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1.  Evaluating an audit and feedback intervention for reducing antibiotic prescribing behaviour in general dental practice (the RAPiD trial): a partial factorial cluster randomised trial protocol 
Background
Antibiotic prescribing in dentistry accounts for 9% of total antibiotic prescriptions in Scottish primary care. The Scottish Dental Clinical Effectiveness Programme (SDCEP) published guidance in April 2008 (2nd edition, August 2011) for Drug Prescribing in Dentistry, which aims to assist dentists to make evidence-based antibiotic prescribing decisions. However, wide variation in prescribing persists and the overall use of antibiotics is increasing.
Methods
RAPiD is a 12-month partial factorial cluster randomised trial conducted in NHS General Dental Practices across Scotland. Its aim is to compare the effectiveness of individualised audit and feedback (A&F) strategies for the translation into practice of SDCEP recommendations on antibiotic prescribing. The trial uses routinely collected electronic healthcare data in five aspects of its design in order to: identify the study population; apply eligibility criteria; carry out stratified randomisation; generate the trial intervention; analyse trial outcomes.
Eligibility was determined on contract status and a minimum level of recent NHS treatment provision. All eligible dental practices in Scotland were simultaneously randomised at baseline either to current audit practice or to an intervention group. Randomisation was stratified by single-handed/multi-handed practices. General dental practitioners (GDPs) working at intervention practices will receive individualised graphical representations of their antibiotic prescribing rate from the previous 14 months at baseline and an update at six months. GDPs could not be blinded to their practice allocation. Intervention practices were further randomised using a factorial design to receive feedback with or without: a health board comparator; a supplementary text-based intervention; additional feedback at nine months. The primary outcome is the total antibiotic prescribing rate per 100 courses of treatment over the year following delivery of the baseline intervention.
A concurrent qualitative process evaluation will apply theory-based approaches using the Consolidated Framework for Implementation Research to explore the acceptability of the interventions and the Theoretical Domains Framework to identify barriers and enablers to evidence-based antibiotic prescribing behaviour by GDPs.
Discussion
RAPiD will provide a robust evaluation of A&F in dentistry in Scotland. It also demonstrates that linked administrative datasets have the potential to be used efficiently and effectively across all stages of an randomised controlled trial.
Trial registration
Current Controlled Trials ISRCTN49204710
doi:10.1186/1748-5908-9-50
PMCID: PMC4108126  PMID: 24758164
Prescribing; Antibiotics; Dental
2.  Eurocan plus report: feasibility study for coordination of national cancer research activities 
Summary
The EUROCAN+PLUS Project, called for by the European Parliament, was launched in October 2005 as a feasibility study for coordination of national cancer research activities in Europe. Over the course of the next two years, the Project process organized over 60 large meetings and countless smaller meetings that gathered in total over a thousand people, the largest Europe–wide consultation ever conducted in the field of cancer research.
Despite a strong tradition in biomedical science in Europe, fragmentation and lack of sustainability remain formidable challenges for implementing innovative cancer research and cancer care improvement. There is an enormous duplication of research effort in the Member States, which wastes time, wastes money and severely limits the total intellectual concentration on the wide cancer problem. There is a striking lack of communication between some of the biggest actors on the European scene, and there are palpable tensions between funders and those researchers seeking funds.
It is essential to include the patients’ voice in the establishment of priority areas in cancer research at the present time. The necessity to have dialogue between funders and scientists to establish the best mechanisms to meet the needs of the entire community is evident. A top priority should be the development of translational research (in its widest form), leading to the development of effective and innovative cancer treatments and preventive strategies. Translational research ranges from bench–to–bedside innovative cancer therapies and extends to include bringing about changes in population behaviours when a risk factor is established.
The EUROCAN+PLUS Project recommends the creation of a small, permanent and independent European Cancer Initiative (ECI). This should be a model structure and was widely supported at both General Assemblies of the project. The ECI should assume responsibility for stimulating innovative cancer research and facilitating processes, becoming the common voice of the cancer research community and serving as an interface between the cancer research community and European citizens, patients’ organizations, European institutions, Member States, industry and small and medium enterprises (SMEs), putting into practice solutions aimed at alleviating barriers to collaboration and coordination of cancer research activities in the European Union, and dealing with legal and regulatory issues. The development of an effective ECI will require time, but this entity should be established immediately. As an initial step, coordination efforts should be directed towards the creation of a platform on translational research that could encompass (1) coordination between basic, clinical and epidemiological research; (2) formal agreements of co–operation between comprehensive cancer centres and basic research laboratories throughout Europe and (3) networking between funding bodies at the European level.
The European Parliament and its instruments have had a major influence in cancer control in Europe, notably in tobacco control and in the implementation of effective population–based screening. To make further progress there is a need for novelty and innovation in cancer research and prevention in Europe, and having a platform such as the ECI, where those involved in all aspects of cancer research can meet, discuss and interact, is a decisive development for Europe.
Executive Summary
Cancer is one of the biggest public health crises facing Europe in the 21st century—one for which Europe is currently not prepared nor preparing itself. Cancer is a major cause of death in Europe with two million casualties and three million new cases diagnosed annually, and the situation is set to worsen as the population ages.
These facts led the European Parliament, through the Research Directorate-General of the European Commission, to call for initiatives for better coordination of cancer research efforts in the European Union. The EUROCAN+PLUS Project was launched in October 2005 as a feasibility study for coordination of national cancer research activities. Over the course of the next two years, the Project process organized over 60 large meetings and countless smaller meetings that gathered in total over a thousand people. In this respect, the Project became the largest Europe-wide consultation ever conducted in the field of cancer research, implicating researchers, cancer centres and hospitals, administrators, healthcare professionals, funding agencies, industry, patients’ organizations and patients.
The Project first identified barriers impeding research and collaboration in research in Europe. Despite a strong tradition in biomedical science in Europe, fragmentation and lack of sustainability remain the formidable challenges for implementing innovative cancer research and cancer care improvement. There is an enormous duplication of research effort in the Member States, which wastes time, wastes money and severely limits the total intellectual concentration on the wide cancer problem. There is a striking lack of communication between some of the biggest actors on the European scene, and there are palpable tensions between funders and those researchers seeking funds.
In addition, there is a shortage of leadership, a multiplicity of institutions each focusing on its own agenda, sub–optimal contact with industry, inadequate training, non–existent career paths, low personnel mobility in research especially among clinicians and inefficient funding—all conspiring against efficient collaboration in cancer care and research. European cancer research today does not have a functional translational research continuum, that is the process that exploits biomedical research innovations and converts them into prevention methods, diagnostic tools and therapies. Moreover, epidemiological research is not integrated with other types of cancer research, and the implementation of the European Directives on Clinical Trials 1 and on Personal Data Protection 2 has further slowed the innovation process in Europe. Furthermore, large inequalities in health and research exist between the EU–15 and the New Member States.
The picture is not entirely bleak, however, as the European cancer research scene presents several strengths, such as excellent basic research and clinical research and innovative etiological research that should be better exploited.
When considering recommendations, several priority dimensions had to be retained. It is essential that proposals include actions and recommendations that can benefit all Member States of the European Union and not just States with the elite centres. It is also essential to have a broader patient orientation to help provide the knowledge to establish cancer control possibilities when we exhaust what can be achieved by the implementation of current knowledge. It is vital that the actions proposed can contribute to the Lisbon Strategy to make Europe more innovative and competitive in (cancer) research.
The Project participants identified six areas for which consensus solutions should be implemented in order to obtain better coordination of cancer research activities. The required solutions are as follows. The proactive management of innovation, detection, facilitation of collaborations and maintenance of healthy competition within the European cancer research community.The establishment of an exchange portal of information for health professionals, patients and policy makers.The provision of guidance for translational and clinical research including the establishment of a translational research platform involving comprehensive cancer centres and cancer research centres.The coordination of calls and financial management of cancer research projects.The construction of a ‘one–stop shop’ as a contact interface between the industry, small and medium enterprises, scientists and other stakeholders.The support of greater involvement of healthcare professionals in translational research and multidisciplinary training.
