The value of health service-based research to health service organisations: a qualitative study with senior health service executives.

BACKGROUND: Research evidence has demonstrably improved health care practices and patient outcomes. However, systemic translation of evidence into practice is far from optimal. The reasons are complex, but often because research is not well aligned with health service priorities. The aim of this study was to explore the experiences and perspectives of senior health service executives on two issues: (1) the alignment between local research activity and the needs and priorities of their health services, and (2) the extent to which research is or can be integrated as part of usual health care practice. METHODS: In this qualitative study, semi-structured interviews were conducted with senior health leaders from four large health service organisations that are members of Sydney Health Partners (SHP), one of Australia's nationally accredited research translation centres committed to accelerating the translation of research findings into evidence-based health care. The interviews were conducted between November 2022 and January 2023, and were either audio-recorded and transcribed verbatim or recorded in the interviewer field notes. A thematic analysis of the interview data was conducted by two researchers, using the framework method to identify common themes. RESULTS: Seventeen health executives were interviewed, including chief executives, directors of medical services, nursing, allied health, research, and others in executive leadership roles. Responses to issue (1) included themes on re-balancing curiosity- and priority-driven research; providing more support for research activity within health organisations; and helping health professionals and researchers discuss researchable priorities. Responses to issue (2) included identification of elements considered essential for embedding research in health care; and the need to break down silos between research and health care, as well as within health organisations. CONCLUSIONS: Health service leaders value research but want more research that aligns with their needs and priorities. Discussions with researchers about those priorities may need some facilitation. Making research a more integrated part of health care will require strong and broad executive leadership, resources and infrastructure, and investing in capacity- and capability-building across health clinicians, managers and executive staff.

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states.

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data.

Antibody drug conjugates (ADCs) have made impressive strides in the clinic in recent years with 11 Food and Drug Administration approvals, including 6 for the treatment of patients with solid tumors. Despite this success, the development of new agents remains challenging with a high failure rate in the clinic. Here, we show that current approved ADCs for the treatment of patients with solid tumors can all show substantial efficacy in some mouse models when administered at a similar weight-based [milligrams per kilogram (mg/kg)] dosing in mice that is tolerated in the clinic. Mechanistically, equivalent mg/kg dosing results in a similar drug concentration in the tumor and a similar tissue penetration into the tumor due to the unique delivery features of ADCs. Combined with computational approaches, which can account for the complex distribution within the tumor microenvironment, these scaling concepts may aid in the evaluation of new agents and help design therapeutics with maximum clinical efficacy.

Mitigating animal methods bias to reduce animal use and improve biomedical translation.

Nonanimal biomedical research methods have advanced rapidly over the last decade making them the first-choice model for many researchers due to improved translatability and avoidance of ethical concerns. Yet confidence in novel nonanimal methods is still being established and they remain a small portion of nonclinical biomedical research, which can lead peer reviewers to evaluate animal-free studies or grant proposals in a biased manner. This "animal methods bias" is the preference for animal-based research methods where they are not necessary or where nonanimal-based methods are suitable. It affects the fair consideration of animal-free biomedical research, hampering the uptake and dissemination of these approaches by putting pressure on researchers to conduct animal experiments and potentially perpetuating the use of poorly translatable model systems. An international team of researchers and advocates called the Coalition to Illuminate and Address Animal Methods Bias (COLAAB) aims to provide concrete evidence of the existence and consequences of this bias and to develop and implement solutions towards overcoming it. The COLAAB recently developed the first of several mitigation tools: the Author Guide for Addressing Animal Methods Bias in Publishing, which is described herein along with broader implications and future directions of this work.

Editorial: No short-cuts - translating neurobiological knowledge to clinical practice requires moving away from stand-alone biomarkers to an integrative biopsychosocial approach.

Although decades of research have shown the importance of neurobiological factors in the development of mental health problems in children and adolescents, the translation of this knowledge to use in clinical practice has proven difficult. One of the pitfalls is the false assumption that biological factors are so fundamental that they overrule all other factors and can be used as stand-alone biomarkers or tests for diagnostic purposes and treatment decisions. This assumption is false because all neurodevelopmental disorders result from complex interactions between biology and environment. Therefore, neurobiological assessments should never be used as a shortcut for diagnostic assessments that include the environment, including family, peers, and society at large. Instead, they should be integrated in the diagnostic process. This calls for empirically supported guidance on how to weigh information from neurobiological and psychosocial assessments in the diagnostic and treatment decision process.

What predicts citation counts and translational impact in headache research? A machine learning analysis.

