Translational Research Activities Research Articles

Evaluating Use of Generative Artificial Intelligence in Clinical Pathology Practice: Opportunities and the Way Forward.

Generative artificial intelligence (GAI) technologies are likely to dramatically impact health care workflows in clinical pathology (CP). Applications in CP include education, data mining, decision support, result summaries, and patient trend assessments. To review use cases of GAI in CP, with a particular focus on large language models. Specific examples are provided for the applications of GAI in the subspecialties of clinical chemistry, microbiology, hematopathology, and molecular diagnostics. Additionally, the review addresses potential pitfalls of GAI paradigms. Current literature on GAI in health care was reviewed broadly. The use case scenarios for each CP subspecialty review common data sources generated in each subspecialty. The potential for utilization of CP data in the GAI context was subsequently assessed, focusing on issues such as future reporting paradigms, impact on quality metrics, and potential for translational research activities. GAI is a powerful tool with the potential to revolutionize health care for patients and practitioners alike. However, GAI must be implemented with much caution considering various shortcomings of the technology such as biases, hallucinations, practical challenges of implementing GAI in existing CP workflows, and end-user acceptance. Human-in-the-loop models of GAI implementation have the potential to revolutionize CP by delivering deeper, meaningful insights into patient outcomes both at an individual and population level.

NCI Resources for Cancer Immunoprevention Research.

Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation's strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the NCI is the federal government's principal component devoted to promoting and supporting innovative cancer prevention research. Recent advances in tumor immunology, cancer immunotherapy, and vaccinology strongly suggest that the host immune system can be effectively harnessed to elicit protective immunity against the development of cancer, that is, cancer immunoprevention. Cancer immunoprevention may be most effective if the intervention is given before or early in the carcinogenic process while the immune system remains relatively uncompromised. DCP has increased the emphasis on immunoprevention research in recent years and continues to expand program resources and interagency collaborations designed to facilitate research in the immunoprevention field. These resources support a wide array of basic, translational, and clinical research activities, including discovery, development, and validation of biomarkers for cancer risk assessment and early detection (Early Detection Research Network), elucidation of biological and pathophysiological mechanistic determinants of precancer growth and its control (Translational and Basic Science Research in Early Lesions), spatiotemporal multiomics characterization of precancerous lesions (Human Tumor Atlas Network/Pre-Cancer Atlas), discovery of immunoprevention pathways and immune targets (Cancer Immunoprevention Network), and preclinical and clinical development of novel agents for immunoprevention and interception (Cancer Prevention-Interception Targeted Agent Discovery Program, PREVENT Cancer Preclinical Drug Development Program, and Cancer Prevention Clinical Trials Network).

The rocky road to translational science: An analysis of Clinical and Translational Science Awards

Abstract Studies point out that the productivity decline in biomedicine is in significant part due to difficulties in translating basic science into clinical application. To promote translational research, the US NIH launched the Clinical and Translational Science Awards (CTSA) program in 2006. Prior evaluations of the CTSA program often assumed that the key to translation is inter-organizational collaboration or multidisciplinarity; hence, changes in either of these were measured as evidence of translational science. However, using novel measures of translational science, this study examines the relationship between CTSAs and translational science per se. We define ‘translational science’ as basic science that has translational features, and we employ two distinct, complementary measures of translational science based on publication data. Using 115 Carnegie R1 universities and their translational science publications, we find that receiving a CTSA does not obviously cause receiving institutions to conduct more translational science. Furthermore, our Principal Investigator-level analysis shows that those who received direct support from the CTSA program had already generated more translational science than others and that their research behavior did not change significantly after receiving a CTSA. Future evaluation research can adopt our novel measures of translational science and evaluation research design in the assessment of translational research activities. Finally, we conclude with a discussion of the implications of our findings for science governance.

How long does it take to translate research findings into routine healthcare practice?-the case of biological drugs for rheumatoid arthritis in Brazil.