In the course of the EUROCAN+PLUS consultative process, several key collaborative projects emerged between the various groups and institutes engaged in the consultation. There was a collaboration network established with Europe’s leading Comprehensive Cancer Centres; funding was awarded for a closer collaboration of Owners of Cancer Registries in Europe (EUROCOURSE); there was funding received from FP7 for an extensive network of leading Biological Resource Centres in Europe (BBMRI); a Working Group identified the special needs of Central, Eastern and South–eastern Europe and proposed a remedy (‘Warsaw Declaration’), and the concept of developing a one–stop shop for dealing with academia and industry including the Innovative Medicines Initiative (IMI) was discussed in detail.
Several other dimensions currently lacking were identified. There is an absolute necessity to include the patients’ voice in the establishment of priority areas in cancer research at the present time. It was a salutary lesson when it was recognized that all that is known about the quality of life of the cancer patient comes from the experience of a tiny proportion of cancer patients included in a few clinical trials. The necessity to have dialogue between funders and scientists to establish the best mechanisms to meet the needs of the entire community was evident. A top priority should be the development of translational research (in its widest form) and the development of effective and innovative cancer treatments and preventative strategies in the European Union. Translational research ranges from bench-to-bedside innovative cancer therapies and extends to include bringing about changes in population behaviours when a risk factor is established.
Having taken note of the barriers and the solutions and having examined relevant examples of existing European organizations in the field, it was agreed during the General Assembly of 19 November 2007 that the EUROCAN+PLUS Project had to recommend the creation of a small, permanent and neutral ECI. This should be a model structure and was widely supported at both General Assemblies of the project. The proposal is based on the successful model of the European Molecular Biology Organisation (EMBO), and its principal aims include providing a forum where researchers from all backgrounds and from all countries can meet with members of other specialities including patients, nurses, clinicians, funders and scientific administrators to develop priority programmes to make Europe more competitive in research and more focused on the cancer patient.
The ECI should assume responsibility for: stimulating innovative cancer research and facilitating processes;becoming the common voice of the cancer research community and serving as an interface between the cancer research community and European citizens, patients’ and organizations;European institutions, Member States, industry and small and medium enterprises;putting into practice the aforementioned solutions aimed at alleviating barriers and coordinating cancer research activities in the EU;dealing with legal and regulatory issues.
Solutions implemented through the ECI will lead to better coordination and collaboration throughout Europe, more efficient use of resources, an increase in Europe’s attractiveness to the biomedical industry and better quality of cancer research and education of health professionals.
The Project considered that European legal instruments currently available were inadequate for addressing many aspects of the barriers identified and for the implementation of effective, lasting solutions. Therefore, the legal environment that could shelter an idea like the ECI remains to be defined but should be done so as a priority. In this context, the initiative of the European Commission for a new legal entity for research infrastructure might be a step in this direction. The development of an effective ECI will require time, but this should be established immediately. As an initial step, coordination efforts should be directed towards the creation of a platform on translational research that could encompass: (1) coordination between basic, clinical and epidemiological research; (2) formal agreements of co-operation between comprehensive cancer centres and basic research laboratories throughout Europe; (3) networking between funding bodies at the European level. Another topic deserving immediate attention is the creation of a European database on cancer research projects and cancer research facilities.
Despite enormous progress in cancer control in Europe during the past two decades, there was an increase of 300,000 in the number of new cases of cancer diagnosed between 2004 and 2006. The European Parliament and its instruments have had a major influence in cancer control, notably in tobacco control and in the implementation of effective population–based screening. To make further progress there is a need for novelty and innovation in cancer research and prevention in Europe, and having a platform such as the ECI, where those involved in all aspects of cancer research can meet, discuss and interact, is a decisive development for Europe.
doi:10.3332/ecancer.2011.84
PMCID: PMC3234055  PMID: 22274749
3.  Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments 
PLoS Medicine  2013;10(7):e1001489.
Background
The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address.
Methods and Findings
We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria—most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.
Conclusions
By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development process for new drugs is lengthy and complex. It begins in the laboratory, where scientists investigate the causes of diseases and identify potential new treatments. Next, promising interventions undergo preclinical research in cells and in animals (in vivo animal experiments) to test whether the intervention has the expected effect and to support the generalization (extension) of this treatment–effect relationship to patients. Drugs that pass these tests then enter clinical trials, where their safety and efficacy is tested in selected groups of patients under strictly controlled conditions. Finally, the government bodies responsible for drug approval review the results of the clinical trials, and successful drugs receive a marketing license, usually a decade or more after the initial laboratory work. Notably, only 11% of agents that enter clinical testing (investigational drugs) are ultimately licensed.
Why Was This Study Done?
The frequent failure of investigational drugs during clinical translation is potentially harmful to trial participants. Moreover, the costs of these failures are passed onto healthcare systems in the form of higher drug prices. It would be good, therefore, to reduce the attrition rate of investigational drugs. One possible explanation for the dismal success rate of clinical translation is that preclinical research, the key resource for justifying clinical development, is flawed. To address this possibility, several groups of preclinical researchers have issued guidelines intended to improve the design and execution of in vivo animal studies. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the authors identify the experimental practices that are commonly recommended in these guidelines and organize these recommendations according to the type of threat to validity (internal, construct, or external) that they address. Internal threats to validity are factors that confound reliable inferences about treatment–effect relationships in preclinical research. For example, experimenter expectation may bias outcome assessment. Construct threats to validity arise when researchers mischaracterize the relationship between an experimental system and the clinical disease it is intended to represent. For example, researchers may use an animal model for a complex multifaceted clinical disease that only includes one characteristic of the disease. External threats to validity are unseen factors that frustrate the transfer of treatment–effect relationships from animal models to patients.
What Did the Researchers Do and Find?
The researchers identified 26 preclinical guidelines that met their predefined eligibility criteria. Twelve guidelines addressed preclinical research for neurological and cerebrovascular drug development; other disorders covered by guidelines included cardiac and circulatory disorders, sepsis, pain, and arthritis. Together, the guidelines offered 55 different recommendations for the design and execution of preclinical in vivo animal studies. Nineteen recommendations addressed threats to internal validity. The most commonly included recommendations of this type called for the use of power calculations to ensure that sample sizes are large enough to yield statistically meaningful results, random allocation of animals to treatment groups, and “blinding” of researchers who assess outcomes to treatment allocation. Among the 25 recommendations that addressed threats to construct validity, the most commonly included recommendations called for characterization of the properties of the animal model before experimentation and matching of the animal model to the human manifestation of the disease. Finally, six recommendations addressed threats to external validity. The most commonly included of these recommendations suggested that preclinical research should be replicated in different models of the same disease and in different species, and should also be replicated independently.
What Do These Findings Mean?
This systematic review identifies a range of investigational recommendations that preclinical researchers believe address threats to the validity of preclinical efficacy studies. Many of these recommendations are not widely implemented in preclinical research at present. Whether the failure to implement them explains the frequent discordance between the results on drug safety and efficacy obtained in preclinical research and in clinical trials is currently unclear. These findings provide a starting point, however, for the improvement of existing preclinical research guidelines for specific diseases, and for the development of similar guidelines for other diseases. They also provide an evidence-based platform for the analysis of preclinical evidence and for the study and evaluation of preclinical research practice. These findings should, therefore, be considered by investigators, institutional review bodies, journals, and funding agents when designing, evaluating, and sponsoring translational research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001489.
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals; its Patient Network provides a step-by-step description of the drug development process that includes information on preclinical research
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides information about all aspects of the scientific evaluation and approval of new medicines in the UK; its My Medicine: From Laboratory to Pharmacy Shelf web pages describe the drug development process from scientific discovery, through preclinical and clinical research, to licensing and ongoing monitoring
The STREAM website provides ongoing information about policy, ethics, and practices used in clinical translation of new drugs
The CAMARADES collaboration offers a “supporting framework for groups involved in the systematic review of animal studies” in stroke and other neurological diseases
doi:10.1371/journal.pmed.1001489
PMCID: PMC3720257  PMID: 23935460
4.  Theory of Change: a theory-driven approach to enhance the Medical Research Council's framework for complex interventions 
Trials  2014;15:267.
Background
The Medical Research Councils’ framework for complex interventions has been criticized for not including theory-driven approaches to evaluation. Although the framework does include broad guidance on the use of theory, it contains little practical guidance for implementers and there have been calls to develop a more comprehensive approach. A prospective, theory-driven process of intervention design and evaluation is required to develop complex healthcare interventions which are more likely to be effective, sustainable and scalable.
