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Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies., (© 2024. The Author(s).)

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes., (© 2024. The Author(s).)

Obesity is a serious global illness that is frequently associated with metabolic syndrome. Adipocytes are the typical cells of adipose organ, which is composed of at least two different tissues, white and brown adipose tissue. They functionally cooperate, interconverting each other under physiological conditions, but differ in their anatomy, physiology, and endocrine functions. Different cellular models have been proposed to study adipose tissue in vitro. They are also useful for elucidating the mechanisms that are responsible for a pathological condition, such as obesity, and for testing therapeutic strategies. Each cell model has its own characteristics, culture conditions, advantages and disadvantages. The choice of one model rather than another depends on the specific study the researcher is conducting. In recent decades, three-dimensional cultures, such as adipose spheroids, have become very attractive because they more closely resemble the phenotype of freshly isolated cells. The use of such models has developed in parallel with the evolution of translational research, an interdisciplinary branch of the biomedical field, which aims to learn a scientific translational approach to improve human health and longevity. The focus of the present review is on the growing body of data linking the use of new cell models and the spread of translational research. Also, we discuss the possibility, for the future, to employ new three-dimensional adipose tissue cell models to promote the transition from benchside to bedsite and vice versa, allowing translational research to become routine, with the final goal of obtaining clinical benefits in the prevention and treatment of obesity and related disorders., (© 2024. The Author(s).)

Background: Communication is a multifaceted process, ranging from linear, one-way approaches, such as transmitting a simple message, to continuous exchanges and feedback loops among stakeholders. In particular the COVID-19 pandemic underscored the critical need for timely, effective and credible evidence communication to increase awareness, levels of trust, and evidence uptake in policy and practice. However, whether to improve policy responses in crises or address more commonplace societal challenges, comprehensive guidance on evidence communication to decision-makers in health policies and systems remains limited. Our objective was to identify and systematize the global evidence on frameworks, guidance and tools supporting effective communication of research evidence to facilitate knowledge translation and evidence-informed policy-making processes, while also addressing barriers and facilitators., Methods: We conducted a rapid scoping review following the Joanna Briggs Manual. Literature searches were performed across eight indexed databases and two sources of grey literature, without language or time restrictions. The methodological quality of included studies was assessed, and a narrative-interpretative synthesis was applied to present the findings., Results: We identified 16 documents presenting either complete frameworks or framework components, including guidance and tools, aimed at supporting evidence communication for policy development. These frameworks outlined strategies, theoretical models, barriers and facilitators, as well as insights into policy-makers' perspectives, communication needs, and preferences. Three primary evidence communication strategies, comprising eleven sub-strategies, emerged: "Health information packaging", "Targeting and tailoring messages to the audience", and "Combined communication strategies". Based on the documented barriers and facilitators at micro, meso and macro levels, critical factors for successful communication of evidence to policy-makers were identified., Conclusions: Effective communication is indispensable for facilitating knowledge translation and evidence-informed policy-making. Nonetheless gaps persist in frameworks designed to enhance research communication to policy-makers, particularly regarding the effectiveness of multiple communication strategies. To advance in this field, the development of comprehensive frameworks incorporating implementation strategies is warranted. Additionally, barriers and facilitators to implementing effective communication must be recognized and addressed taking diverse contexts into consideration. Registration https://zenodo.org/record/5578550., (© 2024. The Author(s).)

Background: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects., Methods: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs., Results: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects., Conclusions: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC., (© 2024. The Author(s).)

