Implementation of interventions targeting the uptake of genetic testing services for breast cancer risk: protocol for a systematic review.

INTRODUCTION: The timely identification of breast cancer-related pathogenic variants can help to identify the risk of potential disease development and determine healthcare choices. However, the uptake rate of genetic testing services for breast cancer risk remains low in many countries. Interventions targeting the uptake of these services among individuals potentially at risk for inherited breast cancer are often complex and have multiple components, and are therefore difficult to implement, replicate and disseminate to new contexts. Our aim is to systematically review studies targeting the uptake of genetic testing services for breast cancer risk and critically assess the quality of implementation outcomes and the reporting of intervention descriptions. METHODS AND ANALYSIS: PubMed, CINAHL, PsycINFO, Embase, Cochrane Library and all Campbell Coordinating Group databases will be searched for intervention studies that target individuals' participation in breast cancer genetic testing programmes. Papers published in English within the time period from January 2005 until October 2019 will be considered for inclusion. Titles, abstracts and full papers will be screened for eligibility by two pairs of reviewers independently. For data analysis and synthesis, study-level and intervention-level characteristics will be abstracted. We will present all implementation outcomes that are mentioned in each of the studies and register the number of studies that do not at all look at or report implementation outcomes. The quality of implementation will be checked using a 5-point rubric item, and the quality and completeness of reporting of intervention description will be evaluated using the 12-item Template for Intervention Description and Replication (TIDieR). ETHICS AND DISSEMINATION: Ethical approval is not required to conduct this review. Review findings will be disseminated to academic and non-specialist audiences via peer-reviewed academic journals and presented at appropriate conferences, workshops and meetings to policymakers, practitioners and organisations that work with our population of interest. PROSPERO REGISTRATION NUMBER: CRD42018105732.

Thioridazine affects transcription of genes involved in cell wall biosynthesis in methicillin-resistant Staphylococcus aureus.

The antipsychotic drug thioridazine is a candidate drug for an alternative treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in combination with the ß-lactam antibiotic oxacillin. The drug has been shown to have the capability to resensitize MRSA to oxacillin. We have previously shown that the expression of some resistance genes is abolished after treatment with thioridazine and oxacillin. To further understand the mechanism underlying the reversal of resistance, we tested the expression of genes involved in antibiotic resistance and cell wall biosynthesis in response to thioridazine in combination with oxacillin. We observed that the oxacillin-induced expression of genes belonging to the VraSR regulon is reduced by the addition of thioridazine. The exclusion of such key factors involved in cell wall biosynthesis will most likely lead to a weakened cell wall and affect the ability of the bacteria to sustain oxacillin treatment. Furthermore, we found that thioridazine itself reduces the expression level of selected virulence genes and that selected toxin genes are not induced by thioridazine. In the present study, we find indications that the mechanism underlying reversal of resistance by thioridazine relies on decreased expression of specific genes involved in cell wall biosynthesis.

Searching for small σB-regulated genes in Staphylococcus aureus.

In recent years, small RNAs (sRNAs) have been identified as important regulators of gene expression in bacteria. Most sRNAs are encoded from intergenic regions and are only expressed under highly specific growth conditions. In Staphylococcus aureus, the alternative sigma factor, σ(B), is known to contribute to the overall stress response, antibiotic resistance, and virulence. The σ(B) regulon in S. aureus is well described and comprises approximately 200 annotated genes, including several genes encoding virulence factors. In the present study, we have identified three novel σ(B)-dependent transcripts encoded from genomic regions previously annotated as intergenic. All three transcripts, named SbrA, SbrB, and SbrC, are highly conserved in S. aureus, and we confirmed their presence in four different isolates (SH1000, Newman, COL, and UAMS-1). Curiously, two of these genes (sbrA and sbrB) were found to contain open reading frames encoding small, highly basic peptides that are conserved among Staphylococci. The third transcript (SbrC) did not contain any likely open reading frame and thus constitute a genuine non-coding sRNA. The functions of these genes are currently unknown but are likely to be important for the σ(B)-mediated response of S. aureus to adverse conditions.

Identification of a sigma B-dependent small noncoding RNA in Listeria monocytogenes.

In Listeria monocytogenes, the alternative sigma factor sigma(B) plays important roles in stress tolerance and virulence. Here, we present the identification of SbrA, a novel small noncoding RNA that is produced in a sigma(B)-dependent manner. This finding adds the sigma(B) regulon to the growing list of stress-induced regulatory circuits that include small noncoding RNAs.

The two-component system CesRK controls the transcriptional induction of cell envelope-related genes in Listeria monocytogenes in response to cell wall-acting antibiotics.

The two-component system CesRK of Listeria monocytogenes responds to cell wall-acting antibiotics. We show here that CesRK controls the transcription of several cell envelope-related genes. The CesRK-dependent induction of these genes may be viewed as an attempt by L. monocytogenes to protect itself against the damaging effects of cell wall-acting antibiotics.