Methods
We propose a theory-driven approach to the design and evaluation of complex interventions by adapting and integrating a programmatic design and evaluation tool, Theory of Change (ToC), into the MRC framework for complex interventions. We provide a guide to what ToC is, how to construct one, and how to integrate its use into research projects seeking to design, implement and evaluate complex interventions using the MRC framework. We test this approach by using ToC within two randomized controlled trials and one non-randomized evaluation of complex interventions.
Results
Our application of ToC in three research projects has shown that ToC can strengthen key stages of the MRC framework. It can aid the development of interventions by providing a framework for enhanced stakeholder engagement and by explicitly designing an intervention that is embedded in the local context. For the feasibility and piloting stage, ToC enables the systematic identification of knowledge gaps to generate research questions that strengthen intervention design. ToC may improve the evaluation of interventions by providing a comprehensive set of indicators to evaluate all stages of the causal pathway through which an intervention achieves impact, combining evaluations of intervention effectiveness with detailed process evaluations into one theoretical framework.
Conclusions
Incorporating a ToC approach into the MRC framework holds promise for improving the design and evaluation of complex interventions, thereby increasing the likelihood that the intervention will be ultimately effective, sustainable and scalable. We urge researchers developing and evaluating complex interventions to consider using this approach, to evaluate its usefulness and to build an evidence base to further refine the methodology.
Trial registration
Clinical trials.gov: NCT02160249
doi:10.1186/1745-6215-15-267
PMCID: PMC4227087  PMID: 24996765
Complex interventions; Theory of Change; MRC framework for complex interventions
5.  Can't do it, won't do it! Developing a theoretically framed intervention to encourage better decontamination practice in Scottish dental practices 
Background
Guidance on the cleaning of dental instruments in primary care has recently been published. The aims of this study are to determine if the publication of the guidance document was enough to influence decontamination best practice and to design an implementation intervention strategy, should it be required.
Methods
A postal questionnaire assessing current decontamination practice and beliefs was sent to a random sample of 200 general dental practitioners.
Results
Fifty-seven percent (N = 113) of general dental practitioners responded. The survey showed large variation in what dentists self-reported doing, perceived as necessary or practical to do, were willing to do, felt able to do, as well as what they planned to change. Only 15% self-reported compliance with the five key guideline-recommended individual-level decontamination behaviours; only 2% reported compliance with all 11 key practice-level behaviours. The results also showed that our participants were almost equally split between dentists who were completely unmotivated to implement best decontamination practice or else highly motivated. The results suggested there was scope for further enhancing the implementation of decontamination guidance, and that an intervention with the greatest likelihood of success would require a tailored format, specifically targeting components of the theory of planned behaviour (attitude, perceived behavioural control, intention) and implementation intention theory (action planning).
Conclusion
Considerable resources are devoted to encouraging clinicians to implement evidence-based practice using interventions with erratic success records, or no known applicability to a specific clinical behaviour, selected mainly by means of researchers' intuition or optimism. The methodology used to develop this implementation intervention is not limited to decontamination or to a single segment of primary care. It is also in accordance with the preliminary stages of the framework for evaluating complex interventions suggested by the medical research council. The next phases of this work are to test the intervention feasibility and evaluate its effectiveness in a randomised control trial.
doi:10.1186/1748-5908-4-31
PMCID: PMC2701915  PMID: 19500342
6.  Design, implementation, and evaluation of a knowledge translation intervention to increase organ donation after cardiocirculatory death in Canada: a study protocol 
Background
A shortage of transplantable organs is a global problem. There are two types of organ donation: living and deceased. Deceased organ donation can occur following neurological determination of death (NDD) or cardiocirculatory death. Donation after cardiocirculatory death (DCD) accounts for the largest increments in deceased organ donation worldwide. Variations in the use of DCD exist, however, within Canada and worldwide. Reasons for these discrepancies are largely unknown. The purpose of this study is to develop, implement, and evaluate a theory-based knowledge translation intervention to provide practical guidance about how to increase the numbers of DCD organ donors without reducing the numbers of standard NDD donors.
Methods
We will use a mixed method three-step approach. In step one, we will conduct semi-structured interviews, informed by the Theoretical Domains Framework, to identify and describe stakeholders’ beliefs and attitudes about DCD and their perceptions of the multi-level factors that influence DCD. We will identify: determinants of the evidence-practice gap; specific behavioural changes and/or process changes needed to increase DCD; specific group(s) of clinicians or organizations (e.g., provincial donor organizations) in need of behaviour change; and specific targets for interventions. In step two, using the principles of intervention mapping, we will develop a theory-based knowledge translation intervention that encompasses behavior change techniques to overcome the identified barriers and enhance the enablers to DCD. In step three, we will roll out the intervention in hospitals across the 10 Canadian provinces and evaluate its effectiveness using a multiple interrupted time series design.
Discussion
We will adopt a behavioural approach to define and test novel, theory-based, and ethically-acceptable knowledge translation strategies to increase the numbers of available DCD organ donors in Canada. If successful, this study will ultimately lead to more transplantations, reducing patient morbidity and mortality at a population-level.
doi:10.1186/1748-5908-9-80
PMCID: PMC4082291  PMID: 24950719
7.  Application of theory to enhance audit and feedback interventions to increase the uptake of evidence-based transfusion practice: an intervention development protocol 
Background
Audits of blood transfusion demonstrate around 20% transfusions are outside national recommendations and guidelines. Audit and feedback is a widely used quality improvement intervention but effects on clinical practice are variable, suggesting potential for enhancement. Behavioural theory, theoretical frameworks of behaviour change and behaviour change techniques provide systematic processes to enhance intervention. This study is part of a larger programme of work to promote the uptake of evidence-based transfusion practice.
Objectives
The objectives of this study are to design two theoretically enhanced audit and feedback interventions; one focused on content and one on delivery, and investigate the feasibility and acceptability.
Methods
Study A (Content): A coding framework based on current evidence regarding audit and feedback, and behaviour change theory and frameworks will be developed and applied as part of a structured content analysis to specify the key components of existing feedback documents. Prototype feedback documents with enhanced content and also a protocol, describing principles for enhancing feedback content, will be developed. Study B (Delivery): Individual semi-structured interviews with healthcare professionals and observations of team meetings in four hospitals will be used to specify, and identify views about, current audit and feedback practice. Interviews will be based on a topic guide developed using the Theoretical Domains Framework and the Consolidated Framework for Implementation Research. Analysis of transcripts based on these frameworks will form the evidence base for developing a protocol describing an enhanced intervention that focuses on feedback delivery. Study C (Feasibility and Acceptability): Enhanced interventions will be piloted in four hospitals. Semi-structured interviews, questionnaires and observations will be used to assess feasibility and acceptability.
Discussion
This intervention development work reflects the UK Medical Research Council’s guidance on development of complex interventions, which emphasises the importance of a robust theoretical basis for intervention design and recommends systematic assessment of feasibility and acceptability prior to taking interventions to evaluation in a full-scale randomised study. The work-up includes specification of current practice so that, in the trials to be conducted later in this programme, there will be a clear distinction between the control (usual practice) conditions and the interventions to be evaluated.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-014-0092-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13012-014-0092-1
PMCID: PMC4243714  PMID: 25070404
Audit and feedback; Blood transfusion; Implementation; Health services research; Study protocol; Health professional behaviour change
8.  Knowledge translation strategies to improve the use of evidence in public health decision making in local government: intervention design and implementation plan 
Background
Knowledge translation strategies are an approach to increase the use of evidence within policy and practice decision-making contexts. In clinical and health service contexts, knowledge translation strategies have focused on individual behavior change, however the multi-system context of public health requires a multi-level, multi-strategy approach. This paper describes the design of and implementation plan for a knowledge translation intervention for public health decision making in local government.
Methods
Four preliminary research studies contributed findings to the design of the intervention: a systematic review of knowledge translation intervention effectiveness research, a scoping study of knowledge translation perspectives and relevant theory literature, a survey of the local government public health workforce, and a study of the use of evidence-informed decision-making for public health in local government. A logic model was then developed to represent the putative pathways between intervention inputs, processes, and outcomes operating between individual-, organizational-, and system-level strategies. This formed the basis of the intervention plan.