Background: Embedded researchers are a novel intervention to improve the translation of research evidence into policy and practice settings, including public health. These roles are being implemented with increasing popularity, but they often lack clear evaluative frameworks. Understanding initial levels of research activity, including associated barriers and opportunities, is essential to developing theories of change and thus shaping the roles and defining expectations. We aimed to identify the principal determinants of research activity in public health that contextualise embedded researcher roles, including attributes of the embedded researcher themselves., Methods: We undertook seventeen semi-structured interviews with embedded researchers in diverse public health settings in English local government. Interviews were analysed using thematic analysis., Results: We identified thirteen interlinked determinants of research activity within local government public health settings. Research and interpersonal skills, as well as pre-existing connections and knowledge within local government, were highly valued individual attributes for embedded researchers. Resource deficiencies (funding, time, and infrastructure) were primary barriers to research activity, whereas a strong local appetite for evidence informed decision making presented a valuable opportunity. However, there was inconsistencies across public health teams relating to perceptions of what constituted "research" and the resources that would be required., Conclusions: Our results suggest that successful embedded researchers will have equally strong research and communication skills and should be offered mentorship and clear career progression pathways. Perceptions of research within local government are closely linked to resource deficiencies and senior endorsement. Embedded researchers could benefit from taking the time to develop locally contextualised knowledge of this research culture. Theories of change for embedded researchers should conceptualise the interconnections across individual, interpersonal, and organisational barriers and opportunities underlying local government research activity. Further research is needed to identify methods for exploring the influence of embedded researchers as well as to unpack the stages of research activity within local government and the associated behaviours., (© 2024. The Author(s).)

Background: Identifying chemical mentions within the Alzheimer's and dementia literature can provide a powerful tool to further therapeutic research. Leveraging the Chemical Entities of Biological Interest (ChEBI) ontology, which is rich in hierarchical and other relationship types, for entity normalization can provide an advantage for future downstream applications. We provide a reproducible hybrid approach that combines an ontology-enhanced PubMedBERT model for disambiguation with a dictionary-based method for candidate selection., Results: There were 56,553 chemical mentions in the titles of 44,812 unique PubMed article abstracts. Based on our gold standard, our method of disambiguation improved entity normalization by 25.3 percentage points compared to using only the dictionary-based approach with fuzzy-string matching for disambiguation. For the CRAFT corpus, our method outperformed baselines (maximum 78.4%) with a 91.17% accuracy. For our Alzheimer's and dementia cohort, we were able to add 47.1% more potential mappings between MeSH and ChEBI when compared to BioPortal., Conclusion: Use of natural language models like PubMedBERT and resources such as ChEBI and PubChem provide a beneficial way to link entity mentions to ontology terms, while further supporting downstream tasks like filtering ChEBI mentions based on roles and assertions to find beneficial therapies for Alzheimer's and dementia., (© 2024. The Author(s).)

Background: Effects of preoperative drinks on muscle metabolism are unclear despite general recommendations. The aim of the present study was therefore to compare metabolic effects of a preoperative oral nutrition drink, recommended by protocols for enhanced recovery after surgery (ERAS), compared to overnight preoperative peripheral total parenteral nutrition (PPN) on skeletal muscle metabolism in patients aimed at major gastrointestinal cancer surgery., Methods: Patients were randomized, based on diagnosis and clinical characteristics, to receive either a commercial carbohydrate-rich nutrition drink (Drink); or overnight (12 h) peripheral parenteral nutrition (PPN) as study regimens; compared to isotone Ringer-acetate as Control regimen. Arterial blood- and abdominal muscle tissue specimens were collected at start of surgery. Blood chemistry included substrate- and hormone concentrations. Muscle mRNA transcript analyses were performed by microarray and evaluated for changes in gene activities by Gene Ontology algorithms., Results: Patient groups were comparable in all measured preoperative assessments. The Nutrition Drink had significant metabolic alterations on muscle glucose metabolism (p < 0.05), without any significant effects on amino acid- and protein metabolism. PPN showed similar significant effects on glucose metabolism as Drinks (p < 0.05), but indicated also major positive effects on amino acid- (p < 0.001) and protein anabolism (p < 0.05), particularly by inhibition of muscle protein degradation, related to both ubiquitination of proteins and autophagy/lysosome pathways (p < 0.05)., Conclusion: Conventional overnight preoperative PPN seems effective to induce and support improved muscle protein metabolism in patients aimed at major cancer surgery while preoperative oral carbohydrate loading, according to ERAS-protocols, was ineffective to improve skeletal muscle catabolism and should therefore not be recommended before major cancer surgery. Trial registration Clinical trials.gov: NCT05080816, Registered June 10th 2021- Retrospectively registered. https://clinicaltrials.gov/study/NCT05080816., (© 2024. The Author(s).)