BackgroundThe literature reports long time lags between the several processes involved in the translation of drug research and development into clinical application. To expedite these processes, translational research has emerged as a process that can be applied to reduce the lag between scientific discoveries and their practical application. Thus, the objective of this study was to estimate the time lag in translational research of biological drugs for the treatment of rheumatoid arthritis included in the Brazilian Unified Health System [Sistema Único de Saúde (SUS)].MethodsA descriptive retrospective study was conducted based on secondary data loaded by SUS users in public sources and systems to estimate the time lag between the publication of phase I clinical trial results to drug use in clinical settings. The dates of translational research activities were identified from markers and steps. Structured searches were conducted in the literature and reports from the National Commission for the Incorporation of Technologies in the SUS (Conitec) as well as from health authorities, and analyzed.ResultsBetween 2012 and 2019, SUS included five biological agents for the treatment of rheumatoid arthritis. The mean time lag from clinical development to use of these agents was 11.13 years (range, 8.57 to 12.90 years). The mean time lag for the stages of translational research were 5.30 (T1—basic research to clinical research), 5.08 (T2—clinical research to research synthesis), and 0.75 (T3—research synthesis to evidence-based practice) years. A shorter time lag was observed in the Brazilian case when it was possible to compare with other studies.ConclusionsThe estimated time lag of biological drugs used in the treatment of rheumatoid arthritis was determined based on the translational research steps model adapted to the Brazilian context. Brazil has instituted legal frameworks that set deadlines for sanitary registration, health technology assessment (HTA), and the availability of drugs in the SUS, thus, allowing for a reduced stage T2 time lag. Nevertheless, improvements are still required in stages T1 and T2, especially in publishing the results of clinical trials.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

Reflecting on Merck’s I-O biomarker development journey

Eric H Rubin has focused on cancer drug development for over 25 years, initially as a faculty member at the DanaFarber Cancer Institute, then as a senior leader of the Cancer Institute of New Jersey, where he served as the Director of the Investigational Therapeutics Division of that institution. His research efforts focused on mechanisms of resistance to DNA topoisomerase-targeting drugs and his laboratory cloned TOPORS, a novel topoisomerase I- and p53-interacting tumor suppressor gene. In 2008 he was recruited to Merck to lead the clinical oncology development team. Under his leadership, the clinical oncology group underwent a transformational change in an effort to realize the potential of cancer immunotherapy. He led the initial development of the anti-PD-1 antibody pembrolizumab, which was the first anti-PD-1 therapy approved in the USA, and in the identification of the significant activity of this breakthrough therapeutic across several cancer types. In 2014 Dr. Rubin was asked to head up Oncology Early Development for Merck, and in this role he oversees development of a promising and expansive early pipeline, as well as translational oncology research activities. Dr. Rubin has authored over 100 original, peer-reviewed publications and book chapters related to oncology translational research, clinical trials, and drug development. He has served frequently as a member of National Cancer Institute and American Cancer Society study sections, as well as on program committees for the American Association of Cancer Research (AACR) and the American Society of Clinical Oncology. He is a co-chair of the Cancer Steering Committee of the Biomarkers Consortium, Foundation of the National Institute of Health, a member of the Science Policy and Governmental Affairs Committee for AACR, and was a member of the National Cancer Moonshot Initiative/Blue Ribbon Panel Working Group on Expanding Clinical Trials.

CI in single-sided deafness

The cochlear implant (CI) as a treatment option for single-sided deafness (SSD) started with a clinical study looking in to the influence of cochlear implantation with a MED-EL device on incapacitating unilateral tinnitus in SSD. The study began in 2003 and was conducted by P. Van de Heyning and his team in Antwerp, Belgium. The first CI in SSD without tinnitus in Germany was implanted by J. Mueller and R. Jacob in Koblenz in 2005. Translational research activities took place since then to evaluate the CI as a treatment option for SSD not only in adults but also in children. They assessed the hearing performance of SSD patients implanted with CI, importance of long electrode arrays in SSD patients, degree of acceptance of CI by SSD children, importance of early CI implantation in SSD children in developing language skills, music enjoyment by hearing with two ears and evidence on spiral ganglion cell body distribution. In 2013, MED-EL was the first CI manufacturer to receive the CE mark for the indication of SSD and asymmetric hearing loss (AHL) in adults and children. In 2019, MED-EL was the first CI manufacturer to get its CI device approved for patients over the age of five with SSD and AHL, by the FDA in the USA. This article covers the milestones of translational research from the first concept to the widespread clinical use of CI in SSD.

Signal processing & audio processors

Signal processing algorithms are the hidden components in the audio processor that converts the received acoustic signal into electrical impulses while maintaining as much relevant information as possible. Signal processing algorithms should be smart enough to mimic the functionality of external, middle and the inner-ear to provide the cochlear implant (CI) user with a hearing experience as natural as possible. Modern sound processing strategies are based on the continuous interleaved sampling (CIS) strategy proposed by B. Wilson in 1991, which provided envelope information over several intracochlear electrodes. The CIS strategy brought significant gains in speech perception. Translational research activities of MED-EL resulted in further improvements in speech understanding in noisy environments as well as enjoyment of music by not only coding CIS-based envelope information, but by also representing temporal fine structure information in the stimulation patterns of the apical channels. Further developments include “complete cochlear coverage” made possible by deep insertion of the intracochlear electrode, elaborate front end processing, anatomy based fitting (ABF), triphasic pulse stimulation instrumental in the suppression of facial nerve stimulation, and bimodal delay compensation allowing unilateral CI users to experience hearing with hearing aids on the contralateral ear. The large number of hardware developments might be exemplified by the RONDO, the world's first single unit audio processor in 2013. This article covers the milestones of translational research around the signal processing and audio processor topic that took place in association with MED-EL.

Translational research around five categories of CI

Five categories of cochlear implants are introduced: The ‘classic CI’, the ‘combined CI’ – which can be combining a CI based on electric stimulation with acoustic stimulation (EAS) or with mechanical stimulation (EMS) or with electrical stimulation of the vestibular system (VICI) –, the ‘individualised CI’, the ‘augmented CI’ and the ‘totally implantable CI’. The translational research activities leading to and within these categories have been, are and will be numerous and are the subject of the compendium for which this paper is the concluding chapter. Early translational research has resulted in the ‘classic CI’ in 1994. From then on translational research enabled the developments respectively the new indications and reimbursement of CI-systems for bilateral CIs, CI in single sided deafness, the auditory brainstem implant, speech coding and signal processing advances, electrophysiologic measurements for evaluation of cochlear health, all within the classic CI category. Starting points for the four newer categories of CI are either ideas of professionals treating hearing loss or of CI developers. The translational research performed also triggered research that led and leads to improved understanding of the fundamental mechanisms of hearing.

Impact of integrated translational research on clinical exome sequencing

Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Celyad Oncology’s case study: validation approach for accelerated mycoplasma testing

Dr Sarah SnykersCell Therapy Manufacturing Unit Director at CelyadSarah is Director of the Cell Therapy Manufacturing Unit at Celyad, a clinical-stage biotechnology company focused on the discovery and development of chimeric antigen receptor T cell (CAR T) therapies for cancer. She has over 10 years of experience in cell therapy, biomedical research, development and quality control. She is a pharmacist from education and has a PhD in pharmaceutical and biomedical sciences, specialised in stem cell biology. In 2010, she joined Promethera BioSciences, a biopharmaceutical company dedicated to the development of cell therapy products based on allogeneic adult stem cell technology to treat liver diseases. She headed the R&D, QC and Preclinical Departments. In 2015, she joined Celyad. Sarah initially led the immune-oncology program at R&D level, focused on technology transfer, product characterization and optimization. In 2016, she became Head of the QC Department, covering release of clinical products and raw material, analytical method development and translational research activities. In 2020, all operational activities including Production, QC, Validation and Tech transfer of processes, methods, equipment, raw material and viral vector became under her responsibility.

The clinical and translational research activities at the INT \u2013 IRCCS \u201cFondazione Pascale\u201d cancer center (Naples, Italy) during the COVID-19 pandemic

COVID-19 pandemic following the outbreak in China and Western Europe, where it finally lost the momentum, is now devastating North and South America. It has not been identified the reason and the molecular mechanisms of the two different patterns of the pulmonary host responses to the virus from a minimal disease in young subjects to a severe distress syndrome (ARDS) in older subjects, particularly those with previous chronic diseases (including diabetes) and cancer. The Management of the Istituto Nazionale Tumori - IRCCS “Fondazione Pascale” in Naples (INT-Pascale), along with all Health professionals decided not to interrupt the treatment of those hospitalized and to continue, even if after a careful triage in order not to allow SARS-CoV-2 positive subjects to access, to take care of cancer patients with serious conditions. Although very few (n = 3) patients developed a symptomatic COVID-19 and required the transfer to a COVID-19 area of the Institute, no patients died during the hospitalization and completed their oncology treatment. Besides monitoring of the patients, all employees of the Institute (physicians, nurses, researchers, lawyers, accountants, gatekeepers, guardians, janitors) have been tested for a possible exposure. Personnel identified as positive, has been promptly subjected to home quarantine and subdued to health surveillance. One severe case of respiratory distress has been reported in a positive employees and one death of a family member. Further steps to home monitoring of COVID-19 clinical course have been taken with the development of remote Wi-Fi connected digital devices for the detection of early signs of respiratory distress, including heart rate and oxygen saturation.In conclusion cancer care has been performed and continued safely also during COVID-19 pandemic and further remote home strategies are in progress to ensure the appropriate monitoring of cancer patients.

CDC’s Translational Research Activities Addressing Public Health Impacts of Wildfire Smoke Exposure

In recent years, residents of the United States have experienced longer wildfire seasons and increasingly common large and destructive wildfires. Wildfire smoke reduces air quality and affects the health of millions of adults and children, especially those with existing heart and lung conditions. At the U.S. Centers for Disease Control and Prevention’s National Center for Environmental Health, wildfire-related public health activities include responding to needs of state, territorial, local, and tribal health authorities; improving communication and messaging before, during, and after wildfire events; and conducting translational research to improve our understanding of how wildfire smoke affects public health. For this presentation, we will summarize exposure assessment and epidemiologic research activities about the public health impacts of wildfire smoke currently underway at the National Center for Environmental Health. Ongoing analytic projects address data and knowledge gaps about adverse health effects associated with smoke exposure. For example, analyses of modeled smoke predictions indicate that approximately 90% of the counties in the Western U.S. had at least one smoke event in the past decade. Our analyses of concentration-response functions using data from the 2012 wildfires in Oregon estimated a 8.9% increase in the risk of asthma-related emergency room visits for each 10 µg/m3 increase in fine particulate matter (PM2.5) in wildfire smoke. We have also estimated concentration-response profiles for physician visits and medication fills for asthma and other less well-characterized outcomes. Analysis of quick-relief medication fills during the 2015 wildfire season in the western United States indicates that delayed effects of wildfire smoke PM2.5 on medication fills lasted for six days after initial exposure. Taken together, results from analytic projects such as these indicate opportunities for public health action before, during, and after wildfire smoke events.

MERS-CoV in Africa—an enigma with relevance to COVID-19

MERS-CoV in Africa—an enigma with relevance to COVID-19

Conducting Translational Gastrointestinal Research in the Era of COVID-19.

