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Background Improving the uptake of relevant and reliable research is an important priority in long-term care to achieve sustainable and high-quality services for the increasingly older population. Aim The purpose was to assess the effectiveness of a tailored, adaptive and a multifaceted KT capacity program, relative to usual practice, on the implementation of National Early Warning Score 2 (NEWS2). Methods This study was carried out as a pragmatic cluster-randomized controlled trial. The capacity program consisted of an educational part to address implementation capacity gaps and a facilitation-upon-implementation part to address a relevant knowledge gap in nursing homes. A collective decision was made to address the challenge of early detection of clinical deterioration among nursing home residents, by implementing the (NEWS2) as clinical innovation. Public nursing homes in a Norwegian municipality ( n  = 21) with a total of 1 466 beds were eligible for inclusion. The study-period spanned over a 22-month period, including a 12-month follow-up. Data was extracted from the Electronic Patient Journal system and analyzed using multilevel growth model analysis. Results The intervention had a large effect on the use of NEWS2 among care staff in intervention nursing homes, compared to the control group (standardized mean difference, d = 2.42). During the final month of the implementation period, residents in the intervention group was assessed with NEWS2 1.44 times (95% CI: 1.23, 1.64) per month, which is almost four times more often than in the control group (mean = 0.38, 95% CI: 0.19, 0.57). During the follow-up period, the effect of the intervention was not only sustained in the intervention group but there was a substantial increase in the use of NEWS2 in both the intervention (mean = 1.75, 95% CI: 1.55, 1.96) and control groups (mean = 1.45, 95% CI: 1.27, 1.65). Conclusions This tailored implementation strategy had a large effect on the use of NEWS2 among care staff, demonstrating that integrated knowledge translation strategies can be a promising strategy to achieve evidence-based care in the nursing home sector. Trial registration ISRCTN12437773 . Registered 19/3 2020, retrospectively.

Research has shown that engaging in a range of healthy lifestyles or behavioral factors can help reduce the risk of developing dementia. Improved knowledge of modifiable risk factors for dementia may help engage people to reduce their risk, with beneficial impacts on individual and public health. Moreover, many guidelines emphasize the importance of providing education and web-based resources for dementia prevention. Internet-based interventions may be effective, but few have been studied rigorously or widely disseminated. We created DementiaRisk, an award-winning, web- and email-based education platform for the public focused on modifiable risk factors, featuring multimedia e-learning and email \"microlearning\" content, to help raise awareness and improve knowledge of actions to reduce dementia risk. This protocol describes a randomized controlled trial to (1) evaluate whether exposure to DementiaRisk changes knowledge of dementia risk factors, intention to engage in risk reduction activities, and health behaviors related to dementia risk reduction and to (2) explore qualitative aspects including participants' engagement and satisfaction with the intervention and barriers and facilitators to use. Using a sequential explanatory mixed methods design, this study conducts a quantitative analysis followed by a qualitative inquiry to evaluate outcomes and feasibility. In total, 485 participants will be recruited on the web and randomly assigned to 2 groups: one accessing DementiaRisk and the other receiving alternative e-learning on mild cognitive impairment. Assessments will be delivered on the web at baseline (T1), at 4 weeks (T2), and at 2 months after the intervention (T3). Knowledge will be assessed using items from the Dementia Knowledge Assessment Scale, intentions to engage in risk reduction activities will be assessed using items in line with current evidence, and health behaviors related to dementia risk reduction will be assessed using items from the Godin-Shephard Leisure Time Physical Activity Questionnaire along with additional questions related to a range of health status domains. Outcomes and feasibility will be assessed using the Information Assessment Method for patients and consumers. A linear mixed effects model will be used to examine the relationship between each outcome score by group and time point. This study was approved by the Hamilton Integrated Research Ethics Board on August 24, 2022 (project ID 14886) and received funding in February 2023. Recruitment took place from March 28, 2023, to April 28, 2023, with the final participants completing the intervention by August 18, 2023. Analyses and interpretation of data are ongoing. DementiaRisk is a readily scalable, technology-enhanced solution for dementia prevention education. It has been designed using evidence-based principles of multimedia learning. It has the potential to scale and spread widely using the open internet, so it may be able to reach a wider audience than traditional in-person educational interventions. ClinicalTrials.gov NCT05383118; https://clinicaltrials.gov/study/NCT05383118. DERR1-10.2196/64718.

Background Few studies have systematically examined whether knowledge translation (KT) strategies can be successfully implemented within the long-term care (LTC) setting. In this study, we examined the effectiveness of a multifaceted, interdisciplinary KT intervention for improving the prescribing of vitamin D, calcium and osteoporosis medications over 12-months. Methods We conducted a pilot, cluster randomized controlled trial in 40 LTC homes (21 control; 19 intervention) in Ontario, Canada. LTC homes were eligible if they had more than one prescribing physician and received services from a large pharmacy provider. Participants were interdisciplinary care teams (physicians, nurses, consultant pharmacists, and other staff) who met quarterly. Intervention homes participated in three educational meetings over 12 months, including a standardized presentation led by expert opinion leaders, action planning for quality improvement, and audit and feedback review. Control homes did not receive any additional intervention. Resident-level prescribing and clinical outcomes were collected from the pharmacy database; data collectors and analysts were blinded. In addition to feasibility measures, study outcomes were the proportion of residents taking vitamin D (≥800 IU/daily; primary), calcium ≥500 mg/day and osteoporosis medications (high-risk residents) over 12 months. Data were analyzed using the generalized estimating equations technique accounting for clustering within the LTC homes. Results At baseline, 5,478 residents, mean age 84.4 (standard deviation (SD) 10.9), 71% female, resided in 40 LTC homes, mean size = 137 beds (SD 76.7). In the intention-to-treat analysis (21 control; 19 intervention clusters), the intervention resulted in a significantly greater increase in prescribing from baseline to 12 months between intervention versus control arms for vitamin D (odds ratio (OR) 1.82, 95% confidence interval (CI): 1.12, 2.96) and calcium (OR 1.33, 95% CI: 1.01, 1.74), but not for osteoporosis medications (OR 1.17, 95% CI: 0.91, 1.51). In secondary analyses, excluding seven nonparticipating intervention homes, ORs were 3.06 (95% CI: 2.18, 4.29), 1.57 (95% CI: 1.12, 2.21), 1.20 (95% CI: 0.90, 1.60) for vitamin D, calcium and osteoporosis medications, respectively. Conclusions Our KT intervention significantly improved the prescribing of vitamin D and calcium and is a model that could potentially be applied to other areas requiring quality improvement. Trial Registration ClinicalTrials.gov: NCT01398527 . Registered: 19 July 2011.

Key Points This Review describes recent progress in directing human pluripotent stem cells (hPSCs) into specific progeny that could have therapeutic purposes for a range of diseases. It also addresses major hurdles in the transition of hPSC-based cell therapies from the bench to the bedside. Neural induction of hPSCs can be achieved in several ways. Recent protocols use defined neural inducers — such as inhibitors of transforming growth factor-β (TGFβ) and bone morphogenetic protein (BMP) (that is, dual SMAD inhibition) — to greatly enhance the efficiency and the speed of neural induction. The derivation of dopamine neurons from hPSCs has been achieved a decade ago, but the cells did not show good engraftment. Recent data shows that those neurons lacked expression of forkhead box protein A2 (FOXA2), which is a DNA-binding transcription factor that is fundamental for authentic midbrain identity. A novel protocol derives dopamine neurons through a floor plate intermediate, which show genetic, biochemical and physiological features of authentic midbrain neurons. They also survive and ameliorate Parkinson's disease-like behaviour in vivo . Improved protocols for the derivation of medium spiny striatal neurons from hPSCs has been reported, and evidence shows survival and behavioural improvement in a lesion model of Huntington's disease. The derivation of glial cells from hPSCs is faced with the challenge of protracted developmental timing in vitro , which is similar to the in vivo situation. The derivation of oligodendrocytes has been achieved using long-term in vitro cultures; these cells have been grafted in neonatal Shiverer -expressing mice with good cell survival, remyelination and extended lifespan in these mice. The current derivation of non-neural cell types — such as cardiomyocytes, pancreatic islet cells and engraftable haematopoietic stem cells — faces substantial challenges owing to the immature nature of the differentiated cells (for cardiomyocytes), the need for in vivo differentiation (for pancreatic islet cells) and poor in vivo homing (for haematopoietic stem cells). New developments in cell differentiation include the use of potent small molecules that allow the direct manipulation of multiple signalling pathways and, in some cases, the acceleration of differentiation timelines. Other approaches include cell purification and three-dimensional cultures that harness the self-organizing potential of hPSC-derived lineages. Defining cell identity in vitro is a fundamental element in designing directed differentiation strategies and includes expression of cell type-specific markers, transcriptional profiles and assessments of the epigenetic or enhancer landscapes. Assessment of in vivo function includes electrophysiology, the use of genetically encoded calcium sensors, microdialysis and optogenetic techniques, as well as behavioural studies. Autologous cell sources, such as patient-derived induced pluripotent stem cells, are of great interest but currently face substantial hurdles for clinical implementation that are related to safety and regulatory requirements. The translation of direct reprogramming and nuclear transfer strategies are in early stages of development. A spinal cord trial using human embryonic stem cell (hESC)-derived oligodendrocytes has not reported any major adverse effects, although the trial has been abandoned. Ongoing clinical trials using hESC-derived retinal pigment epithelial in eye repair are promising. The derivation of disease-relevant cell types from pluripotent stem cells holds much promise for disease therapy. The recent progress in directed differentiation and the challenges ahead are discussed in this Review. After years of incremental progress, several recent studies have succeeded in deriving disease-relevant cell types from human pluripotent stem cell (hPSC) sources. The prospect of an unlimited cell source, combined with promising preclinical data, indicates that hPSC technology may be on the verge of clinical translation. In this Review, we discuss recent progress in directed differentiation, some of the new technologies that have facilitated the success of hPSC therapies and the remaining hurdles on the road towards developing hPSC-based cell therapies.

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.Progress in precision medicine for colorectal cancer continues to lag behind the rapid improvements seen in patients with certain other solid tumour types. Nonetheless, owing largely to the availability of better translational models, novel and effective targeted therapy strategies based on tumour biology are beginning to be developed for subsets of patients. In this Review, the authors summarize these developments and discuss future directions in this rapidly evolving area of research.