Results
The systematic and scoping reviews identified that effective and promising strategies to increase access to research evidence require an integrated intervention of skill development, access to a knowledge broker, resources and tools for evidence-informed decision making, and networking for information sharing. Interviews and survey analysis suggested that the intervention needs to operate at individual and organizational levels, comprising workforce development, access to evidence, and regular contact with a knowledge broker to increase access to intervention evidence; develop skills in appraisal and integration of evidence; strengthen networks; and explore organizational factors to build organizational cultures receptive to embedding evidence in practice. The logic model incorporated these inputs and strategies with a set of outcomes to measure the intervention’s effectiveness based on the theoretical frameworks, evaluation studies, and decision-maker experiences.
Conclusion
Documenting the design of and implementation plan for this knowledge translation intervention provides a transparent, theoretical, and practical approach to a complex intervention. It provides significant insights into how practitioners might engage with evidence in public health decision making. While this intervention model was designed for the local government context, it is likely to be applicable and generalizable across sectors and settings.
Trial registration
Australia New Zealand Clinical Trials Register ACTRN12609000953235.
doi:10.1186/1748-5908-8-121
PMCID: PMC3853093  PMID: 24107358
Knowledge translation; Evidence; Public health; Decision-making
9.  Evaluating the successful implementation of evidence into practice using the PARiHS framework: theoretical and practical challenges 
Background
The PARiHS framework (Promoting Action on Research Implementation in Health Services) has proved to be a useful practical and conceptual heuristic for many researchers and practitioners in framing their research or knowledge translation endeavours. However, as a conceptual framework it still remains untested and therefore its contribution to the overall development and testing of theory in the field of implementation science is largely unquantified.
Discussion
This being the case, the paper provides an integrated summary of our conceptual and theoretical thinking so far and introduces a typology (derived from social policy analysis) used to distinguish between the terms conceptual framework, theory and model – important definitional and conceptual issues in trying to refine theoretical and methodological approaches to knowledge translation.
Secondly, the paper describes the next phase of our work, in particular concentrating on the conceptual thinking and mapping that has led to the generation of the hypothesis that the PARiHS framework is best utilised as a two-stage process: as a preliminary (diagnostic and evaluative) measure of the elements and sub-elements of evidence (E) and context (C), and then using the aggregated data from these measures to determine the most appropriate facilitation method. The exact nature of the intervention is thus determined by the specific actors in the specific context at a specific time and place.
In the process of refining this next phase of our work, we have had to consider the wider issues around the use of theories to inform and shape our research activity; the ongoing challenges of developing robust and sensitive measures; facilitation as an intervention for getting research into practice; and finally to note how the current debates around evidence into practice are adopting wider notions that fit innovations more generally.
Summary
The paper concludes by suggesting that the future direction of the work on the PARiHS framework is to develop a two-stage diagnostic and evaluative approach, where the intervention is shaped and moulded by the information gathered about the specific situation and from participating stakeholders. In order to expedite the generation of new evidence and testing of emerging theories, we suggest the formation of an international research implementation science collaborative that can systematically collect and analyse experiences of using and testing the PARiHS framework and similar conceptual and theoretical approaches.
We also recommend further refinement of the definitions around conceptual framework, theory, and model, suggesting a wider discussion that embraces multiple epistemological and ontological perspectives.
doi:10.1186/1748-5908-3-1
PMCID: PMC2235887  PMID: 18179688
10.  Information-Seeking Behaviors of Dental Practitioners in Three Practice-Based Research Networks 
Journal of dental education  2013;77(2):152-160.
Research on the information-seeking behaviors of dental practitioners is scarce. Knowledge of dentists’ information-seeking behaviors should advance the translational gap between clinical dental research and dental practice. A cross-sectional survey was conducted to examine the self-reported information-seeking behaviors of dentists in three dental practice-based research networks (PBRNs). A total of 950 dentists (65 percent response rate) completed the survey. Dental journals and continuing dental education (CDE) sources used and their influence on practice guidance were assessed. PBRN participation level and years since dental degree were measured. Full-participant dentists reported reading the Journal of the American Dental Association and General Dentistry more frequently than did their reference counterparts. Printed journals were preferred by most dentists. A lower proportion of full participants obtained their CDE credits at dental meetings compared to partial participants. Experienced dentists read other dental information sources more frequently than did less experienced dentists. Practitioners involved in a PBRN differed in their approaches to accessing information sources. Peer-reviewed sources were more frequently used by full participants and dentists with fifteen years of experience or more. Dental PBRNs potentially play a significant role in the dissemination of evidence-based information. This study found that specific educational sources might increase and disseminate knowledge among dentists.
PMCID: PMC3832844  PMID: 23382524
evidence-based dentistry; evidence-based practice; information-seeking behaviors; information sources; continuing dental education; dental practitioners; dentists; practice-based research networks
11.  Effective process or dangerous precipice: qualitative comparative embedded case study with young people with epilepsy and their parents during transition from children’s to adult services 
BMC Pediatrics  2013;13:169.
Background
Transition from children’s to adult epilepsy services is known to be challenging. Some young people partially or completely disengage from contact with services, thereby risking their health and wellbeing. We conducted a mixed-method systematic review that showed current epilepsy transition models enabling information exchange and developing self-care skills were not working well. We used synthesised evidence to develop a theoretical framework to inform this qualitative study. The aim was to address a critical research gap by exploring communication, information needs, and experiences of knowledge exchange in clinical settings by young people and their parents, during transition from children’s to adult epilepsy services.
Method
Qualitative comparative embedded Case study with 2 'transition’ cases (epilepsy services) in two hospitals. Fifty-eight participants: 30 young people (13–19 years) and 28 parents were interviewed in-depth (individual or focus group). Clinical documents/guidelines were collated. 'Framework’ thematic analysis was used. The theoretical framework was tested using themes, pattern matching and replication logic. Theory-based evaluation methods were used to understand how and why different models of service delivery worked.
Results
A joint epilepsy clinic for young people 14–17 years coordinated by children’s and adult services was more likely to influence young people’s behaviour by facilitating more positive engagement with adult healthcare professionals and retention of epilepsy-related self-care information. Critical success factors were continuity of care, on-going and consistent age-appropriate and person centred communication and repeated information exchange. Three young people who experienced a single handover clinic disengaged from services. Psychosocial care was generally inadequate and healthcare professionals lacked awareness of memory impairment. Parents lacked knowledge, skills and support to enable their child to independently self-care. Translation of transition policies/guidelines into practice was weak.
Conclusion
Findings make a significant contribution to understanding why young people disengage from epilepsy services, why some parents prevent independent self-care, and what constitutes good communication and transition from the perspective of young people and parents. The type of service configuration, delivery and organisation influenced the behaviours of young people at transition to adult services. The novel theoretical framework was substantially supported, underwent further post-hoc development and can be used in future practice/intervention development and research.
doi:10.1186/1471-2431-13-169
PMCID: PMC4016204  PMID: 24131769
Young people; Parents; Epilepsy; Transition; Qualitative case-study; Theory-based evaluation; Communication; Information needs; Knowledge exchange; Epilepsy nurse specialist
12.  Developing theory-informed behaviour change interventions to implement evidence into practice: a systematic approach using the Theoretical Domains Framework 
Background
There is little systematic operational guidance about how best to develop complex interventions to reduce the gap between practice and evidence. This article is one in a Series of articles documenting the development and use of the Theoretical Domains Framework (TDF) to advance the science of implementation research.
Methods
The intervention was developed considering three main components: theory, evidence, and practical issues. We used a four-step approach, consisting of guiding questions, to direct the choice of the most appropriate components of an implementation intervention: Who needs to do what, differently? Using a theoretical framework, which barriers and enablers need to be addressed? Which intervention components (behaviour change techniques and mode(s) of delivery) could overcome the modifiable barriers and enhance the enablers? And how can behaviour change be measured and understood?
Results
A complex implementation intervention was designed that aimed to improve acute low back pain management in primary care. We used the TDF to identify the barriers and enablers to the uptake of evidence into practice and to guide the choice of intervention components. These components were then combined into a cohesive intervention. The intervention was delivered via two facilitated interactive small group workshops. We also produced a DVD to distribute to all participants in the intervention group. We chose outcome measures in order to assess the mediating mechanisms of behaviour change.
Conclusions
We have illustrated a four-step systematic method for developing an intervention designed to change clinical practice based on a theoretical framework. The method of development provides a systematic framework that could be used by others developing complex implementation interventions. While this framework should be iteratively adjusted and refined to suit other contexts and settings, we believe that the four-step process should be maintained as the primary framework to guide researchers through a comprehensive intervention development process.
doi:10.1186/1748-5908-7-38
PMCID: PMC3443064  PMID: 22531013
13.  Autism 
Clinical Evidence  2010;2010:0322.
Introduction
Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child’s Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.
Key Points
Autism is one of a group of pervasive developmental disorders, and is characterised by qualitative impairments in communication and social interaction, and by repetitive and stereotyped behaviours and interests. Abnormal development is present before the age of 3 years. A quarter of affected children show developmental regression, with loss of previously acquired skills.One third of children with autism have epilepsy, and three quarters have mental retardation. Only 15% of adults with autism will lead independent lives.Twin and family studies suggest that most cases of autism occur because of a combination of genetic factors. Autism is not caused by perinatal factors or by the MMR vaccine.
It may be difficult to apply the results of research in practice, as improvements in outcomes assessed in RCTs using standardised assessment tools may not correlate with improvements in function in a particular child with autism.
Some interventions are administered by (or in conjunction with) parents, and may be carried out in the home. Consideration of the direct financial costs, indirect costs (through possible lost earnings), and the impact on relationships within the family (to siblings or spouse) must be balanced against likely and possible improvements in outcome for the child with autism.
There is a lack of good-quality evidence on the effectiveness of early multidisciplinary intervention programmes, or for other treatments for children with autism. There is consensus, supported by a systematic review, that early intensive behavioural interventions are likely to be beneficial in children with autism.Attendance at a "More Than Words" training course for parents may improve communication between parents and children, as may participation in Child's Talk. There is consensus that the Autism Preschool Programme and TEACCH may be effective, although no RCTs or cohort studies evaluating these interventions have been found.We don't know whether early intervention using the EarlyBird programme, the Portage scheme, Relationship-Development Intervention, Social stories, music therapy, CBT, facilitated communication or Son-Rise are beneficial in children with autism.
Methylphenidate may reduce hyperactivity in children with autism. Methylphenidate may increase social withdrawal and irritability. Growth and blood pressure monitoring are required.
Risperidone may improve behaviour in children with autism compared with placebo, but its use is limited by adverse effects such as weight gain, drowsiness, prolactinaemia, and tremors.
There is consensus that selective serotonin reuptake inhibitors (SSRIs) improve symptoms in children with autism, although no RCTs have been found. The adverse effects of SSRIs, including possible increases in agitation, hostility, and suicidal ideation, are well documented.
We don't know whether auditory integration training, sensory integration training, chelation, a gluten- and casein-free diet, digestive enzymes, omega-3 fish oil, secretin, vitamin A, vitamin B6 plus magnesium, melatonin, olanzapine, or vitamin C are beneficial for treating children with autism, as few studies have been found.
PMCID: PMC2907623  PMID: 21729335
14.  Developing a framework for transferring knowledge into action: a thematic analysis of the literature 
Objectives
Although there is widespread agreement about the importance of transferring knowledge into action, we still lack high quality information about what works, in which settings and with whom. Whilst there are a large number of models and theories for knowledge transfer interventions, they are untested meaning that their applicability and relevance is largely unknown. This paper describes the development of a conceptual framework of translating knowledge into action and discusses how it can be used for developing a useful model of the knowledge transfer process.
Methods
A narrative review of the knowledge transfer literature identified 28 different models which explained all or part of the knowledge transfer process. The models were subjected to a thematic analysis to identify individual components and the types of processes used when transferring knowledge into action. The results were used to build a conceptual framework of the process.
Results
Five common components of the knowledge transfer process were identified: problem identification and communication; knowledge/research development and selection; analysis of context; knowledge transfer activities or interventions; and knowledge/research utilization. We also identified three types of knowledge transfer processes: a linear process; a cyclical process; and a dynamic multidirectional process. From these results a conceptual framework of knowledge transfer was developed. The framework illustrates the five common components of the knowledge transfer process and shows that they are connected via a complex, multidirectional set of interactions. As such the framework allows for the individual components to occur simultaneously or in any given order and to occur more than once during the knowledge transfer process.
Conclusion
Our framework provides a foundation for gathering evidence from case studies of knowledge transfer interventions. We propose that future empirical work is designed to test and refine the relevant importance and applicability of each of the components in order to build more useful models of knowledge transfer which can serve as a practical checklist for planning or evaluating knowledge transfer activities.
doi:10.1258/jhsrp.2009.008120
PMCID: PMC2933505  PMID: 19541874
15.  Programmatic assessment of competency-based workplace learning: when theory meets practice 
BMC Medical Education  2013;13:123.
Background
In competency-based medical education emphasis has shifted towards outcomes, capabilities, and learner-centeredness. Together with a focus on sustained evidence of professional competence this calls for new methods of teaching and assessment. Recently, medical educators advocated the use of a holistic, programmatic approach towards assessment. Besides maximum facilitation of learning it should improve the validity and reliability of measurements and documentation of competence development. We explored how, in a competency-based curriculum, current theories on programmatic assessment interacted with educational practice.
Methods
In a development study including evaluation, we investigated the implementation of a theory-based programme of assessment. Between April 2011 and May 2012 quantitative evaluation data were collected and used to guide group interviews that explored the experiences of students and clinical supervisors with the assessment programme. We coded the transcripts and emerging topics were organised into a list of lessons learned.
Results
The programme mainly focuses on the integration of learning and assessment by motivating and supporting students to seek and accumulate feedback. The assessment instruments were aligned to cover predefined competencies to enable aggregation of information in a structured and meaningful way. Assessments that were designed as formative learning experiences were increasingly perceived as summative by students. Peer feedback was experienced as a valuable method for formative feedback. Social interaction and external guidance seemed to be of crucial importance to scaffold self-directed learning. Aggregating data from individual assessments into a holistic portfolio judgement required expertise and extensive training and supervision of judges.
Conclusions
A programme of assessment with low-stakes assessments providing simultaneously formative feedback and input for summative decisions proved not easy to implement. Careful preparation and guidance of the implementation process was crucial. Assessment for learning requires meaningful feedback with each assessment. Special attention should be paid to the quality of feedback at individual assessment moments. Comprehensive attention for faculty development and training for students is essential for the successful implementation of an assessment programme.
doi:10.1186/1472-6920-13-123
PMCID: PMC3851012  PMID: 24020944
Programmatic assessment; Workplace learning; Undergraduate (veterinary) medical education; (Peer) Feedback; Mentoring; Personal development
16.  Disseminating research findings: what should researchers do? A systematic scoping review of conceptual frameworks 
Background
Addressing deficiencies in the dissemination and transfer of research-based knowledge into routine clinical practice is high on the policy agenda both in the UK and internationally.
However, there is lack of clarity between funding agencies as to what represents dissemination. Moreover, the expectations and guidance provided to researchers vary from one agency to another. Against this background, we performed a systematic scoping to identify and describe any conceptual/organising frameworks that could be used by researchers to guide their dissemination activity.
Methods
We searched twelve electronic databases (including MEDLINE, EMBASE, CINAHL, and PsycINFO), the reference lists of included studies and of individual funding agency websites to identify potential studies for inclusion. To be included, papers had to present an explicit framework or plan either designed for use by researchers or that could be used to guide dissemination activity. Papers which mentioned dissemination (but did not provide any detail) in the context of a wider knowledge translation framework, were excluded. References were screened independently by at least two reviewers; disagreements were resolved by discussion. For each included paper, the source, the date of publication, a description of the main elements of the framework, and whether there was any implicit/explicit reference to theory were extracted. A narrative synthesis was undertaken.
Results
Thirty-three frameworks met our inclusion criteria, 20 of which were designed to be used by researchers to guide their dissemination activities. Twenty-eight included frameworks were underpinned at least in part by one or more of three different theoretical approaches, namely persuasive communication, diffusion of innovations theory, and social marketing.
Conclusions
There are currently a number of theoretically-informed frameworks available to researchers that can be used to help guide their dissemination planning and activity. Given the current emphasis on enhancing the uptake of knowledge about the effects of interventions into routine practice, funders could consider encouraging researchers to adopt a theoretically-informed approach to their research dissemination.
doi:10.1186/1748-5908-5-91
PMCID: PMC2994786  PMID: 21092164
17.  The Cost and Impact of Scaling Up Pre-exposure Prophylaxis for HIV Prevention: A Systematic Review of Cost-Effectiveness Modelling Studies 
PLoS Medicine  2013;10(3):e1001401.
Gabriela Gomez and colleagues systematically review cost-effectiveness modeling studies of pre-exposure prophylaxis (PrEP) for preventing HIV transmission and identify the main considerations to address when considering the introduction of PrEP to HIV prevention programs.
Background
Cost-effectiveness studies inform resource allocation, strategy, and policy development. However, due to their complexity, dependence on assumptions made, and inherent uncertainty, synthesising, and generalising the results can be difficult. We assess cost-effectiveness models evaluating expected health gains and costs of HIV pre-exposure prophylaxis (PrEP) interventions.
Methods and Findings
We conducted a systematic review comparing epidemiological and economic assumptions of cost-effectiveness studies using various modelling approaches. The following databases were searched (until January 2013): PubMed/Medline, ISI Web of Knowledge, Centre for Reviews and Dissemination databases, EconLIT, and region-specific databases. We included modelling studies reporting both cost and expected impact of a PrEP roll-out. We explored five issues: prioritisation strategies, adherence, behaviour change, toxicity, and resistance. Of 961 studies retrieved, 13 were included. Studies modelled populations (heterosexual couples, men who have sex with men, people who inject drugs) in generalised and concentrated epidemics from Southern Africa (including South Africa), Ukraine, USA, and Peru. PrEP was found to have the potential to be a cost-effective addition to HIV prevention programmes in specific settings. The extent of the impact of PrEP depended upon assumptions made concerning cost, epidemic context, programme coverage, prioritisation strategies, and individual-level adherence. Delivery of PrEP to key populations at highest risk of HIV exposure appears the most cost-effective strategy. Limitations of this review include the partial geographical coverage, our inability to perform a meta-analysis, and the paucity of information available exploring trade-offs between early treatment and PrEP.
Conclusions
Our review identifies the main considerations to address in assessing cost-effectiveness analyses of a PrEP intervention—cost, epidemic context, individual adherence level, PrEP programme coverage, and prioritisation strategy. Cost-effectiveness studies indicating where resources can be applied for greatest impact are essential to guide resource allocation decisions; however, the results of such analyses must be considered within the context of the underlying assumptions made.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year approximately 2.5 million people are infected with HIV, the virus that causes AIDS. Behavioral strategies like condom use and reduction of sexual partners have been the hallmarks of HIV prevention efforts. However, biological prevention measures have also recently been shown to be effective. These include male circumcision, treatment as prevention (treating HIV-infected people with antiretroviral drugs to reduce transmission), and pre-exposure prophylaxis (PrEP), where people not infected with HIV take antiretroviral drugs to reduce the probability of transmission. Strategies such as PrEP may be viable prevention measure for couples in long-term relationships where one partner is HIV-positive and the other is HIV-negative (HIV serodiscordant couples) or groups at higher risk of HIV infection, such as men who have sex with men, and injection drug users.
Why Was This Study Done?
The findings from recent clinical trials that demonstrate PrEP can reduce HIV transmission have led to important policy discussions and in the US, Southern Africa, and the UK new clinical guidelines have been developed on the use of PrEP for the prevention of HIV infection. For those countries that are considering whether to introduce PrEP into HIV prevention programs, national policy and decision makers need to determine potential costs and health outcomes. Cost-effectiveness models—mathematical models that simulate cost and health effects of different interventions—can help inform such decisions. However, the cost-effectiveness estimates that could provide guidance for PrEP programs are dependent on, and limited by, the assumptions included in the models, which can make their findings difficult to generalize. A systematic comparison of published cost-effectiveness models of HIV PrEP interventions would be useful for policy makers who are considering introducing PrEP intervention programs.
What Did the Researchers Do and Find?
The researchers performed a systematic review to identify published cost-effectiveness models that evaluated the health gains and costs of HIV PrEP interventions. Systematic reviews attempt to identify, appraise, and synthesize all the empirical evidence that meets pre-specified eligibility criteria to answer a given research question by using explicit methods aimed at minimizing bias. By searching databases the authors identified 13 published studies that evaluated the impact of PrEP in different populations (heterosexual couples, men who have sex with men, and injection drug users) in different geographic settings, which included Southern Africa, Ukraine, US, and Peru.
The authors identified seven studies that assessed the introduction of PrEP into generalized HIV epidemics in Southern Africa. These studies suggest that PrEP may be a cost effective intervention to prevent heterosexual transmission. However, the authors note that funding PrEP while other cost-effective HIV prevention methods are underfunded in this setting may have high opportunity costs. The authors identified five studies where PrEP was introduced for concentrated epidemics among men who have sex with men (four studies in the US and one in Peru). These studies suggest that PrEP may have a substantial impact on the HIV epidemic but may not be affordable at current drug prices. The authors also identified a single study that modeled the introduction of PrEP for people who inject drugs in the Ukraine, which found PrEP not to be cost effective.
In all settings the price of antiretroviral drugs was found to be a limiting factor in terms of affordability of PrEP programs. Behavioral changes and adherence to PrEP were estimated to have potentially significant impacts on program effectiveness but the emergence of drug resistance or PrEP-related toxicity did not significantly affect cost-effectiveness estimates. Several PrEP prioritization strategies were explored in included studies and delivering PrEP to populations at highest risk of HIV exposure was shown to improve cost-effectiveness estimates. However, the extra costs of identifying and engaging with high-risk populations were not taken into consideration. The authors note that the geographic coverage of identified studies was limited and that the findings are very dependent on the setting which limits generalizability.
What Do these Findings Mean?
These findings suggest that PrEP could be a cost-effective tool to reduce new HIV infections in some settings. However, the cost-effectiveness of PrEP is dependent upon cost, the epidemic context, program coverage and prioritization strategies, participants' adherence to the drug regimen, and PrEP efficacy estimates. These findings will aid decision makers quantify and compare the reductions in HIV incidence that could be achieved by implementing a PrEP program.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001401.
The US National Institute of Allergy and Infectious Diseases has information on HIV/AIDS
aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and has a section on PrEP
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including HIV prevention
AVAC Global Advocacy for HIV Prevention provides information on HIV prevention, including PrEP
The US Centers for Disease Control and Prevention also has information on PrEP
The World Health Organization has a page on its WHO-CHOICE criteria for cost-effectiveness
doi:10.1371/journal.pmed.1001401
PMCID: PMC3595225  PMID: 23554579
18.  Knowledge translation within a population health study: how do you do it? 
Background
Despite the considerable and growing body of knowledge translation (KT) literature, there are few methodologies sufficiently detailed to guide an integrated KT research approach for a population health study. This paper argues for a clearly articulated collaborative KT approach to be embedded within the research design from the outset.
Discussion
Population health studies are complex in their own right, and strategies to engage the local community in adopting new interventions are often fraught with considerable challenges. In order to maximise the impact of population health research, more explicit KT strategies need to be developed from the outset. We present four propositions, arising from our work in developing a KT framework for a population health study. These cover the need for an explicit theory-informed conceptual framework; formalizing collaborative approaches within the design; making explicit the roles of both the stakeholders and the researchers; and clarifying what counts as evidence. From our deliberations on these propositions, our own co-creating (co-KT) Framework emerged in which KT is defined as both a theoretical and practical framework for actioning the intent of researchers and communities to co-create, refine, implement and evaluate the impact of new knowledge that is sensitive to the context (values, norms and tacit knowledge) where it is generated and used. The co-KT Framework has five steps. These include initial contact and framing the issue; refining and testing knowledge; interpreting, contextualising and adapting knowledge to the local context; implementing and evaluating; and finally, the embedding and translating of new knowledge into practice.
