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator

A Single Amino Acid Mutation in SNAP-25 Induces Anxiety-Related Behavior in Mouse

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic protein essential for neurotransmitter release. Previously, we demonstrate that protein kinase C (PKC) phosphorylates Ser187 of SNAP-25, and enhances neurotransmitter release by recruiting secretory vesicles near to the plasma membrane. As PKC is abundant in the brain and SNAP-25 is essential for synaptic transmission, SNAP-25 phosphorylation is likely to play a crucial role in the central nervous system. We therefore generated a mutant mouse, substituting Ser187 of SNAP-25 with Ala using “knock-in” technology. The most striking effect of the mutation was observed in their behavior. The homozygous mutant mice froze readily in response to environmental change, and showed strong anxiety-related behavior in general activity and light and dark preference tests. In addition, the mutant mice sometimes exhibited spontaneously occurring convulsive seizures. Microdialysis measurements revealed that serotonin and dopamine release were markedly reduced in amygdala. These results clearly indicate that PKC-dependent SNAP-25 phosphorylation plays a critical role in the regulation of emotional behavior as well as the suppression of epileptic seizures, and the lack of enhancement of monoamine release is one of the possible mechanisms underlying these defects

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors