Identifying Barriers and Facilitators for Increasing Uptake of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in British Columbia, Canada, using the Consolidated Framework for Implementation Research

Background: Care gaps remain in modern health care despite the availability of robust, evidence-based medications. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated profound benefits in improving both cardiovascular and kidney outcomes in patients, the uptake of these medications remain suboptimal, and the causes have not been systematically explored. Objective: The purpose of this study was to use the Consolidated Framework for Implementation Research (CFIR) to describe the barriers and facilitators faced by clinicians in British Columbia, Canada, when prescribing an SGLT2 inhibitor. To achieve this, we conducted semistructured interviews using the CFIR with practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Design: Semistructured interviews. Setting: British Columbia, Canada. Participants: Actively practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Methods: Twenty-one clinicians were interviewed using questions derived from the CFIR. The audio recordings were transcribed verbatim, and each transcription was individually analyzed in duplicate using thematic analysis. The analysis focused on identifying barriers and facilitators to using SGLT2 inhibitors in clinical practice and coded using the CFIR constructs. Once the transcriptions were coded, overarching themes were created. Results: Five overarching themes were identified to the barriers and facilitators to using SGLT2 inhibitors: current perceptions and beliefs, clinician factors, patient factors, medication factors, and health care system factors. The current perceptions and beliefs were that SGLT2 inhibitors are efficacious and have distinct advantages over other agents but are underutilized in British Columbia. Clinician factors included varying levels of knowledge of and comfort in prescribing SGLT2 inhibitors, and patient factors included intolerable adverse events and additional pill burden, but many were enthusiastic about potential benefits. Multiple SGLT2 inhibitor related adverse events like mycotic infections and euglycemic diabetic ketoacidosis and the difficulty in obtaining reimbursement for these medications were also identified as a barrier to prescribing these medications. Facilitators for the use of SGLT2 inhibitors included consensus among colleagues, influential leaders, and peers in support of their use, and endorsement by national guidelines. Limitations: The experience from the clinicians regarding costs and the reimbursement process is limited to British Columbia as each province has its own procedures. There may be responder bias as clinicians were approached through purposive sampling. Conclusion: This study highlights different themes to the barriers and facilitators of using SGLT2 inhibitors in British Columbia. The identification of these barriers provides a specific target for improvement, and the facilitators can be leveraged for the increased use of SGLT2 inhibitors. Efforts to address and optimize these barriers and facilitators in a systematic approach may lead to an increase in the use of these efficacious medications

PLE induction results in accelerated cell lysis.

<p>(A) Survival of <i>V</i>. <i>cholerae</i> 15 minutes after infection with ICP1_2006_E ΔCRISPR at an MOI = 5. (B) OD₆₀₀ values of phage-infected PLE^- versus PLE-containing strains of <i>V</i>. <i>cholerae</i>. Strains were grown to OD₆₀₀ = 0.3 and then infected with ICP1_2006_E ΔCRISPR at an MOI = 5. Representative curves are based on results from three independent assays. (C) Cell lysis dynamics of phage-infected PLE^- versus PLE 1-containing strains of <i>V</i>. <i>cholerae</i> as determined by fluorescence microscopy following infection with ICP1_2006_E ΔCRISPR at an MOI = 5. Quantification of three independent biological replicates of (D), which show selected images of representative of PLE^- and PLE 1 <i>V</i>. <i>cholerae</i> infected with ICP1_2006_E ΔCRISPR over time. Samples were stained with the membrane stain FM 4–64 (red), and the DNA stain Sytox Green (green). For panels A and C, error bars indicate standard deviations of biological triplicates.</p

PLE-mediated ICP1 inhibition blocks phage burst and decreases phage genome replication.

<p>(A) One-step growth curve of phage ICP1_2006_E ΔCRISPR on <i>V</i>. <i>cholerae</i> +/- PLE 1. Starting PFU values (~10⁵) represent unabsorbed phage (<1%). These data, and one-step growth curves performed for the other PLEs, were used to calculate the average burst size of ICP1_2006_E ΔCRISPR on <i>V</i>. <i>cholerae</i> with or without the PLE indicated shown in (B). (C) Phage genome replication after infection of <i>V</i>. <i>cholerae</i> PLE 1^+/- with ICP1_2011_A ΔCRISPR as determined by qPCR. To determine fold change, samples 10 and 20 minutes post-infection were compared to the input sampled immediately after adding phage. For all panels, error bars indicate standard deviations of biological triplicates.</p

PLEs are mobilized following infection by ICP1-related phages.