Summary
Although descriptions of how to incorporate KT into research designs are increasing, current theoretical and operational frameworks do not generally span a holistic process from knowledge co-creation to knowledge application and implementation within one project. Population health studies may have greater health impact when KT is incorporated early and explicitly into the research design. This, we argue, will require that particular attention be paid to collaborative approaches, stakeholder identification and engagement, the nature and sources of evidence used, and the role of the research team working with the local study community.
doi:10.1186/1748-5908-8-54
PMCID: PMC3674953  PMID: 23694753
Knowledge translation; Population health; Engaged scholarship; co-KT Framework; Health system redesign
19.  Risk Assessment and Communication Tools for Genotype Associations with Multifactorial Phenotypes: The Concept of “Edge Effect” and Cultivating an Ethical Bridge between Omics Innovations and Society 
Applications of omics technologies in the postgenomics era swiftly expanded from rare monogenic disorders to multifactorial common complex diseases, pharmacogenomics, and personalized medicine. Already, there are signposts indicative of further omics technology investment in nutritional sciences (nutrigenomics), environmental health/ecology (ecogenomics), and agriculture (agrigenomics). Genotype–phenotype association studies are a centerpiece of translational research in omics science. Yet scientific and ethical standards and ways to assess and communicate risk information obtained from association studies have been neglected to date. This is a significant gap because association studies decisively influence which genetic loci become genetic tests in the clinic or products in the genetic test marketplace. A growing challenge concerns the interpretation of large overlap typically observed in distribution of quantitative traits in a genetic association study with a polygenic/multifactorial phenotype. To remedy the shortage of risk assessment and communication tools for association studies, this paper presents the concept of edge effect. That is, the shift in population edges of a multi-factorial quantitative phenotype is a more sensitive measure (than population averages) to gauge the population level impact and by extension, policy significance of an omics marker. Empirical application of the edge effect concept is illustrated using an original analysis of warfarin pharmacogenomics and the VKORC1 genetic variation in a Brazilian population sample. These edge effect analyses are examined in relation to regulatory guidance development for association studies. We explain that omics science transcends the conventional laboratory bench space and includes a highly heterogeneous cast of stakeholders in society who have a plurality of interests that are often in conflict. Hence, communication of risk information in diagnostic medicine also demands attention to processes involved in production of knowledge and human values embedded in scientific practice, for example, why, how, by whom, and to what ends association studies are conducted, and standards are developed (or not). To ensure sustainability of omics innovations and forecast their trajectory, we need interventions to bridge the gap between omics laboratory and society. Appreciation of scholarship in history of omics science is one remedy to responsibly learn from the past to ensure a sustainable future in omics fields, both emerging (nutrigenomics, ecogenomics), and those that are more established (pharmacogenomics). Another measure to build public trust and sustainability of omics fields could be legislative initiatives to create a multidisciplinary oversight body, at arm's length from conflict of interests, to carry out independent, impartial, and transparent innovation analyses and prospective technology assessment.
doi:10.1089/omi.2009.0011
PMCID: PMC2727354  PMID: 19290811
20.  Risk Assessment and Communication Tools for Genotype Associations with Multifactorial Phenotypes: The Concept of “Edge Effect” and Cultivating an Ethical Bridge between Omics Innovations and Society 
Abstract
Applications of omics technologies in the postgenomics era swiftly expanded from rare monogenic disorders to multifactorial common complex diseases, pharmacogenomics, and personalized medicine. Already, there are signposts indicative of further omics technology investment in nutritional sciences (nutrigenomics), environmental health/ecology (ecogenomics), and agriculture (agrigenomics). Genotype–phenotype association studies are a centerpiece of translational research in omics science. Yet scientific and ethical standards and ways to assess and communicate risk information obtained from association studies have been neglected to date. This is a significant gap because association studies decisively influence which genetic loci become genetic tests in the clinic or products in the genetic test marketplace. A growing challenge concerns the interpretation of large overlap typically observed in distribution of quantitative traits in a genetic association study with a polygenic/multifactorial phenotype. To remedy the shortage of risk assessment and communication tools for association studies, this paper presents the concept of edge effect. That is, the shift in population edges of a multifactorial quantitative phenotype is a more sensitive measure (than population averages) to gauge the population level impact and by extension, policy significance of an omics marker. Empirical application of the edge effect concept is illustrated using an original analysis of warfarin pharmacogenomics and the VKORC1 genetic variation in a Brazilian population sample. These edge effect analyses are examined in relation to regulatory guidance development for association studies. We explain that omics science transcends the conventional laboratory bench space and includes a highly heterogeneous cast of stakeholders in society who have a plurality of interests that are often in conflict. Hence, communication of risk information in diagnostic medicine also demands attention to processes involved in production of knowledge and human values embedded in scientific practice, for example, why, how, by whom, and to what ends association studies are conducted, and standards are developed (or not). To ensure sustainability of omics innovations and forecast their trajectory, we need interventions to bridge the gap between omics laboratory and society. Appreciation of scholarship in history of omics science is one remedy to responsibly learn from the past to ensure a sustainable future in omics fields, both emerging (nutrigenomics, ecogenomics), and those that are more established (pharmacogenomics). Another measure to build public trust and sustainability of omics fields could be legislative initiatives to create a multidisciplinary oversight body, at arm's length from conflict of interests, to carry out independent, impartial, and transparent innovation analyses and prospective technology assessment.
doi:10.1089/omi.2009.0011
PMCID: PMC2727354  PMID: 19290811
21.  Knowledge Translation Tools are Emerging to Move Neck Pain Research into Practice 
Development or synthesis of the best clinical research is in itself insufficient to change practice. Knowledge translation (KT) is an emerging field focused on moving knowledge into practice, which is a non-linear, dynamic process that involves knowledge synthesis, transfer, adoption, implementation, and sustained use. Successful implementation requires using KT strategies based on theory, evidence, and best practice, including tools and processes that engage knowledge developers and knowledge users. Tools can provide instrumental help in implementing evidence. A variety of theoretical frameworks underlie KT and provide guidance on how tools should be developed or implemented. A taxonomy that outlines different purposes for engaging in KT and target audiences can also be useful in developing or implementing tools. Theoretical frameworks that underlie KT typically take different perspectives on KT with differential focus on the characteristics of the knowledge, knowledge users, context/environment, or the cognitive and social processes that are involved in change. Knowledge users include consumers, clinicians, and policymakers. A variety of KT tools have supporting evidence, including: clinical practice guidelines, patient decision aids, and evidence summaries or toolkits. Exemplars are provided of two KT tools to implement best practice in management of neck pain—a clinician implementation guide (toolkit) and a patient decision aid. KT frameworks, taxonomies, clinical expertise, and evidence must be integrated to develop clinical tools that implement best evidence in the management of neck pain.
doi:10.2174/1874325001307010582
PMCID: PMC3805983  PMID: 24155807
Knowledge translation; neck pain; tools; implementation.
22.  Brief oral health promotion intervention among parents of young children to reduce early childhood dental decay 
BMC Public Health  2013;13:245.
Background
Severe untreated dental decay affects a child’s growth, body weight, quality of life as well as cognitive development, and the effects extend beyond the child to the family, the community and the health care system. Early health behavioural factors, including dietary practices and eating patterns, can play a major role in the initiation and development of oral diseases, particularly dental caries. The parent/caregiver, usually the mother, has a critical role in the adoption of protective health care behaviours and parental feeding practices strongly influence children’s eating behaviours. This study will test if an early oral health promotion intervention through the use of brief motivational interviewing (MI) and anticipatory guidance (AG) approaches can reduce the incidence of early childhood dental decay and obesity.
Methods
The study will be a randomised controlled study with parents and their new-born child/ren who are seen at 6–12 weeks of age by a child/community health nurse. Consenting parents will complete a questionnaire on oral health knowledge, behaviours, self-efficacy, oral health fatalism, parenting stress, prenatal and peri-natal health and socio-demographic factors at study commencement and at 12 and 36 months. Each child–parent pair will be allocated to an intervention or a standard care group, using a computer-generated random blocks. The standard group will be managed through the standard early oral health screening program; “lift the lip”. The intervention group will be provided with tailored oral health counselling by oral health consultants trained in MI and AG.
Participating children will be examined at 24, and 36 months for the occurrence of dental decay and have their height and weight recorded. Dietary information obtained from a food frequency chart will be used to determine food and dietary patterns. Data analysis will use intention to treat and per protocol analysis and will use tests of independent proportions and means. Multivariate statistical tests will also be used to take account of socio-economic and demographic factors in addition to parental knowledge, behaviour, self-efficacy, and parent/child stress.