Spread of the novel coronavirus SARS-CoV-2 has resulted in a global pandemic that is affecting the health and economy of all World Health Organization [WHO] regions. Clinical and translational research activities have been affected drastically by this global catastrophe. In this document we provide a suggested roadmap for resuming gastrointestinal translational research activities, emphasising physical distancing and use of personal protective equipment. We discuss modes of virus transmission in enclosed environments [including clinical workplaces and laboratories] and potential risks of exposure in the endoscopy environment for research staff. The proposed guidelines should be considered in conjunction with local institutional and government guidelines so that translational research can be resumed as safely as possible.

Genomics of periodontal disease and tooth morbidity.

In this review we critically summarize the evidence base and the progress to date regarding the genomic basis of periodontal disease and tooth morbidity (ie, dental caries and tooth loss), and discuss future applications and research directions in the context of precision oral health and care. Evidence for these oral/dental traits from genome‐wide association studies first emerged less than a decade ago. Basic and translational research activities in this domain are now under way by multiple groups around the world. Key departure points in the oral health genomics discourse are: (a) some heritable variation exists for periodontal and dental diseases; (b) the environmental component (eg, social determinants of health and behavioral risk factors) has a major influence on the population distribution but probably interacts with factors of innate susceptibility at the person‐level; (c) sizeable, multi‐ethnic, well‐characterized samples or cohorts with high‐quality measures on oral health outcomes and genomics information are required to make decisive discoveries; (d) challenges remain in the measurement of oral health and disease, with current periodontitis and dental caries traits capturing only a part of the health‐disease continuum, and are little or not informed by the underlying biology; (e) the substantial individual heterogeneity that exists in the clinical presentation and lifetime trajectory of oral disease can be identified and leveraged in a precision medicine framework or, if unappreciated, can hamper translational efforts. In this review we discuss how composite or biologically informed traits may offer improvements over clinically defined ones for the genomic interrogation of oral diseases. We demonstrate the utility of the results of genome‐wide association studies for the development and testing of a genetic risk score for severe periodontitis. We conclude that exciting opportunities lie ahead for improvements in the oral health of individual patients and populations via advances in our understanding of the genomic basis of oral health and disease. The pace of new discoveries and their equitable translation to practice will largely depend on investments in the education and training of the oral health care workforce, basic and population research, and sustained collaborative efforts..

Environmental Health Practice Challenges and Research Needs for U.S. Health Departments.

Background:Environmental health (EH) professionals, one of the largest segments of the public health workforce, are responsible for delivery of essential environmental public health services. The challenges facing these professionals and research needs to improve EH practice are not fully understood, but 26% of EH professionals working in health departments of the United States plan to retire in 5 y, while only 6% of public health students are currently pursuing EH concentrations.Objectives:A groundbreaking initiative was recently launched to understand EH practice in health departments of the United States. This commentary article aims to identify priority EH practice challenges and related research needs for health departments.Methods:A horizon scanning approach was conducted in which challenges facing EH professionals were provided by 1,736 respondents working at health departments who responded to a web-based survey fielded in November 2017. Thematic analyses of the responses and determining the frequency at which respondents reported specific issues and opportunities identified primary EH topic areas. These topic areas and related issues informed focus group discussions at an in-person workshop held in Anaheim, California. The purpose of the in-person workshop was to engage each of the topic areas and issues, through facilitated focus groups, leading to the formation of four to five related problem statements for each EH topic.Discussion:EH professionals are strategically positioned to diagnose, intervene, and prevent public health threats. Focus group engagement resulted in 29 priority problem statements partitioned among 6 EH topic areas: a) drinking water quality, b) wastewater management, c) healthy homes, d) food safety, e) vectors and public health pests, and f) emerging issues. This commentary article identifies priority challenges and related research needs to catalyze effective delivery of essential environmental public health services for common EH program areas in health departments. An unprecedented initiative to revitalize EH practice with timely and strategic recommendations for student and professional training, nontraditional partnerships, and basic and translational research activities is recommended. https://doi.org/10.1289/EHP5161

Preventing Translational Scientists From Extinction: The Long-Term Impact of a Personalized Training Program in Translational Medicine on the Careers of Translational Scientists.

