Opportunities to Enhance Diagnostic Testing and Antimicrobial Stewardship: A Qualitative Multinational Survey of Healthcare Professionals.

INTRODUCTION: Antimicrobial resistance (AMR) is a global public health challenge. Global efforts to decrease AMR through antimicrobial stewardship (AMS) initiatives include education and optimising the use of diagnostic technologies and antibiotics. Despite this, economic and societal challenges hinder AMS efforts. The objective of this study was to obtain insights from healthcare professionals (HCPs) on current challenges and identify opportunities for optimising diagnostic test utilisation and AMS efforts. METHODS: Three hundred HCPs from six countries (representing varied gross national incomes per capita, healthcare system structure, and AMR rates) were surveyed between November 2022 through January 2023. A targeted literature review and expert interviews were conducted to inform survey development. Descriptive statistics were used to summarise survey responses. RESULTS: These findings suggest that the greatest challenges to diagnostic test utilisation were economic in nature; many HCPs reported that AMS initiatives were lacking investment (32.3%) and resourcing (40.3%). High resistance rates were considered the greatest barriers to appropriate antimicrobial use (52.0%). Most HCPs found local and national guidelines to be very useful (≥ 51.0%), but areas for improvement were noted. The importance of AMS initiatives was confirmed; diagnostic practices were acknowledged to have a positive impact on decreasing AMR (70.3%) and improving patient outcomes (81.0%). CONCLUSION: AMS initiatives, including diagnostic technology utilisation, are pivotal to decreasing AMR rates. Interpretation of these survey results suggests that while HCPs consider diagnostic practices to be important in AMS efforts, several barriers to successful implementation still exist including patient/institutional costs, turnaround time of test results, resourcing, AMR burden, and education. While some barriers differ by country, these survey results highlight areas of opportunities in all countries for improved use of diagnostic technologies and broader AMS efforts, as perceived by HCPs. Greater investment, resourcing, education, and updated guidelines offer opportunities to further strengthen global AMS efforts.

Antimicrobials are medications used to treat infections caused by bacteria (e.g. antibiotics), viruses, parasites, and fungi. Over time, these microbes may become resistant to antimicrobials, limiting how well they work. This often happens as a result of overuse, using antimicrobials when there is not an infection, or using an inappropriate antimicrobial. Antimicrobial resistance is a growing global problem. Antimicrobial stewardship programs aim to improve appropriate use of antimicrobials. Diagnostic testing plays an important role in these programs by identifying the microbes responsible for infections so patients can be given the right treatment as quickly as possible. We aimed to obtain the perspective of healthcare professionals from six countries on the challenges of and ways to improve diagnostic testing and antimicrobial stewardship programs. We found that some of the greatest challenges were related to costs. Approximately one-third of participants said that antimicrobial stewardship initiatives were lacking investment (32.3%) and resourcing (40.3%). High rates of antimicrobial resistance were identified as the greatest barriers to appropriate antimicrobial use (52.0%). Participants said that diagnostic practices have a positive impact on decreasing antimicrobial resistance (70.3%) and improving patient outcomes (81.0%). Overall, we found that healthcare professionals consider diagnostic tests to be an important part of antimicrobial stewardship, but there are several barriers to their success, including patient/hospital costs, turnaround time of test results, resourcing, antimicrobial resistance, and education. To overcome these barriers, increased funding, education, and resourcing, regular guideline updates, and development of optimised testing algorithms may help to improve antimicrobial stewardship and ultimately decrease antimicrobial resistance.

Introduction to the EQIPD quality system.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

Systematic review of guidelines for internal validity in the design, conduct and analysis of preclinical biomedical experiments involving laboratory animals.

Over the last two decades, awareness of the negative repercussions of flaws in the planning, conduct and reporting of preclinical research involving experimental animals has been growing. Several initiatives have set out to increase transparency and internal validity of preclinical studies, mostly publishing expert consensus and experience. While many of the points raised in these various guidelines are identical or similar, they differ in detail and rigour. Most of them focus on reporting, only few of them cover the planning and conduct of studies. The aim of this systematic review is to identify existing experimental design, conduct, analysis and reporting guidelines relating to preclinical animal research. A systematic search in PubMed, Embase and Web of Science retrieved 13 863 unique results. After screening these on title and abstract, 613 papers entered the full-text assessment stage, from which 60 papers were retained. From these, we extracted unique 58 recommendations on the planning, conduct and reporting of preclinical animal studies. Sample size calculations, adequate statistical methods, concealed and randomised allocation of animals to treatment, blinded outcome assessment and recording of animal flow through the experiment were recommended in more than half of the publications. While we consider these recommendations to be valuable, there is a striking lack of experimental evidence on their importance and relative effect on experiments and effect sizes.

Guidelines and Initiatives for Good Research Practice.