Discussion
The study will test the effects of an oral health promotion intervention to affect oral health and general health and have the potential to demonstrate the “common risk factor” approach to health promotion.
Trial registration
Australian New Zealand Clinical Trials Registry: http://ACTRN12611000997954
doi:10.1186/1471-2458-13-245
PMCID: PMC3610190  PMID: 23509932
Motivational interviewing; Anticipatory guidance; Early childhood dental decay; Oral health promotion
23.  Understanding diagnosis and management of dementia and guideline implementation in general practice: a qualitative study using the theoretical domains framework 
Background
Dementia is a growing problem, causing substantial burden for patients, their families, and society. General practitioners (GPs) play an important role in diagnosing and managing dementia; however, there are gaps between recommended and current practice. The aim of this study was to explore GPs’ reported practice in diagnosing and managing dementia and to describe, in theoretical terms, the proposed explanations for practice that was and was not consistent with evidence-based guidelines.
Methods
Semi-structured interviews were conducted with GPs in Victoria, Australia. The Theoretical Domains Framework (TDF) guided data collection and analysis. Interviews explored the factors hindering and enabling achievement of 13 recommended behaviours. Data were analysed using content and thematic analysis. This paper presents an in-depth description of the factors influencing two behaviours, assessing co-morbid depression using a validated tool, and conducting a formal cognitive assessment using a validated scale.
Results
A total of 30 GPs were interviewed. Most GPs reported that they did not assess for co-morbid depression using a validated tool as per recommended guidance. Barriers included the belief that depression can be adequately assessed using general clinical indicators and that validated tools provide little additional information (theoretical domain of ‘Beliefs about consequences’); discomfort in using validated tools (‘Emotion’), possibly due to limited training and confidence (‘Skills’; ‘Beliefs about capabilities’); limited awareness of the need for, and forgetting to conduct, a depression assessment (‘Knowledge’; ‘Memory, attention and decision processes’). Most reported practising in a manner consistent with the recommendation that a formal cognitive assessment using a validated scale be undertaken. Key factors enabling this were having an awareness of the need to conduct a cognitive assessment (‘Knowledge’); possessing the necessary skills and confidence (‘Skills’; ‘Beliefs about capabilities’); and having adequate time and resources (‘Environmental context and resources’).
Conclusions
This is the first study to our knowledge to use a theoretical approach to investigate the barriers and enablers to guideline-recommended diagnosis and management of dementia in general practice. It has identified key factors likely to explain GPs’ uptake of the guidelines. The results have informed the design of an intervention aimed at supporting practice change in line with dementia guidelines, which is currently being evaluated in a cluster randomised trial.
doi:10.1186/1748-5908-9-31
PMCID: PMC4015883  PMID: 24581339
Dementia; General practitioners (GPs); Cognitive assessment; Depression assessment; Theoretical Domains Framework (TDF); Guideline implementation
24.  Patient-Reported Outcome Measures in Safety Event Reporting: PROSPER Consortium Guidance 
Drug Safety  2013;36(12):1129-1149.
The Patient-Reported Outcomes Safety Event Reporting (PROSPER) Consortium was convened to improve safety reporting by better incorporating the perspective of the patient. PROSPER comprises industry, regulatory authority, academic, private sector and patient representatives who are interested in the area of patient-reported outcomes of adverse events (PRO-AEs). It has developed guidance on PRO-AE data, including the benefits of wider use and approaches for data capture and analysis. Patient-reported outcomes (PROs) encompass the full range of self-reporting, rather than only patient reports collected by clinicians using validated instruments. In recent years, PROs have become increasingly important across the spectrum of healthcare and life sciences. Patient-centred models of care are integrating shared decision making and PROs at the point of care; comparative effectiveness research seeks to include patients as participatory stakeholders; and industry is expanding its involvement with patients and patient groups as part of the drug development process and safety monitoring. Additionally, recent pharmacovigilance legislation from regulatory authorities in the EU and the USA calls for the inclusion of patient-reported information in benefit–risk assessment of pharmaceutical products. For patients, technological advancements have made it easier to be an active participant in one’s healthcare. Simplified internet search capabilities, electronic and personal health records, digital mobile devices, and PRO-enabled patient online communities are just a few examples of tools that allow patients to gain increased knowledge about conditions, symptoms, treatment options and side effects. Despite these changes and increased attention on the perceived value of PROs, their full potential has yet to be realised in pharmacovigilance. Current safety reporting and risk assessment processes remain heavily dependent on healthcare professionals, though there are known limitations such as under-reporting and discordant perspectives between patient reports and clinician perceptions of adverse outcomes. PROSPER seeks to support the wider use of PRO-AEs. The scope of this guidance document, which was completed between July 2011 and March 2013, considered a host of domains related to PRO-AEs, including definitions and suitable taxonomies, the range of datasets that could be used, data collection mechanisms, and suitable analytical methodologies. PROSPER offers an innovative framework to differentiate patient populations. This framework considers populations that are prespecified (such as those in clinical trials, prospective observational studies and some registries) and non-prespecified populations (such as those in claims databases, PRO-enabled online patient networks, and social websites in general). While the main focus of this guidance is on post-approval PRO-AEs from both prespecified and non-prespecified population groups, PROSPER has also considered pre-approval, prespecified populations. The ultimate aim of this guidance is to ensure that the patient ‘voice’ and perspective feed appropriately into collection of safety data. The guidance also covers a minimum core dataset for use by industry or regulators to structure PRO-AEs (accessible in the online appendix) and how data, once collected, might be evaluated to better inform on the safe and effective use of medicinal products. Structured collection of such patient data can be considered both a means to an end (improving patient safety) as well as an end in itself (expressing the patient viewpoint). The members of the PROSPER Consortium therefore direct this PRO-AE guidance to multiple stakeholders in drug safety, including industry, regulators, prescribers and patients. The use of this document across the entirety of the drug development life cycle will help to better define the benefit–risk profile of new and existing medicines. Because of the clinical relevance of ‘real-world’ data, PROs have the potential to contribute important new knowledge about the benefits and risks of medicinal products, communicated through the voice of the patient.
Electronic supplementary material
The online version of this article (doi:10.1007/s40264-013-0113-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s40264-013-0113-z
PMCID: PMC3834161  PMID: 24092596
25.  Implementing change in primary care practices using electronic medical records: a conceptual framework 
Background
Implementing change in primary care is difficult, and little practical guidance is available to assist small primary care practices. Methods to structure care and develop new roles are often needed to implement an evidence-based practice that improves care. This study explored the process of change used to implement clinical guidelines for primary and secondary prevention of cardiovascular disease in primary care practices that used a common electronic medical record (EMR).
Methods
Multiple conceptual frameworks informed the design of this study designed to explain the complex phenomena of implementing change in primary care practice. Qualitative methods were used to examine the processes of change that practice members used to implement the guidelines. Purposive sampling in eight primary care practices within the Practice Partner Research Network-Translating Researching into Practice (PPRNet-TRIP II) clinical trial yielded 28 staff members and clinicians who were interviewed regarding how change in practice occurred while implementing clinical guidelines for primary and secondary prevention of cardiovascular disease and strokes.
Results
A conceptual framework for implementing clinical guidelines into primary care practice was developed through this research. Seven concepts and their relationships were modelled within this framework: leaders setting a vision with clear goals for staff to embrace; involving the team to enable the goals and vision for the practice to be achieved; enhancing communication systems to reinforce goals for patient care; developing the team to enable the staff to contribute toward practice improvement; taking small steps, encouraging practices' tests of small changes in practice; assimilating the electronic medical record to maximize clinical effectiveness, enhancing practices' use of the electronic tool they have invested in for patient care improvement; and providing feedback within a culture of improvement, leading to an iterative cycle of goal setting by leaders.
Conclusion
This conceptual framework provides a mental model which can serve as a guide for practice leaders implementing clinical guidelines in primary care practice using electronic medical records. Using the concepts as implementation and evaluation criteria, program developers and teams can stimulate improvements in their practice settings. Investing in collaborative team development of clinicians and staff may enable the practice environment to be more adaptive to change and improvement.
doi:10.1186/1748-5908-3-3
PMCID: PMC2254645  PMID: 18199330

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