Translational Value of Skilled Reaching Assessment in Clinical and Preclinical Studies on Motor Recovery After Stroke.

BACKGROUND: Assessment of skilled reaching enables extensive analysis of upper limb function in clinical and preclinical studies on poststroke outcome. However, translational research if often limited by lack of correspondence between tests of human and rodent motor function. OBJECTIVES: To determine (1) the translational value of skilled reaching performance for preclinical research by comparing the behavioral recovery profiles of skilled reaching characteristics between humans and rats recovering from stroke and (2) the relationship between skilled reaching performance and commonly used clinical outcome measures after stroke. METHODS: Twelve patients with ischemic or hemorrhagic stroke and 17 rats with photothrombotic stroke underwent an equivalent skilled reaching test at different time points, representing early to late subacute stages poststroke. Success scores and a movement element rating scale were used to measure the skilled reaching performance. The Fugl-Meyer Upper Extremity (FM-UE) assessment and the Action Research Arm Test (ARAT) were used as clinical outcome measures. RESULTS: Both species had muscle flaccidity at the early subacute stage after stroke and showed motor recovery following a proximal-distal principle toward the early subacute stage, albeit for rats within a shorter time course. Human skilled reaching scores and FM-UE and ARAT scores in the first 3 months poststroke were significantly correlated (P < .05). CONCLUSIONS: Our study demonstrates that poststroke changes in skilled reaching performance are highly similar between rats and humans and correspond with standard clinical outcome measures. Skilled reaching testing therefore offers an effective and highly translational means for assessment of motor recovery in experimental and clinical stroke settings.

Single-cell sequencing in translational cancer research and challenges to meet clinical diagnostic needs.

The ability to capture alterations in the genome or transcriptome by next-generation sequencing has provided critical insight into molecular changes and programs underlying cancer biology. With the rapid technological development in single-cell sequencing, it has become possible to study individual cells at the transcriptional, genetic, epigenetic, and protein level. Using single-cell analysis, an increased resolution of fundamental processes underlying cancer development is obtained, providing comprehensive insights otherwise lost by sequencing of entire (bulk) samples, in which molecular signatures of individual cells are averaged across the entire cell population. Here, we provide a concise overview on the application of single-cell analysis of different modalities within cancer research by highlighting key articles of their respective fields. We furthermore examine the potential of existing technologies to meet clinical diagnostic needs and discuss current challenges associated with this translation.

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics.

Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.

Putting Policy Into Practice: School-Level Compliance With and Implementation of State Concussion Laws.

CONTEXT: Each year, approximately 2 million US children 18 years or younger sustain a concussion, a type of mild traumatic brain injury (TBI). Concussions can have detrimental effects on physical, cognitive, emotional, or sleep health. POLICY: Between 2009 and 2014, all 50 US states and Washington, District of Columbia, enacted state concussion laws aimed to increase awareness about concussion and reduce the prevalence and severity of this injury. Most state laws include the following core tenets: (1) immediate removal from play after an actual or suspected concussion; (2) medical clearance before an athlete can return to play (RTP); and (3) concussion education for athletes, parents, and coaches. IMPLEMENTATION: State concussion laws allow for substantial interpretation at the school level, resulting in considerable variation in the content of school written concussion policies and the level of implementation of state law requirements at the school level. EVALUATION: We assessed the degree of high school written concussion policy compliance with the respective state law and examined the relationship between concussion policy compliance and school-level implementation of concussion laws. Seventy-one school officials completed a semistructured telephone interview and submitted their school's written concussion policy. Of the 71 policies analyzed, most complied with the removal-from-play, RTP, and concussion education tenets (90.1%, 97.2%, and 76.1%, respectively). The majority of participants reported that their school implemented the removal-from-play (91.5%), RTP (93.0%), and concussion education (80.6%) tenets well or very well. No significant relationships were found between researcher-rated school policy compliance and school-reported implementation of state law requirements at the school level. DISCUSSION: Our findings suggest that most participating schools complied with their state concussion law and implemented law requirements well or very well. Future studies should identify facilitators and barriers to the implementation of state concussion laws at the school level.

Improving the trustworthiness, usefulness, and ethics of biomedical research through an innovative and comprehensive institutional initiative.

The reproducibility crisis triggered worldwide initiatives to improve rigor, reproducibility, and transparency in biomedical research. There are many examples of scientists, journals, and funding agencies adopting responsible research practices. The QUEST (Quality-Ethics-Open Science-Translation) Center offers a unique opportunity to examine the role of institutions. The Berlin Institute of Health founded QUEST to increase the likelihood that research conducted at this large academic medical center would be trustworthy, useful for scientists and society, and ethical. QUEST researchers perform "science of science" studies to understand problems with standard practices and develop targeted solutions. The staff work with institutional leadership and local scientists to incentivize and support responsible practices in research, funding, and hiring. Some activities described in this paper focus on the institution, whereas others may benefit the national and international scientific community. Our experience, approaches, and recommendations will be informative for faculty leadership, administrators, and researchers interested in improving scientific practice.

Bridging the Gaps in Personalized Medicine Value Assessment: A Review of the Need for Outcome Metrics across Stakeholders and Scientific Disciplines.

Despite monumental advances in genomics, relatively few health care provider organizations in the United States offer personalized or precision medicine as part of the routine clinical workflow. The gaps between research and applied genomic medicine may be a result of a cultural gap across various stakeholders representing scientists, clinicians, patients, policy makers, and third party payers. Scientists are trained to assess the health care value of genomics by either quantifying population-scale effects, or through the narrow lens of clinical trials where the standard of care is compared with the predictive power of a single or handful of genetic variants. While these metrics are an essential first step in assessing and documenting the clinical utility of genomics, they are rarely followed up with other assessments of health care value that are critical to stakeholders who use different measures to define value. The limited value assessment in both the research and implementation science of precision medicine is likely due to necessary logistical constraints of these teams; engaging bioethicists, health care economists, and individual patient belief systems is incredibly daunting for geneticists and informaticians conducting research. In this narrative review, we concisely describe several definitions of value through various stakeholder viewpoints. We highlight the existing gaps that prevent clinical translation of scientific findings generally as well as more specifically using two present-day, extreme scenarios: (1) genetically guided warfarin dosing representing a handful of genetic markers and more than 10 years of basic and translational research, and (2) next-generation sequencing representing genome-dense data lacking substantial evidence for implementation. These contemporary scenarios highlight the need for various stakeholders to broadly adopt frameworks designed to define and collect multiple value measures across different disciplines to ultimately impact more universal acceptance of and reimbursement for genomic medicine.

Taking an integrated knowledge translation approach in research to develop the CONSORT-Equity 2017 reporting guideline: an observational study.

OBJECTIVE: We describe the use of an integrated knowledge translation (KT) approach in the development of the CONsolidated Standards Of Reporting Trials extension for equity ('CONSORT-Equity 2017'), and advisory board-research team members' ('the team') perceptions of the integrated KT process. DESIGN: This is an observational study to describe team processes and experience with a structured integrated KT approach to develop CONSORT-Equity 2017. Participant observation to describe team processes and a survey were used with the 38 team members. SETTING: Use of the CONSORT health research reporting guideline contributes to an evidence base for health systems decision-making, and CONSORT-Equity 2017 may improve reporting about health equity-relevant evidence. An integrated KT research approach engages knowledge users (those for whom the research is meant to be useful) with researchers to co-develop research evidence and is more likely to produce findings that are applied in practice or policy. PARTICIPANTS: Researchers adopted an integrated KT approach and invited knowledge users to form a team. RESULTS: An integrated KT approach was used in the development of CONSORT-Equity 2017 and structured replicable steps. The process for co-developing the reporting guideline involved two stages: (1) establishing guiding features for co-development and (2) research actions that supported the co-development of the reporting guideline. Stage 1 consisted of four steps: finding common ground, forming an advisory board, committing to ethical guidance and clarifying theoretical research assumptions. Bound by the stage 1 guiding features of an integrated KT approach, stage 2 consisted of five steps during which studies for consensus-based reporting guidelines were conducted. Of 38 team members, 25 (67.5%) completed a survey about their perceptions of the integrated KT approach. CONCLUSIONS: An integrated KT approach can be used to engage a team to co-develop reporting guidelines. Further study is needed to understand the use of an integrated KT approach in the development of reporting guidelines.

Evaluating the impact of image guidance in the surgical setting: a systematic review.

BACKGROUND: Image guidance has been clinically available for over a period of 20 years. Although research increasingly has a translational emphasis, overall the clinical uptake of image guidance systems in surgery remains low. The objective of this review was to establish the metrics used to report on the impact of surgical image guidance systems used in a clinical setting. METHODS: A systematic review of the literature was carried out on all relevant publications between January 2000 and April 2016. Ovid MEDLINE and Embase databases were searched using a title strategy. Reported outcome metrics were grouped into clinically relevant domains and subsequent sub-categories for analysis. RESULTS: In total, 232 publications were eligible for inclusion. Analysis showed that clinical outcomes and system interaction were consistently reported. However, metrics focusing on surgeon, patient and economic impact were reported less often. No increase in the quality of reporting was observed during the study time period, associated with study design, or when the clinical setting involved a surgical specialty that had been using image guidance for longer. CONCLUSIONS: Publications reporting on the clinical use of image guidance systems are evaluating traditional surgical outcomes and neglecting important human and economic factors, which are pertinent to the uptake, diffusion and sustainability of image-guided surgery. A framework is proposed to assist researchers in providing comprehensive evaluation metrics, which should also be considered in the design phase. Use of these would help demonstrate the impact in the clinical setting leading to increased clinical integration of image guidance systems.

The characteristics and reporting quality of research impact case studies: A systematic review.

Despite the growing expectation that researchers report the impact of their research using a case study approach, systematic reviews of research impact have focused on frameworks, indicators, methods of data collection and assessment rather than impact case studies. Our aim is to provide an overview of the characteristics of published research impact case studies, including translation activities, and their reporting quality. We searched for peer-reviewed impact studies published between 2000 and 2018 using a case study approach and selected 25 suitable papers. We applied descriptive statistics to study characteristics, conducted thematic analysis of research translation activities and assessed reporting quality using the 10-point ISRIA statement. 24 papers reported intermediate impacts, such as advocacy, or the development of statements, tools, or technology. 4 reported on longer-term societal impacts, such as health outcomes and economic return on investment. 7 reported on translation activities. Papers scored well against the ISRIA statement on 5 domains of reporting quality. Weakest scores centred around identification of stakeholder needs and stakeholder involvement, and ethics and conflict of interest. We identified the need for more consistency in reporting through a case study approach, more systematic reporting of translation pathways and greater transparency concerning estimated costs and benefits of the research and its translation and impact assessment.

Training the Twenty-First Century Cancer Epidemiologist.

To assess and advance training of twenty-first century cancer epidemiologists, the National Cancer Institute (NCI) sought to obtain a snapshot of the cancer epidemiology training landscape by conducting a survey across academic institutions and cancer centers, focusing on four key training areas driving current cancer epidemiology research ("drivers"): (1) collaboration, (2) novel methods/technologies, (3) multilevel analysis, and (4) knowledge integration. Complementary to the survey, we conducted a portfolio analysis of active NCI-funded training grants. In the present report, we provide our findings from this effort and contribute to the on-going conversation regarding the training of next-generation cancer epidemiologists. Analyses and insights gained from conversations with leaders/educators across 24 academic institutions/cancer centers and the portfolio analysis of training grants echoed contemporaneous conversation that cancer epidemiology training must adapt to meet the needs of the changing research environment. Currently, with the exception of novel methods/technologies, cancer epidemiology trainees receive the majority of their training in collaboration, multilevel approaches, and knowledge integration/translation either informally, ad hoc, or not at all; exposure to these identified drivers varied considerably by institution, mentor, and other external as well as internal factors.

Developing priorities to achieve health equity through diabetes translation research: a concept mapping study.

Introduction: The goal of diabetes translation research is to advance research into practice and ensure equitable benefit from scientific evidence. This study uses concept mapping to inform and refine future directions of diabetes translation research with the goal of achieving health equity in diabetes prevention and control. Research design and methods: This study used concept mapping and input from a national network of diabetes researchers and public health practitioners. Concept mapping is a mixed-method, participant-based process. First, participants generated statements by responding to a focus prompt ("To eliminate disparities and achieve health equity in the prevention and treatment of diabetes, research should…"). Participants then sorted statements by conceptual similarity and rated each statement on importance and feasibility (Likert scale of 1-5). A cluster map was created using multidimensional scaling and hierarchical cluster analysis; statements were plotted by average importance and feasibility. Results: Ten clusters were identified containing between 6 and 12 statements from 95 total generated statements. The ranges of average importance and feasibility ratings for clusters were fairly high and narrow (3.62-4.09; 3.10-3.93, respectively). Clusters with the most statements in the "go-zone" quadrant (above average importance/feasibility) were community and partner engagement (n=7), dissemination and implementation principles (n=4), and enrichment and capacity building (n=4). Clusters with the most statements in the "innovative-targets" quadrant (above average importance, below average feasibility) included next generation interventions (n=6), policy approaches (n=4), and interventions for specific populations (n=4). Conclusions: This study created a framework of 10 priority areas to guide current and future efforts in diabetes translation research to achieve health equity. Themes rated as highly important and feasible provide the basis to evaluate current research support. Future efforts should explore how to best support innovative-targets, those rated highly important but less feasible.

Development and Content Validation of a Transcultural Instrument to Assess Organizational Readiness for Knowledge Translation in Healthcare Organizations: The OR4KT.

BACKGROUND: Implementing effective interventions in healthcare requires organizations to be ready to support change. This study aimed to develop, adapt transculturally, and assess the content and face validity of the Organizational Readiness for Knowledge Translation (OR4KT) tool. The OR4KT was designed to measure the readiness of healthcare organizations to implement evidence-informed change across a variety of services. METHODS: Based on systematic reviews of the literature, a Delphi exercise, and expert consultation, we first generated an initial pool of items. Second, we developed and assessed content validity of the pilot OR4KT questionnaire in English. Third, we created French and Spanish versions using a sequential forward and backward translation approach, and transcultural adaptation by a consensus process. Finally, we conducted pilot studies in three contexts - the Basque country region (Spain), and the provinces of Québec and Ontario (Canada) - where 30 experts assessed the face validity of the three versions of OR4KT. RESULTS: We selected 59 items, grouped in 6 dimensions (organizational climate, context, change content, leadership, organizational support, and motivation) for the final English version of OR4KT. Translation and transcultural adaptation did not identify any content or language problems. Our findings indicate that the English, French and Spanish versions of OR4KT are linguistically equivalents and have high face validity. Only minor revisions to the wording of some items were recommended. CONCLUSION: The OR4KT holds promise as a measure of readiness for knowledge translation (KT) in healthcare organizations. The validity and reliability of the three versions of the OR4KT will be assessed in real-life contexts of implementation of evidence-based changes in healthcare.

Defining and Measuring Community Engagement and Community-Engaged Research: Clinical and Translational Science Institutional Practices.