BACKGROUND: We aimed to develop the first machine learning models to predict citation counts and the translational impact, defined as inclusion in guidelines or policy documents, of headache research, and assess which factors are most predictive. METHODS: Bibliometric data and the titles, abstracts, and keywords from 8600 publications in three headache-oriented journals from their inception to 31 December 2017 were used. A series of machine learning models were implemented to predict three classes of 5-year citation count intervals (0-5, 6-14 and, >14 citations); and the translational impact of a publication. Models were evaluated out-of-sample with area under the receiver operating characteristics curve (AUC). RESULTS: The top performing gradient boosting model predicted correct citation count class with an out-of-sample AUC of 0.81. Bibliometric data such as page count, number of references, first and last author citation counts and h-index were among the most important predictors. Prediction of translational impact worked optimally when including both bibliometric data and information from the title, abstract and keywords, reaching an out-of-sample AUC of 0.71 for the top performing random forest model. CONCLUSION: Citation counts are best predicted by bibliometric data, while models incorporating both bibliometric data and publication content identifies the translational impact of headache research.

Time for Medicine and Public Health to Leave Platform X.

Unlabelled: For more than 50 years, digital technologies have been employed for the creation and distribution of knowledge in health services. In the last decade, digital social media have been developed for applications in clinical decision support and population health monitoring. Recently, these technologies have also been used for knowledge translation, such as in the process where research findings created in academic settings are established as evidence and distributed for use in clinical practice, policy making, and health self-management. To date, it has been common for medical and public health institutions to have social media accounts for the dissemination of novel research findings and to facilitate conversations about these findings. However, recent events such as the transformation of the microblog Twitter to platform X have brought to light the need for the social media industry to exploit user data to generate revenue. In this viewpoint, it is argued that a redirection of social media use is required in the translation of knowledge to action in the fields of medicine and public health. A new kind of social internet is currently forming, known as the "fediverse," which denotes an ensemble of open social media that can communicate with each other while remaining independent platforms. In several countries, government institutions, universities, and newspapers use open social media to distribute information and enable discussions. These organizations control their own channels while being able to communicate with other platforms through open standards. Examples of medical knowledge translation via such open social media platforms, where users are less exposed to disinformation than in general platforms, are also beginning to appear. The current status of the social media industry calls for a broad discussion about the use of social technologies by health institutions involving researchers and health service practitioners, academic leaders, scientific publishers, social technology providers, policy makers, and the public. This debate should not primarily take place on social media platforms but rather at universities, in scientific journals, at public seminars, and other venues, allowing for the transparent and undisturbed communication and formation of opinions.

Liver Diseases: From Bench to Bedside.

The human genome encodes at least 500 protein kinases, and among them, there are at least 90 tyrosine kinases [...].

Recent Translational Research Models of Intracranial Atherosclerotic Disease.

Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke worldwide. However, research on the pathophysiology of ICAD is scarce due to the relative inaccessibility of histology samples and the lack of comprehensive experimental models. As a result, much of the current understanding of ICAD relies on research on extracranial atherosclerosis. This approach is problematic as intracranial and extracranial arteries are anatomically, structurally, physiologically, and metabolically distinct, indicating that intracranial and extracranial atherosclerosis likely develop through different biologic pathways. The current standard of care for ICAD treatment relies predominantly on therapeutics developed to treat extracranial atherosclerosis and is insufficient given the alarmingly high risk of stroke. To provide a definitive treatment for the disease, a deeper understanding of the pathophysiology underlying ICAD is specifically required. True mechanistic understanding of disease pathogenesis is only possible using robust experimental models. In this review, we aim to identify the advantages and limitations of the existing in vivo and in vitro models of ICAD and basic atherosclerotic processes, which may be used to inform better models of ICAD in the future and drive new therapeutic strategies to reduce stroke risk.

A Translational Case Study of a Multisite COVID-19 Public Health Intervention Across Sequenced Research Trials: Embedding Implementation in a Community Engagement Phased Framework.

Through a COVID-19 public health intervention implemented across sequenced research trials, we present a community engagement phased framework that embeds intervention implementation: (1) consultation and preparation, (2) collaboration and implementation, and (3) partnership and sustainment. Intervention effects included mitigation of psychological distress and a 0.28 increase in the Latinx population tested for SARS-CoV-2. We summarize community engagement activities and implementation strategies that took place across the trials to illustrate the value of the framework for public health practice and research. (Am J Public Health. 2024;114(S5):S396-S401. https://doi.org/10.2105/AJPH.2024.307669).

Innovation at the Intersection: Emerging Translational Research in Neurology and Psychiatry.

Translational research in neurological and psychiatric diseases is a rapidly advancing field that promises to redefine our approach to these complex conditions [...].

Updates in Translational Science for Esophageal and Gastric Cancers.

In this article, the authors summarize the current state of translational science for esophageal and gastric cancers. The available targeted therapies, immunotherapies, and recently discovered molecular targets are reviewed. The authors introduce circulating tumor deoxyribonucleic acid and its promise as a biomarker to detect disease recurrence. The authors present patient-derived organoids as a new model for studying carcinogenesis and treatment responses. Finally, we discuss the implications of organoid models for precision oncology and describe exciting new work applying gene editing technology to organoids and studying tumor-microenvironment interactions using 3-dimensional co-culture systems.