This chapter explores existing data reproducibility and robustness initiatives from a cross-section of large funding organizations, granting agencies, policy makers, journals, and publishers with the goal of understanding areas of overlap and potential gaps in recommendations and requirements. Indeed, vigorous stakeholder efforts to identify and address irreproducibility have resulted in the development of a multitude of guidelines but with little harmonization. This likely results in confusion for the scientific community and may pose a barrier to strengthening quality standards instead of being used as a resource that can be meaningfully implemented. Guidelines are also often framed by funding bodies and publishers as recommendations instead of requirements in order to accommodate scientific freedom, creativity, and innovation. However, without enforcement, this may contribute to uneven implementation. The text concludes with an analysis to provide recommendations for future guidelines and policies to enhance reproducibility and to align on a consistent strategy moving forward.

Protocol for a systematic review of guidelines for rigour in the design, conduct and analysis of biomedical experiments involving laboratory animals.

OBJECTIVE: Within the last years, there has been growing awareness of the negative repercussions of unstandardized planning, conduct and reporting of preclinical and biomedical research. Several initiatives have set the aim of increasing validity and reliability in reporting of studies and publications, and publishers have formed similar groups. Additionally, several groups of experts across the biomedical spectrum have published experience and opinion-based guidelines and guidance on potential standardized reporting. While all these guidelines cover reporting of experiments, an important step prior to this should be rigours planning and conduction of studies. The aim of this systematic review is to identify and harmonize existing experimental design, conduct and analysis guidelines relating to internal validity and reproducibility of preclinical animal research. The review will also identify literature describing risks of bias pertaining to the design, conduct and analysis of preclinical biomedical research. SEARCH STRATEGY: PubMed, Embase and Web of Science will be searched systematically to identify guidelines published in English language in peer-reviewed journals before January 2018 (box 1). All articles or systematic reviews in English language that describe or review guidelines on the internal validity and reproducibility of animal studies will be included. Google search for guidelines published on the websites of major funders and professional organisations can be found in (Box 2). SCREENING AND ANNOTATION: Unique references will be screened in two phases: screening for eligibility based on title and abstract, followed by screening for definitive inclusion based on full text. Screening will be performed in SyRF (http://syrf.org.uk). Each reference will be randomly presented to two independent reviewers. Disagreements between reviewers will be resolved by additional screening of the reference by a third, senior researcher. DATA MANAGEMENT AND REPORTING: All data, including extracted text and guidelines, will be stored in the SyRF platform. Elements of the included guidelines will be identified using a standardized extraction form. Reporting will follow the PRISMA guidelines as far as applicable.

Improving and accelerating drug development for nervous system disorders.

Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development, and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development, the Institute of Medicine's Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience.

Rural mass casualty preparedness and response: the Institute of Medicine's Forum on Medical and Public Health Preparedness for Catastrophic Events.

The Institute of Medicine's Forum on Medical and Public Health Preparedness for Catastrophic Events hosted a workshop at the request of the Federal Interagency Committee on Emergency Medical Services (FICEMS) that brought together a range of stakeholders to broadly identify and confront gaps in rural infrastructure that challenge mass casualty incident (MCI) response and potential mechanisms to fill them. This report summarizes the presentations and discussions around 6 major issues specific to rural MCI preparedness and response: (1) improving rural response to MCI through improving daily capacity and capability, (2) leveraging current and emerging technology to overcome infrastructure deficits, (3) sustaining and strengthening relationships, (4) developing and sharing best practices across jurisdictions and sectors, (5) establishing metrics research and development, and (6) fostering the need for federal leadership to expand and integrate EMS into a broader rural response framework.

The Institute of Medicine's Forum on Medical and Public Health Preparedness for Catastrophic Events: regional workshop series on the 2009 H1N1 influenza vaccination campaign.

In response to the 2009 H1N1 influenza pandemic, public health authorities launched an ambitious vaccination program to protect tens of millions of Americans from the virus. In April and May 2010, the Institute of Medicine Forum on Medical and Public Health Preparedness for Catastrophic Events hosted a series of 3 regional workshops to examine the 2009 H1N1 vaccination campaign. The workshops brought together stakeholders involved in distributing and dispensing H1N1 vaccine to discuss successes and challenges and to identify strategies to improve future vaccination programs and other medical countermeasure dispensing campaigns. On the basis of the presentations and the discussions that followed, several themes and opportunities for future efforts were identified in the following areas: vaccine supply and demand; state and local implementation of Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices recommendations, including prioritization for vaccination; vaccine formulations and priority groups; opportunities for developing partnerships; opportunities to increase seasonal vaccination rates among pregnant women and health care workers and to increase acceptance of live attenuated nasal spray vaccine; standardization and improvement of immunization information management systems; opportunities to simplify, systematize, and automate processes and practices; and research needs and opportunities.

Medical countermeasures dispensing: emergency use authorization and the postal model: workshop summary

Report which provides an overview of current threats, recent progress made in the public health system for distributing and dispensing countermeasures, and remaining vulnerabilities. Summary from the Forum on Medical and Public Health Preparedness for Catastrophic Events held in November 18, 2009. Download the publication in pdf file by signing in.

Institute of Medicine's Forum on Medical and Public Health Preparedness for Catastrophic Events: current initiatives.