Sleep disorders are very common across neurodevelopmental disorders and place a large burden on affected children, adolescents, and their families. Sleep disturbances seem to involve a complex interplay of genetic, neurobiological, and medical/environmental factors in neurodevelopmental disorders. In this review, we discuss animal models of sleep problems and characterize their presence in two single gene disorders, Rett Syndrome, and Angelman Syndrome and two more commonly occurring neurodevelopmental disorders, Down Syndrome, and autism spectrum disorders. We then discuss strategies for novel methods of assessment using wearable sensors more broadly for neurodevelopmental disorders in general, including the importance of analytical validation. An increased understanding of the mechanistic contributions and potential biomarkers of disordered sleep may offer quantifiable targets for interventions that improve overall quality of life for affected individuals and their families., (© 2024. The Author(s).)

Glioma is the most common malignant tumor in central nervous system, with significant health burdens to patients. Due to the intrinsic characteristics of glioma and the lack of breakthroughs in treatment modalities, the prognosis for most patients remains poor. This results in a heavy psychological and financial load worldwide. In recent years, cannabidiol (CBD) has garnered widespread attention and research due to its anti-tumoral, anti-inflammatory, and neuroprotective properties. This review comprehensively summarizes the preclinical and clinical research on the use of CBD in glioma therapy, as well as the current status of nanomedicine formulations of CBD, and discusses the potential and challenges of CBD in glioma therapy in the future., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia-reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury., (© 2024. The Author(s).)

Knowledge Translation (KT) aims to convey novel ideas to relevant stakeholders, motivating their response or action to improve people's health. Initially, the KT literature focused on evidence-based medicine, applying findings from laboratory and clinical research to disease diagnosis and treatment. Since the early 2000s, the scope of KT has expanded to include decision-making with health policy implications.This systematic scoping review aims to assess the evolving knowledge-to-policy concepts, that is, macro-level KT theories, models and frameworks (KT TMFs). While significant attention has been devoted to transferring knowledge to healthcare settings (i.e. implementing health policies, programmes or measures at the meso-level), the definition of 'context' in the realm of health policymaking at the macro-level remains underexplored in the KT literature. This study aims to close the gap.A total of 32 macro-level KT TMFs were identified, with only a limited subset of them offering detailed insights into contextual factors that matter in health policymaking. Notably, the majority of these studies prompt policy changes in low- and middle-income countries and received support from international organisations, the European Union, development agencies or philanthropic entities., (© 2024. The Author(s).)

Background and Objectives: Without strategic actions in its support, the translation of scientific research evidence into health policy is often absent or delayed. This review systematically maps and assesses national-level strategic documents in the field of knowledge translation (KT) for health policy, and develops a practical template that can support Evidence-informed Policy Network (EVIPNet) Europe countries in producing national strategies for evidence-informed policy-making., Methods: Websites of organizations with strategic responsibilities in KT were electronically searched, on the basis of pre-defined criteria, in July-August 2017, and an updated search was carried out in April-June 2021. We included national strategies or elements of national strategies that dealt with KT activities, as well as similar strategies of individual institutions with a national policy focus. Two reviewers screened the strategies for inclusion. Data were analysed using qualitative content analysis., Results: A total of 65 unique documents were identified, of which 17 were eligible and analysed for their structure and content. Of the 17, 1 document was a national health KT action plan and 6 documents were institution-level KT strategies. The remaining 10 strategies, which were also included were 2 national health strategies, 5 national health research strategies and 3 national KT strategies (not specific to the field of health alone). In all, 13 structural elements and 7 major themes of health policy KT strategies were identified from the included documents., Conclusion: KT in health policy, as emerged from the national strategies that our mapping identified, is based on the production and accessibility of policy-relevant research, its packaging for policy-making and the activities related to knowledge exchange. KT strategies may play different roles in the complex and context-specific process of policy-making. Our findings show that the main ideas of health-specific evidence-informed policy literature appear in these strategies, but their effectiveness depends on the way stakeholders use them. Specific knowledge-brokering institutions and organizational capacity, advocacy about the use of evidence, and close collaboration and co-decision-making with key stakeholders are essential in furthering the policy uptake of research results., (© 2024. World Health Organization.)