BACKGROUND: The institutions that comprise the Clinical and Translational Science Award (CTSA) consortium and the National Center for Advancing Translational Sciences continue to explore and develop community-engaged research strategies and to study the role of community academic partnerships in advancing the science of community engagement. OBJECTIVES: To explore CTSA institutions in relation to an Institute of Medicine recommendation that community engagement occur in all stages of translational research and be defined and evaluated consistently. METHODS: A sequential multimethods study starting with an online pilot survey followed by survey respondents and site informant interviews. A revised survey was sent to the community engagement and evaluation leads at each CTSA institution, requesting a single institutional response about the definitions, indicators, and metrics of community engagement and community-engaged research. RESULTS: A plurality of CTSA institutions selected the definition of community engagement from the Principles of Community Engagement. Although claiming unique institutional priorities create barriers to developing shared metrics, responses indicate an overall lack of attention to the development and deployment of metrics to assess community engagement in and contributions to research. CONCLUSIONS: Although definitions of community engagement differ among CTSAs, there seem to be more similarities than differences in the indicators and measures tracked and reported on across all definitions, perhaps owing to commonalities among program infrastructures and goals. Metrics will likely need to be specific to translational research stages. The assessment of community engagement within translational science will require increased institutional commitment.

FDA and NIST collaboration on standards development activities supporting innovation and translation of regenerative medicine products.

The development of standards for the field of regenerative medicine has been noted as a high priority by several road-mapping activities. Additionally, the U.S. Congress recognizes the importance of standards in the 21st Century Cure Act. Standards will help to accelerate and streamline cell and gene therapy product development, ensure the quality and consistency of processes and products, and facilitate their regulatory approval. Although there is general agreement for the need of additional standards for regenerative medicine products, a shared understanding of standards is required for real progress toward the development of standards to advance regenerative medicine. Here, we describe the roles of standards in regenerative medicine as well as the process for standards development and the interactions of different entities in the standards development process. Highlighted are recent coordinated efforts between the U.S. Food and Drug Administration and the National Institute of Standards and Technology to facilitate standards development and foster science that underpins standards development.

Translating Benzodiazepine Utilization Data into Meaningful Population Exposure: Integration of Two Metrics for Improved Reporting.

Drug utilization research on benzodiazepines remains important for measuring trends in consumption within and across borders over time for the sake of monitoring prescribing patterns and identifying potential population safety concerns. The defined daily dose (DDD) system by the World Health Organization (WHO) remains the internationally accepted standard for measuring drug consumption; however, beyond consumption, DDD-based results are difficult to interpret when individual agents are compared with one another or are pooled into a total class-based estimate. The diazepam milligram equivalent (DME) system provides approximate conversions between benzodiazepines and Z-drugs (i.e. zopiclone, zolpidem, zaleplon) based on their pharmacologic potency. Despite this, conversion of total dispensed benzodiazepine quantities into DME values retains diazepam milligrams as the total unit of measurement, which is also impractical for population-level interpretation. In this paper, we propose the use of an integrated DME-DDD metric to obviate the limitations encountered when the component metrics are used in isolation. Through a case example, we demonstrate significant change in results between the DDD and DME-DDD method. Unlike the DDD method, the integrated DME-DDD metric offers estimation of population pharmacologic exposure, and enables superior interpretation of drug utilization results, especially for drug class summary reporting.

Sickle cell disease: Translating clinical care to low-resource countries through international research collaborations.

The vast majority of the world's population of children and adults with sickle cell disease (SCD) are born in low-resource settings, particularly in sub-Saharan Africa, the Caribbean, the Middle East, and India. As a result numerous well-established, cost-effective, and evidence-based strategies for managing SCD such as newborn screening, early education, vaccinations, screening for stroke prevention, and treatments with safe transfusions and hydroxyurea are often unavailable, leading to substantial morbidity and increased mortality. Collaborations between high-income countries and these low-resource settings (North-South partnerships) have been advocated, with the goal of improving clinical care. Based on directives promulgated by the World Health Organization, we have developed a strategy of developing prospective research programs that focus on training, capacity building, and local data collection. This strategy involves consideration of important guiding principles, full partnerships, proper planning, and financial issues before program launch, after which rigorous program management is required for full effect and long-term sustainability. Ultimately these collaborative research programs should help create national guidelines and lead to improved clinical care for all children and adults with SCD.