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

Workshop report - interdisciplinary metabolomic epidemiology: the pathway to clinical translation.

Metabolomic epidemiology studies are complex and require a broad array of domain expertise. Although many metabolite-phenotype associations have been identified; to date, few findings have been translated to the clinic. Bridging this gap requires understanding of both the underlying biology of these associations and their potential clinical implications, necessitating an interdisciplinary team approach. To address this need in metabolomic epidemiology, a workshop was held at Metabolomics 2023 in Niagara Falls, Ontario, Canada that highlighted the domain expertise needed to effectively conduct these studies -- biochemistry, clinical science, epidemiology, and assay development for biomarker validation -- and emphasized the role of interdisciplinary teams to move findings towards clinical translation.

Barriers to participation in biosampling-based translational research: A cross-sectional survey of Canadian critical care researchers.

BACKGROUND AND OBJECTIVE: Collection of biosamples for translational research studies is vital for understanding biological pathways, discovering disease-related biomarkers, and identifying novel therapeutic targets. However, a lack of infrastructure for sample procurement, processing, storage, and shipping may hinder the ability of clinical research units to effectively engage in translational research. The purpose of this study was to identify the barriers to biosampling-based translational research in the critical care setting in Canada. METHODS: We administered an online survey to members of the Canadian Critical Care Trials Group (CCCTG), the Canadian Critical Care Translational Biology Group (CCCTBG), and the Canadian Critical Care Research Coordinators Group (CCCRCG). The survey focused on participants' personal experience of biosampling research, research infrastructure, motivating factors, and perceived barriers. RESULTS: We received 59 responses from 31 sites, including 6 community intensive care unit (ICU) sites. The overall response rate was 11.3%. The majority of respondents were research coordinators (44%), followed by clinician-investigators (33.8%), graduate students (10.2%), and PhD-investigators (8.5%). Although most (63.8%) respondents reported an interest in participating in translational research, they also reported that their ICUs were currently contributing to a third of the number of translational studies compared to clinical studies. For respondents with experience in participating in translational research studies, the most common barriers were lack of funding, lack of time, and insufficient research staff. For respondents without previous experience, the perceived facilitators were more interest from their research group, improved training/mentorship, increased funding, and better access to laboratory equipment. CONCLUSIONS: Our survey found that the majority of participants were interested in and recognize the value of participating in biosampling-based translational research but lacked funding, time, and research personnel trained in biosampling protocols. Our survey also identified factors that might encourage participation at new sites. Addressing these barriers will be a key step towards increasing translational research capacity across Canada.

Developing and planning country-specific integrated knowledge translation strategies: experiences from the GELA project in Malawi, Nigeria, and South Africa.

BACKGROUND: The Global Evidence, Local Adaptation (GELA) project aims to maximise the impact of research on poverty-related diseases by increasing researchers' and decision-makers' capacity to use global research to develop locally relevant guidelines for newborn and child health in Malawi, Nigeria and South Africa. To facilitate ongoing collaboration with stakeholders, we adopted an Integrated Knowledge Translation (IKT) approach within GELA. Given limited research on IKT in African settings, we documented our team's IKT capacity and skills, and process and experiences with developing and implementing IKT in these countries. METHODS: Six IKT champions and a coordinator formed the GELA IKT Working Group. We gathered data on our baseline IKT competencies and processes within GELA, and opportunities, challenges and lessons learned, from April 2022 to March 2023 (Year 1). Data was collected from five two-hour Working Group meetings (notes, presentation slides and video recordings); [2] process documents (flowcharts and templates); and [3] an open-ended questionnaire. Data was analysed using a thematic analysis approach. RESULTS: Three overarching themes were identified: [1] IKT approach applied within GELA [2], the capacity and motivations of IKT champions, and [3] the experiences with applying the GELA IKT approach in the three countries. IKT champions and country teams adopted an iterative approach to carry out a comprehensive mapping of stakeholders, determine stakeholders' level of interest in and influence on GELA using the Power-Interest Matrix, and identify realistic indicators for monitoring the country-specific strategies. IKT champions displayed varying capacities, strong motivation, and they engaged in skills development activities. Country teams leveraged existing relationships with their National Ministries of Health to drive responses and participation by other stakeholders, and adopted variable communication modes (e.g. email, phone calls, social media) for optimal engagement. Flexibility in managing competing interests and priorities ensured optimal participation by stakeholders, although the time and resources required by IKT champions were frequently underestimated. CONCLUSIONS: The intentional, systematic, and contextualized IKT approach carried out in the three African countries within GELA, provides important insights for enhancing the implementation, feasibility and effectiveness of other IKT initiatives in Africa and similar low- and middle-income country (LMIC) settings.