Background: The National Institute of Health and Care Research (NIHR), funds, enables and delivers world-leading health and social care research to improve people's health and wellbeing. To achieve this aim, effective knowledge sharing (two-way knowledge sharing between researchers and stakeholders to create new knowledge and enable change in policy and practice) is needed. To date, it is not known which knowledge sharing techniques and approaches are used or how effective these are in creating new knowledge that can lead to changes in policy and practice in NIHR funded studies., Methods: In this restricted systematic review, electronic databases [MEDLINE, The Health Management Information Consortium (including the Department of Health's Library and Information Services and King's Fund Information and Library Services)] were searched for published NIHR funded studies that described knowledge sharing between researchers and other stakeholders. One researcher performed title and abstract, full paper screening and quality assessment (Critical Appraisal Skills Programme qualitative checklist) with a 20% sample independently screened by a second reviewer. A narrative synthesis was adopted., Results: In total 9897 records were identified. After screening, 17 studies were included. Five explicit forms of knowledge sharing studies were identified: embedded models, knowledge brokering, stakeholder engagement and involvement of non-researchers in the research or service design process and organisational collaborative partnerships between universities and healthcare organisations. Collectively, the techniques and approaches included five types of stakeholders and worked with them at all stages of the research cycle, except the stage of formation of the research design and preparation of funding application. Seven studies (using four of the approaches) gave examples of new knowledge creation, but only one study (using an embedded model approach) gave an example of a resulting change in practice. The use of a theory, model or framework to explain the knowledge sharing process was identified in six studies., Conclusions: Five knowledge sharing techniques and approaches were reported in the included NIHR funded studies, and seven studies identified the creation of new knowledge. However, there was little investigation of the effectiveness of these approaches in influencing change in practice or policy., (© 2024. The Author(s).)

Background: Translating research, achieving impact, and assessing impact are important aspirations for all research collaboratives but can prove challenging. The Hunter Cancer Research Alliance (HCRA) was funded from 2014 to 2021 to enhance capacity and productivity in cancer research in a regional centre in Australia. This study aimed to assess the impact and benefit of the HCRA to help inform future research investments of this type., Method: The Framework to Assess the Impact from Translational health research (FAIT) was selected as the preferred methodology. FAIT incorporates three validated methodologies for assessing impact: 1) Modified Payback; 2) Economic Analysis; and 3) Narrative overview and case studies. All three FAIT methods are underpinned by a Program Logic Model. Data were collected from HCRA and the University of Newcastle administrative records, directly from HCRA members, and website searches., Results: In addition to advancing knowledge and providing capacity building support to members via grants, fellowships, scholarships, training, events and targeted translation support, key impacts of HCRA-member research teams included: (i) the establishment of a regional biobank that has distributed over 13,600 samples and became largely self-sustaining; (ii) conservatively leveraging $43.8 M (s.a.$20.5 M - $160.5 M) in funding and support from the initial $9.7 M investment; (iii) contributing to clinical practice guidelines and securing a patent for identification of stem cells for endometrial cell regeneration; (iv) shifting the treatment paradigm for all tumour types that rely on nerve cell innervation, (v) development and implementation of the world's first real-time patient treatment verification system (Watchdog); (vi) inventing the effective 'EAT' psychological intervention to improve nutrition and outcomes in people experiencing radiotherapy for head and neck cancer; (vi) developing effective interventions to reduce smoking rates among priority groups, currently being rolled out to disadvantaged populations in NSW; and (vii) establishing a Consumer Advisory Panel and Consumer Engagement Committee to increase consumer involvement in research., Conclusion: Using FAIT methodology, we have demonstrated the significant impact and downstream benefits that can be achieved by the provision of infrastructure-type funding to regional and rural research collaboratives to help address inequities in research activity and health outcomes and demonstrates a positive return on investment., (© 2024. The Author(s).)