Key Points Endogenous regeneration seen in animal models provides a template for optimal repair of the human heart following myocardial infarction. In the regenerating heart, new cardiomyocytes are produced by proliferation of the existing cardiomyocyte pool. Understanding and targeting the intrinsic mechanisms that regulate cardiomyocyte cell cycle re-entry could enable therapeutic regeneration in the human heart. Repair is modulated by epicardial activation, neoangiogenesis, the immune response and the extracellular matrix. Biological insights from regenerative models, combined with use of high-throughput phenotypic screens and in vivo discovery approaches, are uncovering novel therapeutic targets and compounds to improve repair. Regenerative strategies that emerge from increased understanding of cardiomyocyte lineage specification include transplantation of in vitro -produced cardiomyocytes and in vivo reprogramming of fibroblasts. Current efforts to improve engraftment, maturation and targeting will enable a next generation of clinical trials. Distinct approaches are required for patients in the immediate post-myocardial infarction period and for those with chronic heart failure, and high-risk strategies should initially be targeted at patients with end-stage heart failure. Clinical trial design should be tailored to incorporate informed biological end points alongside functional end points. Regeneration of the heart by cardiomyocyte reconstitution represents an attractive approach to treat heart failure. Here, Riley and colleagues discuss recent insights into the biology of heart regeneration and highlight emerging therapeutic regenerative strategies for heart failure. Challenges and considerations in the translation of regenerative therapies into the clinic are discussed. Current therapies for heart failure after myocardial infarction are limited and non-curative. Although regenerative approaches are receiving significant attention, clinical efforts that involve transplantation of presumed stem and progenitor cells have largely failed to deliver. Recent studies of endogenous heart regeneration in model organisms, such as zebrafish and neonatal mice, are yielding mechanistic insights into the roles of cardiomyocyte proliferation, resident stem cell niches, neovascularization, the immune system and the extracellular matrix. These findings have revealed novel pathways that could be therapeutically targeted to stimulate repair following myocardial infarction and have provided lessons to guide future efforts towards heart regeneration through cellular reprogramming or cardiomyocyte transplantation.

Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer nanomedicine therapies.

There is an ongoing debate about the value of animal experiments to inform medical practice, yet there are limited data on how well therapies developed in animal studies translate to humans. We aimed to assess 2 measures of translation across various biomedical fields: (1) The proportion of therapies which transition from animal studies to human application, including involved timeframes; and (2) the consistency between animal and human study results. Thus, we conducted an umbrella review, including English systematic reviews that evaluated the translation of therapies from animals to humans. Medline, Embase, and Web of Science Core Collection were searched from inception until August 1, 2023. We assessed the proportion of therapeutic interventions advancing to any human study, a randomized controlled trial (RCT), and regulatory approval. We meta-analyzed the concordance between animal and human studies. The risk of bias was probed using a 10-item checklist for systematic reviews. We included 122 articles, describing 54 distinct human diseases and 367 therapeutic interventions. Neurological diseases were the focus of 32% of reviews. The overall proportion of therapies progressing from animal studies was 50% to human studies, 40% to RCTs, and 5% to regulatory approval. Notably, our meta-analysis showed an 86% concordance between positive results in animal and clinical studies. The median transition times from animal studies were 5, 7, and 10 years to reach any human study, an RCT, and regulatory approval, respectively. We conclude that, contrary to widespread assertions, the rate of successful animal-to-human translation may be higher than previously reported. Nonetheless, the low rate of final approval indicates potential deficiencies in the design of both animal studies and early clinical trials. To ameliorate the efficacy of translating therapies from bench to bedside, we advocate for enhanced study design robustness and the reinforcement of generalizability.

Nanomedicines have created a paradigm shift in healthcare. Yet fundamental barriers still exist that prevent or delay the clinical translation of nanomedicines. Critical hurdles inhibiting clinical success include poor understanding of nanomedicines’ physicochemical properties, limited exposure in the cell or tissue of interest, poor reproducibility of preclinical outcomes in clinical trials, and biocompatibility concerns. Barriers that delay translation include industrial scale-up or scale-down and good manufacturing practices, funding and navigating the regulatory environment. Here we propose the DELIVER framework comprising the core principles to be realized during preclinical development to promote clinical investigation of nanomedicines. The proposed framework comes with design, experimental, manufacturing, preclinical, clinical, regulatory and business considerations, which we recommend investigators to carefully review during early-stage nanomedicine design and development to mitigate risk and enable timely clinical success. By reducing development time and clinical trial failure, it is envisaged that this framework will help accelerate the clinical translation and maximize the impact of nanomedicines. The authors propose a framework to be followed during preclinical investigation of nanomedicines to increase their translatability potential.

The term ‘translation’ has emerged as a dominant concept in biomedical science over the last decade, but confusion around what the term means, and how it differs from translational research and translational science, is common. This article aims to help address this issue by clarifying the distinctions.