Far too much biomedical research is wasted and ends in the so called “Valley of Death”: the gap that exists between biomedical research and its clinical application. While the translational process requires collaboration between many disciplines, current translational medicine focuses on single disciplines. Therefore, educational pathways that integrate clinical and research skills in interdisciplinary and interprofessional contexts are needed. The Eureka institute (http://www.eurekainstitute.org/) was founded to address these issues. The institute organizes an annual 1-week international certificate course to educate professionals in the domains of translational medicine.Study design: This study set out to investigate the impact of the Eureka certificate course on the alumni, focusing on their ability to engage in translational activities and thus become more proficient translational professionals. An explanatory, mixed-methods study was executed.Data collection: A questionnaire was distributed to collect quantitative data on the number of alumni who were able to apply what they learned during the Eureka course and engage in translational activities. Questionnaire data were also used to inform the semi-structured interviews that were conducted subsequently.Results: Fifty-one percent of the alumni reported that participating in the Eureka course played a role in their decision to change to a different job or in the way they were accomplishing their everyday work. Ten conditions for change that either hampered or supported the Eureka alumni's engagement in translational research activities were identified. Further, the learning outcomes of the Eureka course that impacted the alumni's professional activities were explored using Personal Professional Theory (PPT). The insight that alumni gained in the full translational spectrum and stakeholders involved stimulated reflection on their own role within that pathway. Further, according to the alumni, the course provided them with the skills and confidence to pursue a career as translational professional. These learning outcomes, in combination with conditions that supported alumni's engagement in translational activities, such as supportive professional partners, opportunities to network or collaborate, and a translational work environment, contributed to the large number of alumni that were able to engage in translational activities.

Mobility disorders and pain, interrelations that need new research concepts and advanced clinical commitments.

This Perspective will discuss topics recently suggested by Prof. Helmut Kern, Vienna, Austria, to advance the research activities of his team, that is: Topic A, 10 years post RISE; Topic B, New research for new solutions on old research questions; Topic C, Working groups on nerve regeneration, training-parameters of seniors in different ages, muscle adaptation; and studies of connective tissue and cartilage. This Perspective summarizes some of the basic concepts and of the evidence-based tools for developing further translational research activities. Clinically relevant results will ask for continuous interests of Basic and Applied Myologists and for the support during the next five to ten years of public and private granting agencies. All together, they will end in protocols, devices and multidisciplinary managements for persons suffering with muscle denervation, neuromuscular-related or non-related pain and for the increasing population of old, older and oldest senior citizens in Europe and beyond.

Principles and Applications of Rabbit Models for Atherosclerosis Research.

Rabbits are one of the most used experimental animals for biomedical research, particularly as a bioreactor for the production of antibodies. However, many unique features of the rabbit have also made it as an excellent species for examining a number of aspects of human diseases such as atherosclerosis. Rabbits are phylogenetically closer to humans than rodents, in addition to their relatively proper size, tame disposition, and ease of use and maintenance in the laboratory facility. Due to their short life spans, short gestation periods, high numbers of progeny, low cost (compared with other large animals) and availability of genomics and proteomics, rabbits usually serve to bridge the gap between smaller rodents (mice and rats) and larger animals, such as dogs, pigs and monkeys, and play an important role in many translational research activities such as pre-clinical testing of drugs and diagnostic methods for patients. The principle of using rabbits rather than other animals as an experimental model is very simple: rabbits should be used for research, such as translational research, that is difficult to accomplish with other species. Recently, rabbit genome sequencing and transcriptomic profiling of atherosclerosis have been successfully completed, which has paved a new way for researchers to use this model in the future. In this review, we provide an overview of the recent progress using rabbits with specific reference to their usefulness for studying human atherosclerosis.