Translational research plays a key role in drug development and biomarker discovery for hepatocellular carcinoma (HCC). However, unique challenges exist in this field because of the limited availability of human tumor samples from surgery, the lack of homogenous oncogenic driver mutations, and the paucity of adequate experimental models. In this review, we provide insights into these challenges and review recent advancements, with a particular focus on the two main agents currently used as mainstream therapies for HCC: anti-angiogenic agents and immunotherapy. First, we examine the pre-clinical and clinical studies to highlight the challenges of determining the optimal therapeutic combinations with biologically effective dosage for HCC. Second, we discuss biomarker studies focusing on anti-PD1/anti-PD-L1-based combination therapy. Finally, we discuss the progress made in our collective understanding of tumor immunology and in multi-omics analysis technology, which enhance our understanding of the mechanisms underlying immunotherapy, characterize different patient subgroups, and facilitate the development of novel combination approaches to improve treatment efficacy. In summary, this review provides a comprehensive overview of efforts in translational research aiming at advancing our understanding of and improving the treatment of HCC., (© 2024. The Author(s).)

Metabolism of polyamines is of critical importance to physiological processes. Ornithine decarboxylase (ODC) antizyme inhibitors (AZINs) are capable of interacting with antizymes (AZs), thereby releasing ODC from ODC-AZs complex, and promote polyamine biosynthesis. AZINs regulate reproduction, embryonic development, fibrogenesis and tumorigenesis through polyamine and other signaling pathways. Dysregulation of AZINs has involved in multiple human diseases, especially malignant tumors. Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post-transcriptional nucleotide modification in humans. Additionally, the high frequencies of RNA-edited AZIN1 in human cancers correlates with increase of cancer cell proliferation, enhancement of cancer cell stemness, and promotion of tumor angiogenesis. In this review, we summarize the current knowledge on the various contribution of AZINs related with potential cancer promotion, cancer stemness, microenvironment and RNA modification, especially underlying molecular mechanisms, and furthermore explored its promising implication for cancer diagnosis and treatment., (© 2023. The Author(s).)

Background: Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function., Methods: We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20 mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20 mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5 mg/kg BID, n = 5), Group C (CER-001 10 mg/kg BID, n = 5), and Group D (CER-001 20 mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers., Results: CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay., Conclusions: CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage., Trial Registration: The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020-004202-60, Protocol CER-001- SEP&#95;AKI&#95;01) and was added to the EU Clinical Trials Register on January 13, 2021., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Building clinician and organisation-level research translation capacity and capability is fundamental for increasing the implementation of research into health practice and policy and improving health outcomes. Research translation capacity and capability building is particularly crucial in rural and regional settings to address complex problems impacting these socially and economically disadvantaged communities. Programs to build clinicians' research translation capability typically involve training and mentoring. Little is known about the features of and influences on mentorships in the context of training for emerging clinician-researchers working in rural and regional healthcare settings. Research translation mentorships were established as part of the Supporting Translation Research in Rural and Regional settings (STaRR) program developed and delivered in Victoria, Australia from 2020 to 2021. The study sought to address the following research questions: 1) What context-specific types of support do research translation mentors provide to emerging researchers?. 2) How does the mentoring element of a rural research translational training program influence research translation capacity and capability development in rural emerging researchers and mentors, if at all?. 3) How does the mentoring element of the program influence translation capacity and capability at the organisational and regional level, if at all?, Methods: We conducted a qualitative descriptive study. Interviews with individuals involved in the STaRR program took place approximately 12 months after the program and explored participants' experiences of the mentored training. Interviews were undertaken via telephone, audio-recorded, and transcribed. Data were analysed using a team-based five-stage framework approach., Results: Participants included emerging researchers (n = 9), mentors (n = 5), and managers (n = 4), from five health services and two universities. We identified four themes in the interview data: (1) Mentors play an educative role; (2) Mentoring enhanced by a collaborative environment; (3) Organisational challenges can influence mentorships, and (4) Mentorships help develop research networks and collective research and translation capacity., Conclusions: Mentorships contributed to the development of research translation capabilities. The capabilities were developed through mentors' deepened understanding of the rural and regional healthcare contexts in which their emerging researchers worked, the broadening and strengthening of rural and regional research networks, and building and sharing research translation knowledge and skills., (© 2023. The Author(s).)