It is only possible to achieve a resilient community and an integrated, comprehensive, and resilient health system that can respond effectively to a public health emergency through active collaboration, coordination, and shared responsibility among a broad group of public and private stakeholders and the community itself. The Institute of Medicine established the Forum on Medical and Public Health Preparedness for Catastrophic Events in 2007 to provide a neutral venue for dialogue and collaboration among stakeholders in the preparedness field. In the Forum's first year, the members began to address topics such as medical countermeasures dispensing, crisis standards of care, and medical surge capacity. In the past 9 months, the Forum members have expanded their areas of interest in response to current events and national areas of focus. Current topics include individual, family, and community preparedness and resiliency; medical countermeasures from development through dispensing; and the response to the 2009 H1N1 influenza pandemic. Across all of the initiatives undertaken by the Forum, the common element is that they tackle problems, gaps, and future opportunities that can only be successfully addressed if multiple stakeholders work together.

Molecules to minds: grand challenges for the 21st century.

The Institute of Medicine's Forum on Neuroscience and Nervous System Disorders established a "Grand Challenges Initiative." The goal is to help frame a broad, integrated research program that would attract substantial funding and generate additional resources to support large-scale efforts to tackle some of the most daunting but important neuroscience questions.

Autism and the environment: challenges and opportunities for research.

Autism spectrum disorder is a complex developmental disorder that dramatically affects the lives of patients and their families and the broader community. The causes of autism are unknown; however, evidence increasingly suggests that a complex interplay among environmental stressors, genetic mutations, and other biological factors likely plays a significant role in the development and/or progression of autism spectrum disorder. On April 18 and 19, 2007, the Institute of Medicine's Forum on Neuroscience and Nervous System Disorders hosted a workshop to provide a venue to bring together scientists; major sponsors of autism-related research; and members of the autism patient, family, and advocacy community to discuss the most promising and urgent scientific questions and opportunities. Broad participation by the autism community enriched the meeting significantly by contributing a valuable and personal perspective that is often missing from scientific meetings. It also began a much improved public-private partnership in which all stakeholders are represented. On the basis of the presentations and the discussions that followed, an array of important scientific opportunities were identified in 5 general categories: (1) opportunities to advance clinical research; (2) opportunities to enhance epidemiologic studies; (3) opportunities to improve the understanding of autism's pathology and etiology; (4) tools and infrastructure needs; and (5) opportunities for public-private partnerships. This workshop demonstrated that full public engagement can greatly enhance activities such as this workshop and its outcomes. Furthermore, we expect that this listing of scientific challenges, needs, and opportunities will help to frame a more comprehensive research agenda.

Four classes of intercellular channels between glial cells in the CNS.

Astrocytes form extensive gap junctions with other astrocytes and with oligodendrocytes. Junctional communication between CNS glia is likely of critical importance because loss of the gap junction channel-forming proteins, connexins Cx32 and Cx47, result in severe demyelination. However, CNS glia express at least six connexins, and the cellular origins and relationships of these proteins have not been determined. We produced a Cx29 reporter mouse in which the connexin coding sequence was replaced with a histological marker, which was used to demonstrate that Cx29, Cx32, and Cx47 are expressed specifically in oligodendrocytes. To determine the relationships between astrocyte and oligodendrocyte connexins, we used double- and triple-immunofluorescence microscopy using semithin sections (<1 microm) of adult mouse spinal cord. Astrocytes form two distinct classes of gap junctions with each other; those composed of Cx26 and those composed of Cx43 and Cx30. In addition, astrocytes establish two classes of intercellular channels with oligodendrocytes, heterotypic Cx26-Cx32 channels and heterotypic Cx30/Cx43-Cx47 channels that may also be heteromeric. In contrast, Cx29 does not colocalize with any of the other five connexins. The data provide the first in vivo demonstration of heterotypic intercellular channels and reveal an unexpected complexity in the composition of glial gap junctions.

Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems.

Although both Schwann cells and oligodendrocytes express connexin32 (Cx32), the loss of this connexin causes demyelination only in the PNS. To determine whether oligodendrocytes might express another connexin that can function in place of Cx32, we searched for novel CNS-specific connexins using reverse transcriptase-PCR and degenerate primers. We identified Cx29, whose transcript was restricted to brain, spinal cord, and sciatic nerve. Developmental expression of Cx29 mRNA in the CNS paralleled that of other myelin-related mRNAs, including Cx32. In the CNS, Cx29 antibodies labeled the internodal and juxtaparanodal regions of small myelin sheaths, whereas Cx32 staining was restricted to large myelinated fibers. In the PNS, Cx29 expression preceded that of Cx32 and declined to lower levels than Cx32 in adulthood. In adult sciatic nerve, Cx29 was primarily localized to the innermost aspects of the myelin sheath, the paranode, the juxtaparanode, and the inner mesaxon. Cx29 displayed a striking coincidence with Kv1.2 K(+) channels, which are localized in the axonal membrane. Both Cx29 and Cx32 were found in the incisures. Cx29 expressed in N2A cells did not induce intercellular conductances but did participate in the formation of active channels when coexpressed with Cx32. Together, these data show that Cx29 and Cx32 are expressed by myelinating glial cells with distinct distributions.