<p>(A) PLE transducing units produced during infection with ICP1_2006_E ΔCRISPR. When the donor strain was a PLE variant harboring the kanamycin resistance cassette elsewhere in the chromosome (designated as chr::<i>kan</i>), no transduction could be detected, but we included only the PLE 1 variant for simplicity. The dashed line indicates the limit of detection for this assay. (B) PLE 1 integration into the <i>V</i>. <i>cholerae</i> superintegron. The <i>V</i>. <i>cholerae</i> superintegron is schematized in the top row: the superintegron integrase gene (<i>intI4)</i> with proximal and distal ORFs defining the superintegron boundaries are shown. ORFs are indicated by white boxes with 3 digit numbers corresponding to the VCA0XXX designation as observed in the N16961 reference genome. The position of PLE 1 in clinical isolates and four recipients generated by ICP1-mediated transduction is indicated by the PLE flanking genes within the superintegron. (C) Experimental PLE 1 transductants show resistance to ICP1 regardless of the position of PLE 1 within the superintegron. The sensitivity of each of the four PLE 1 recipients in (B) to ICP1_2011_A lacking CRISPR is shown. For panel A, error bars indicate standard deviations of biological triplicates.</p

PLEs are induced by and protect against ICP1-related phages.

<p>(A) Agarose gel analysis of PCR products to detect circularized PLE following infection with ICP1_2005_A. The approximate locations of the primers used to detect circularized PLE (black arrows) are indicated on the schematic representation of a PLE integrated into chromosome II of <i>V</i>. <i>cholerae</i>. The resulting bands vary expectedly in size depending on the specific primer pair used to amplify the junction and all PCR products were confirmed by sequencing. (B) The sensitivity of each strain (top row) to different ICP1 isolates lacking CRISPR-Cas (left column) is shown. The efficiency of plaquing (which is the plaque count on the PLE⁺ host strain divided by that on the PLE^- host strain) is ~1 where plaques formed, and below the limit of detection (10⁻⁸) for phages that did not produce plaques.</p

Conserved PLEs are a persistent feature of the <i>V</i>. <i>cholerae</i> mobilome.

<p>(A) Genomic organization and alignment of <i>V</i>. <i>cholerae</i> PLEs. Alignments were performed in MAUVE using the progressiveMAUVE algorithm [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006838#pgen.1006838.ref035" target="_blank">35</a>]. Parts of the similarity plot that are colored lavender are conserved among all five genomes, with the height of the histogram representing nucleotide sequence identity. Regions conserved only among subsets of the PLEs are color coded differently. White regions correspond to unaligned sequences that contain sequence elements specific to each PLE. The dashed lines indicate regions in each PLE with shared sequence identity and serve as orientation points. Annotated genes are shown to scale as black outlined boxes, with genes transcribed from the reverse strand shifted downward. The integrase (<i>int</i>) and genes encoding hypothetical proteins (with numerical ORF designations) are indicated, and those with conserved domains are identified in red as described in the text. Core proteins [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006838#pgen.1006838.ref036" target="_blank">36</a>] encoded by all PLEs are indicated in yellow. (B) History of PLE prevalence in >200 <i>V</i>. <i>cholerae</i> strains isolated between 1949–2011 [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006838#pgen.1006838.ref019" target="_blank">19</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006838#pgen.1006838.ref020" target="_blank">20</a>]. The date range indicated represents the earliest and latest isolation of a given PLE⁺ isolate, and the number corresponds to the numerical PLE designation in panel A. (C) PLEs are found integrated into the <i>V</i>. <i>cholerae</i> small chromosome. ORFs are indicated by white boxes with 3 digit numbers corresponding to the VCA0XXX designation as observed in the N16961 reference genome. The flanking genes indicate the position of each PLE in clinical isolates. The positions of VCRs in the immediate vicinity of each PLE (if applicable) are shown. Diagram is not to scale.</p

Dangerously empty? Hegemony and the construction of the Irish entrepreneur

In this paper we build on Jones and Spicer\u27s (2009) conceptualisation of the entrepreneur as an empty signifier. We explore the function of the signifier \u27entrepreneurship\u27 within a social context marked by crisis: Ireland 2007 to 2010. In doing so, we show how its articulation by government acted to legitimise the continuation of market logics and, relatedly, the existing political status quo. Theoretically, we demonstrate the usefulness of Laclau and Mouffe\u27s conception of hegemony, which shares a Lacanian legacy with Jones and Spicer. This helps us to understand the contradictory nature of the signifier of the entrepreneur in Irish political and social discourse, along with its relationship to the reproduction of political hegemony