Background: Collaborative health research, such as integrated knowledge translation (IKT), requires researchers to have specific knowledge and skills in working in partnership with knowledge users. Graduate students are often not provided with the opportunity to learn skills in how to establish collaborative relationships with knowledge users in the health system or communities, despite its importance in research. The objective of this environmental scan is to identify available guidelines for graduate trainees to use an IKT approach in their research., Methods: We conducted an environmental scan with three separate systematic searches to identify guidelines available to support graduate students in engaging in an IKT approach to research: (i) a customized Google search; (ii) a targeted Canadian university website search; and (iii) emails to administrators of graduate studies programmes asking for available guidelines and documents designed for graduate students. Data were extracted using a standardized data extraction tool and analysed using a directed content analysis approach. Due to the minimal results included based on the a priori eligibility criteria, we returned to the excluded records to further review the current state of the environment on trainee support for IKT research., Results: Our search strategy yielded 22 900 items, and after a two-step screening process with strict inclusion criteria three documents met the eligibility criteria. All three documents highlighted the need for an IKT plan for knowledge user involvement throughout the research process. Furthermore, documents emphasized the need for tangible steps to guide graduate students to engage in effective communication with knowledge users. Due to the lack of documents retrieved, we conducted a post hoc content analysis of relevant IKT documents excluded and identified five themes demonstrating increased education and engagement in an IKT approach at an interpersonal and organizational level., Conclusion: We identified three documents providing guidance to trainees using a collaborative approach in their health research. This scan highlighted two key findings including the importance of supporting trainees to engage knowledge users in research and preparing an IKT plan alongside a research plan. Further research is needed to co-design guidelines to support graduate students and trainees in engaging in an IKT approach., (© 2023. The Author(s).)

Background: Depending on the needs of scientific research at a given time, biobanks make biological samples and data available to researchers. In this article, we aim to describe the reasons and underlying logic that determine the decision to grant or deny consent to the conservation of tumour samples in a biological resource platform for research purposes. We make use of the CARPEM biological resource platform model, where broad consent is required., Methods: The results are based on semi-structured interviews, conducted between 2019 and 2021, with 25 individuals having various profiles., Results: All the people interviewed readily accepted the principle of conserving a tumour sample for research purposes. They explained their decision by citing the desire to participate in research dedicated to improving therapeutic medicine. Their trust in research institutions or in doctors was an important factor in their consent. The tumorous nature of the samples also played an important role, as did the absence of constraints. Finally, the high level of consent was also based on the difficulty they had in conceiving what the future risks might be once the sample had been taken, whereas the fact that they did not know the nature or purpose of the research to be carried out when they signed the consent form posed some problems. These results stem from a lack of a culture of ethics among the people interviewed., Conclusion: The information provided in the context of consent at the CARPEM tumour bank seems inadequate for consent to be considered 'informed', given the low level of knowledge that people have of the risks and issues. Information is missing even though we feel it would not change consent or only marginally. This raises questions, since part of the act of granting consent is based on the implicit trust French people have in the hospital that collects the data and in research practices in general. In the minds of those who participate, transparency is the ground on which trust rests. Lack of transparency could be deleterious for future research practices. However, it is not by striving to improve information leaflets that the consent-related information will improve but, rather, by more effectively helping future patients to assimilate that information., (© 2023. The Author(s).)

Background: Many patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide., Results: A total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks., Conclusions: Through this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks., (© 2023. The Author(s).)

Health-care decision making should consider the best available evidence, often in the form of systematic reviews (SRs). The number of existing SRs and their overlap make their identification and use difficult. Decision makers often rely on de novo SRs instead of using existing SRs. We describe two cases of duplicate reviews (minimum volume threshold of total knee arthroplasties and lung cancer screening) and one case of duplicate primary data analysis (transcatheter aortic valve implantation). All cases have in common that unintended duplication of research occurred between health authorities and academia, demonstrating a lack of communication and coordination between them.It is important to note that academia and health authorities have different incentives. Academics are often measured by the number of peer-reviewed publications and grants awarded. In contrast, health authorities must comply with laws and are commissioned to deliver a specific report within a defined period of time. Most replication is currently unintended. A solution may be the collaboration of stakeholders commonly referred to as integrated knowledge translation (IKT). The IKT approach means that research is conducted in collaboration with the end users of the research. It requires active collaborations between researchers and decision-makers or knowledge users (clinicians, managers, policy makers) throughout the research process. Wherever cooperation is possible in spite of requirements for independence or confidentiality, legal regulations should facilitate and support collaborative approaches between academia and health authorities., (© 2023. The Author(s).)

