A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.

The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.

Do policy-makers find commissioned rapid reviews useful?

BACKGROUND: Rapid reviews are increasingly used by policy agencies to access relevant research in short timeframes. Despite the growing number of programmes, little is known about how rapid reviews are used by health policy agencies. This study examined whether and how rapid reviews commissioned using a knowledge brokering programme were used by Australian policy-makers. METHODS: This study used interview data to examine the use of 139 rapid reviews by health policy agencies that were commissioned between 2006 and 2015. Transcripts were coded to identify how rapid reviews were used, the type of policy processes in which they were used, what evidence of use was provided and what reasons were given when rapid reviews were not used. Fisher's exact test was used to assess variation between types of agencies. RESULTS: Overall, 89% of commissioned rapid reviews were used by the commissioning agencies and 338 separate instances of use were identified, namely, on average, three uses per review. Policy-makers used reviews primarily to determine the details of a policy or programme, identify priorities for future action or investment, negotiate interjurisdictional decisions, evaluate alternative solutions for a policy problem, and communicate information to stakeholders. Some variation in use was observed across agencies. Reasons for non-use were related to changes in organisational structures, resources or key personnel in the commissioning agencies, or changes in the broader political environment. CONCLUSIONS: This study found that almost all rapid reviews had been used by the agencies who commissioned them, primarily in policy and programme development, agenda-setting, and to communicate information to stakeholders. Reviews were used mostly in instrumental and conceptual ways and there was little evidence of symbolic use. Variations in use were identified across agencies. The findings suggest that commissioned rapid reviews are an effective means of providing timely relevant research for use in policy processes and that review findings may be applied in a variety of ways.

What can we learn from interventions that aim to increase policy-makers' capacity to use research? A realist scoping review.

BACKGROUND: Health policy-making can benefit from more effective use of research. In many policy settings there is scope to increase capacity for using research individually and organisationally, but little is known about what strategies work best in which circumstances. This review addresses the question: What causal mechanisms can best explain the observed outcomes of interventions that aim to increase policy-makers' capacity to use research in their work? METHODS: Articles were identified from three available reviews and two databases (PAIS and WoS; 1999-2016). Using a realist approach, articles were reviewed for information about contexts, outcomes (including process effects) and possible causal mechanisms. Strategy + Context + Mechanism = Outcomes (SCMO) configurations were developed, drawing on theory and findings from other studies to develop tentative hypotheses that might be applicable across a range of intervention sites. RESULTS: We found 22 studies that spanned 18 countries. There were two dominant design strategies (needs-based tailoring and multi-component design) and 18 intervention strategies targeting four domains of capacity, namely access to research, skills improvement, systems improvement and interaction. Many potential mechanisms were identified as well as some enduring contextual characteristics that all interventions should consider. The evidence was variable, but the SCMO analysis suggested that tailored interactive workshops supported by goal-focused mentoring, and genuine collaboration, seem particularly promising. Systems supports and platforms for cross-sector collaboration are likely to play crucial roles. Gaps in the literature are discussed. CONCLUSION: This exploratory review tentatively posits causal mechanisms that might explain how intervention strategies work in different contexts to build capacity for using research in policy-making.

Filling the gap between evidence, policy and practice: are 45 and Up Study researchers planning for impact?

AIM: To improve health outcomes, policy and practice decisions should be guided by relevant and timely evidence. High-quality, large-scale population data could play an essential role in supporting evidence-based decision making. The 45 and Up Study is a long-term, large-scale cohort study with more 250 000 participants aged 45 years and over from New South Wales (NSW), Australia. Data collected by the Study is accessible to researchers, government and non-governmental bodies. The study aimed to identify the proportion of researchers using data from the Study who intended to have an impact and achieved impact; the types of impact they intended and achieved; and the pathways through which they achieved it. METHODS: Using data extracted from the application, progress and final report documents for 25 projects using 45 and Up Study data from January 2011 until December 2017, we a) determined the proportion of projects that intended to have policy or practice impact and b) described the type of policy and practice impact achieved. RESULTS: We found that 88% (n = 22) of projects intended to have a policy or practice impact. Of those, 68% (n = 15) planned to influence or inform a policy or program, and 41% (n = 9) planned to share findings at conferences or in journals. Almost half of projects with intended impact (45%, n = 10) did not state how they planned to achieve impact. Approximately 16% of all projects (n = 4) reported achieving an impact on policy or services. The type of impact achieved by all four of these projects was influencing, informing or changing a policy or program. One of these four projects also achieved a change to legislation or regulation. CONCLUSIONS: Further strategies to promote a targeted approach to impact planning in research projects using datasets such as the 45 and Up Study would help guide researchers in achieving impact.

Both clinical and environmental Caulobacter species are virulent in the Galleria mellonella infection model.