Traumatic brain injury (TBI) often results in prolonged or permanent brain dysfunction with over 2.8 million affected annually in the U.S., including over 56,000 deaths, with over 5 million total survivors exhibiting chronic deficits. Mild TBI (also known as concussion) accounts for over 75% of all TBIs every year. Mild TBI is a heterogeneous disorder, and long-term outcomes are dependent on the type and severity of the initial physical event and compounded by secondary pathophysiological consequences, such as reactive astrocytosis, edema, hypoxia, excitotoxicity, and neuroinflammation. Neuroinflammation has gained increasing attention for its role in secondary injury as inflammatory pathways can have both detrimental and beneficial roles. For example, microglia-resident immune cells of the central nervous system (CNS)-influence cell death pathways and may contribute to progressive neurodegeneration but also aid in debris clearance and neuroplasticity. In this review, we will discuss the acute and chronic role of microglia after mild TBI, including critical protective responses, deleterious effects, and how these processes vary over time. These descriptions are contextualized based on interspecies variation, sex differences, and prospects for therapy. We also highlight recent work from our lab that was the first to describe microglial responses out to chronic timepoints after diffuse mild TBI in a clinically relevant large animal model. The scaled head rotational acceleration of our large animal model, paired with the gyrencephalic architecture and appropriate white:gray matter ratio, allows us to produce pathology with the same anatomical patterns and distribution of human TBI, and serves as an exemplary model to examine complex neuroimmune response post-TBI. An improved understanding of microglial influences in TBI could aid in the development of targeted therapeutics to accentuate positive effects while attenuating detrimental post-injury responses over time., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Cancer heterogeneity is a main obstacle for the development of effective therapies, as its replication in in vitro preclinical models is challenging. Around 96% of developed drugs are estimated to fail from discovery to the clinical trial phase probably because of the unsuitability and unreliability of current preclinical models (Front Pharmacol 9:6, 2018; Nat Rev Cancer 8: 147-56, 2008) in replicating the overall biology of tumors, for instance the tumor microenvironment. Breast cancer is the most frequent cancer among women causing the greatest number of cancer-related deaths. Breast cancer can typically be modeled in vitro through the use of tumoroids; however, current approaches using mouse tumoroids fail to reproduce crucial aspect of human breast cancer, while access to human cells is limited and the focus of ethical concerns. New models of breast cancer, such as companion dogs, have emerged given the resemblance of developed spontaneous mammary tumors to human breast cancer in many clinical and molecular aspects; however, they have so far failed to replicate the tumor microenvironment. The present work aimed at developing a robust canine mammary tumor model in the form of tumoroids which recapitulate the tumor diversity and heterogeneity., Results: We conducted a complete characterization of canine mammary tumoroids through histologic, molecular, and proteomic analysis, demonstrating their strong similarity to the primary tumor. We demonstrated that these tumoroids can be used as a drug screening model. In fact, we showed that paclitaxel, a human chemotherapeutic, could kill canine tumoroids with the same efficacy as human tumoroids with 0.1 to 1 μM of drug needed to kill 50% of the cells. Due to easy tissue availability, canine tumoroids can be produced at larger scale and cryopreserved to constitute a biobank. We have demonstrated that cryopreserved tumoroids keep the same histologic and molecular features (ER, PR, and HER2 expression) as fresh tumoroids. Furthermore, two cryopreservation techniques were compared from a proteomic point of view which showed that tumoroids made from frozen material allowed to maintain the same molecular diversity as from freshly dissociated tumor., Conclusions: These findings revealed that canine mammary tumoroids can be easily generated and may provide an adequate and more reliable preclinical model to investigate tumorigenesis mechanisms and develop new treatments for both veterinary and human medicine., (© 2023. The Author(s).)

Background: Most justice-involved youth are supervised in community settings, where assessment and linkage to substance use (SU) treatment services are inconsistent and fragmented. Only 1/3 of youth with an identified SU need receive a treatment referral and even fewer initiate services. Thus, improving identification and linkage to treatment requires coordination across juvenile justice (JJ) and behavioral health (BH) agencies. The current study examines the comparative effectiveness of two bundled implementation intervention strategies for improving SU treatment initiation, engagement, and continuing care among justice-involved youth supervised in community settings. Exploration, Preparation, Implementation, Sustainment (EPIS) served as the conceptual framework for study design and selection/timing of implementation intervention components, and the BH Services Cascade served as the conceptual and measurement framework for identifying and addressing gaps in service receipt., Methods: Part of a larger Juvenile-Justice Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) Cooperative, this study involved a multisite, cluster-randomized control trial where sites were paired then randomly assigned to receive Core (training teams on the BH Services Cascade and data-driven decision making; supporting goal selection) or Core+Enhanced (external facilitation of implementation teams) intervention components. Youth service records were collected from 20 JJ community supervision agencies (in five states) across five study phases (baseline, pre-randomization, early experiment, late experiment, maintenance). Implementation teams comprised of JJ and BH staff collaboratively identified goals along the BH Cascade and used data-driven decision-making to implement change., Results: Results suggest that Core intervention components were effective at increasing service receipt over time relative to baseline, but differences between Core and Core+Enhanced conditions were non-significant. Time to service initiation was shorter among Core+Enhanced sites, and deeper Cascade penetration occurred when external facilitation (of implementation teams) was provided. Wide variation existed in the degree and nature of change across service systems., Conclusions: Findings demonstrate the criticality of early EPIS phases, demonstrating that strategies provided during the formative exploration and preparation phases produced some improvement in service receipt, whereas implementation-focused activities produced incremental improvement in moving youth farther along the Cascade., (© 2022. The Author(s).)

The concept of embodiment has gained widespread popularity within prosthetics research. Embodiment has been claimed to be an indicator of the efficacy of sensory feedback and control strategies. Moreover, it has even been claimed to be necessary for prosthesis acceptance, albeit unfoundedly. Despite the popularity of the term, an actual consensus on how prosthetic embodiment should be used in an experimental framework has yet to be reached. The lack of consensus is in part due to terminological ambiguity and the lack of an exact definition of prosthetic embodiment itself. In a review published parallel to this article, we summarized the definitions of embodiment used in prosthetics literature and concluded that treating prosthetic embodiment as a combination of ownership and agency allows for embodiment to be quantified, and thus useful in translational research. Here, we review the potential mechanisms that give rise to ownership and agency considering temporal, spatial, and anatomical constraints. We then use this to propose a multi-dimensional framework where prosthetic embodiment arises within a spectrum dependent on the integration of volition and multi-sensory information as demanded by the degree of interaction with the environment. This framework allows for the different experimental paradigms on sensory feedback and prosthetic control to be placed in a common perspective. By considering that embodiment lays along a spectrum tied to the interactions with the environment, one can conclude that the embodiment of prosthetic devices should be assessed while operating in environments as close to daily life as possible for it to become relevant., (© 2022. The Author(s).)

Background: One of the challenges for countries implementing food policy measures has been the difficulty in demonstrating impact and retaining stakeholder support. Consequently, research funded to help countries overcome these challenges should assess impact and translation into practice, particularly in low-resource settings. However, there are still few attempts to prospectively, and comprehensively, assess research impact. This protocol describes a study co-created with project implementers, collaborative investigators and key stakeholders to optimize and monitor the impact of a research project on scaling up food policies in Fiji., Methods: To develop this protocol, our team of researchers prospectively applied the Framework to Assess the Impact from Translational health research (FAIT). Activities included (i) developing a logic model to map the pathway to impact and establish domains of benefit; (ii) identifying process and impact indicators for each of these domains; (iii) identifying relevant data for impact indicators and a cost-consequence analysis; and (iv) establishing a process for collecting quantitative and qualitative data to measure progress. Impact assessment data will be collected between September 2022 and December 2024, through reports, routine monitoring activities, group discussions and semi-structured interviews with key implementers and stakeholders. The prospective application of the protocol, and interim and final research impact assessments of each project stream and the project as a whole, will optimize and enable robust measurement of research impact., Discussion: By applying this protocol, we aim to increase understanding of pathways to impact and processes that need to be put in place to achieve this. This impact evaluation will inform future projects with a similar scope and will identify transferable and/or translatable lessons for other Pacific Island states and low- and middle-income countries., (© 2022. The Author(s).)