The Caulobacter genus, including the widely-studied model organism Caulobacter crescentus, has been thought to be non-pathogenic and thus proposed as a bioengineering vector for various environmental remediation and medical purposes. However, Caulobacter species have been implicated as the causative agents of several hospital-acquired infections, raising the question of whether these clinical isolates represent an emerging pathogenic species or whether Caulobacters on whole possess previously-unappreciated virulence capability. Given the proposed environmental and medical applications for C. crescentus, understanding the potential pathogenicity of this bacterium is crucial. Consequently, we sequenced a clinical Caulobacter isolate to determine if it has acquired novel virulence determinants. We found that the clinical isolate represents a new species, Caulobacter mirare that, unlike C. crescentus, grows well in standard clinical culture conditions. C. mirare phylogenetically resembles both C. crescentus and the related C. segnis, which was also thought to be non-pathogenic. The similarity to other Caulobacters and lack of obvious pathogenesis markers suggested that C. mirare is not unique amongst Caulobacters and that consequently other Caulobacters may also have the potential to be virulent. We tested this hypothesis by characterizing the ability of Caulobacters to infect the model animal host Galleria mellonella. In this context, two different lab strains of C. crescentus proved to be as pathogenic as C. mirare, while lab strains of E. coli were non-pathogenic. Further characterization showed that Caulobacter pathogenesis in the Galleria model is mediated by lipopolysaccharide (LPS), and that differences in LPS chemical composition across species could explain their differential toxicity. Taken together, our findings suggest that many Caulobacter species can be virulent in specific contexts and highlight the importance of broadening our methods for identifying and characterizing potential pathogens.

Increasing the use of research in population health policies and programs: a rapid review.

BACKGROUND AND OBJECTIVES: Although the body of literature on factors that impede and enhance the use of research in policy making continues to expand, there is limited evidence about strategies that are effective at fostering the use of research in population health policy and programs. Building on previous reviews, we reviewed the published literature to identify and assess papers describing intervention studies that had outcome measures relating to research use. STUDY TYPE: Rapid review. METHODS: We searched four academic databases and Google Scholar to identify papers published between 2009 and 2015. Our focus was on strategies relevant to population health policy and program delivery. For studies that tested strategies to increase the use of research, we extracted details about the intervention, participants, study sites and methods, and primary and other outcomes. RESULTS: We identified 14 articles reporting on 13 intervention studies. The studies were relatively weak methodologically and together provide few indications of effect. Only one study used an experimental design and one other used pre-/post-test design; the remaining studies were characterised by an absence of control groups, small sample sizes, and self-report data. Of the 13 studies: four intervention studies were related to the theme 'relevant, useful, accessible research'; five studies (described in six papers) tested strategies that facilitated interaction between researchers and research users; three studies assessed strategies aimed at enhancing the capacity of organisations to use research; and one intervention study was related to the theme 'funding research infrastructure and research projects'. CONCLUSION: The level of evidence for the effectiveness of strategies to improve the use of research in policy making is low, and there remains a need for well-designed empirical studies that evaluate interventions. In the absence of strong evidence, efforts to enhance research use should be tailored to organisational needs and may incorporate capability development, improved access to targeted research summaries and syntheses, and greater interaction and collaboration with researchers.

Does knowledge brokering improve the quality of rapid review proposals? A before and after study.

BACKGROUND: Rapid reviews are increasingly being used to help policy makers access research in short time frames. A clear articulation of the review's purpose, questions, scope, methods and reporting format is thought to improve the quality and generalisability of review findings. The aim of the study is to explore the effectiveness of knowledge brokering in improving the perceived clarity of rapid review proposals from the perspective of potential reviewers. To conduct the study, we drew on the Evidence Check program, where policy makers draft a review proposal (a pre knowledge brokering proposal) and have a 1-hour session with a knowledge broker, who re-drafts the proposal based on the discussion (a post knowledge brokering proposal). METHODS: We asked 30 reviewers who had previously undertaken Evidence Check reviews to examine the quality of 60 pre and 60 post knowledge brokering proposals. Reviewers were blind to whether the review proposals they received were pre or post knowledge brokering. Using a six-point Likert scale, reviewers scored six questions examining clarity of information about the review's purpose, questions, scope, method and format and reviewers' confidence that they could meet policy makers' needs. Each reviewer was allocated two pre and two post knowledge brokering proposals, randomly ordered, from the 60 reviews, ensuring no reviewer received a pre and post knowledge brokering proposal from the same review. RESULTS: The results showed that knowledge brokering significantly improved the scores for all six questions addressing the perceived clarity of the review proposal and confidence in meeting policy makers' needs; with average changes of 0.68 to 1.23 from pre to post across the six domains. CONCLUSIONS: This study found that knowledge brokering increased the perceived clarity of information provided in Evidence Check rapid review proposals and the confidence of reviewers that they could meet policy makers' needs. Further research is needed to identify how the knowledge brokering process achieves these improvements and to test the applicability of the findings in other rapid review programs.

Barriers and facilitators to evaluation of health policies and programs: Policymaker and researcher perspectives.

Our research sought to identify the barriers and facilitators experienced by policymakers and evaluation researchers in the critical early stages of establishing an evaluation of a policy or program. We sought to determine the immediate barriers experienced at the point of initiating or commissioning evaluations and how these relate to broader system factors previously identified in the literature. We undertook 17 semi-structured interviews with a purposive sample of senior policymakers (n=9) and senior evaluation researchers (n=8) in Australia. Six themes were consistently raised by participants: political influence, funding, timeframes, a 'culture of evaluation', caution over anticipated results, and skills of policy agency staff. Participants also reflected on the dynamics of policy-researcher relationships including different motivations, physical and conceptual separation of the policy and researcher worlds, intellectual property concerns, and trust. We found that political and system factors act as macro level barriers to good evaluation practice that are manifested as time and funding constraints and contribute to organisational cultures that can come to fear evaluation. These factors then fed into meso and micro level factors. The dynamics of policy-researcher relationship provide a further challenge to evaluating government policies and programs.