The National Institutes of Health Lasker Clinical Research Scholars Program: A Decade of Launching Clinician-Scientist Careers.

PURPOSE: In response to the decades-long decrease in U.S. clinician-scientists, the National Institutes of Health (NIH) and the Albert and Mary Lasker Foundation launched the Lasker Clinical Research Scholars Program in academic year 2011 to 2012. The investigators examined the early outcomes of this program. METHOD: Thirty-nine scholars have matriculated into the program as of May 2023. Productivity was assessed for all scholars who joined the program before October 2020 (n = 31). Extramural early-stage investigators (ESIs) were used as a control group, and coarsened exact matching was used to compare the groups. The scholars were compared with the matched ESIs on 4 productivity metrics: publication count, weighted relative citation ratio, clinical impact, and approximate potential to translate. Publication records for both groups were compiled using the NIH Office of Portfolio Analysis' name disambiguation method and manually curated to ensure integrity of the data set. RESULTS: Of the 39 scholars, 29 were compared with 121 matched extramural ESIs. Five years before matriculation, the 2 groups had comparable numbers of publications, but scholars had a higher median weighted relative citation ratio, clinical impact, and approximate potential to translate score. Five years after matriculation, the scholars had a higher median number of publications than the ESIs, and the gap between scholars and ESIs, with scholars having higher scores, had widened for all metrics except approximate potential to translate scores. Of 10 of the 39 scholars at or approaching tenure eligibility, 6 have attained tenure (3 at NIH and 3 in academic institutions), and 4 are on track to attain tenure at NIH. CONCLUSIONS: All the Lasker clinical research scholars are substantially involved in clinical and translational research. Their productivity matches or exceeds that of a matched cohort of ESIs at U.S. academic institutions.

The Tangential Dialogue Between Science and Medicine: A Case in Point.

The road between a hypothesis about a disease or condition and its cure or palliation is never simply linear. There are many tantalizing tangents to be chased and many seemingly obvious truths with countless exceptions; this is usually a feature, not a bug, as they say in computer programming. In the tangents and exceptions are clues and alternative roads to science and medicine that can provide cures and palliative measures, sometimes for diseases or conditions other than the one being studied. The narrative that follows uses the author's scientific experience in childhood nervous system cancer to illustrate the importance of a robust, bidirectional interaction between the laboratory bench and the clinic bedside in the quest for solutions to problems of health, longevity, and quality of life.

Developing the next-generation cancer research workforce in the National Institutes of Health Intramural Research Program.

Although the National Institutes of Health is renowned for being the largest funder of biomedical research in the world, the research and associated career development programs on its own campuses are relatively unknown. These intramural programs provide many outstanding and programmatically unique opportunities for research-intensive careers and training in cancer biology, prevention, diagnosis, and therapeutics. Their complementary foci, structures, and review mechanisms make the extramural and intramural cancer research contributions of the National Institutes of Health the perfect partners in the quest to rid the world of cancer as we know it.

Proceedings of the First Pediatric Coma and Disorders of Consciousness Symposium by the Curing Coma Campaign, Pediatric Neurocritical Care Research Group, and NINDS: Gearing for Success in Coma Advancements for Children and Neonates.

This proceedings article presents the scope of pediatric coma and disorders of consciousness based on presentations and discussions at the First Pediatric Disorders of Consciousness Care and Research symposium held on September 14th, 2021. Herein we review the current state of pediatric coma care and research opportunities as well as shared experiences from seasoned researchers and clinicians. Salient current challenges and opportunities in pediatric and neonatal coma care and research were identified through the contributions of the presenters, who were Jose I. Suarez, MD, Nina F. Schor, MD, PhD, Beth S. Slomine, PhD Erika Molteni, PhD, and Jan-Marino Ramirez, PhD, and moderated by Varina L. Boerwinkle, MD, with overview by Mark Wainwright, MD, and subsequent audience discussion. The program, executively planned by Varina L. Boerwinkle, MD, Mark Wainwright, MD, and Michelle Elena Schober, MD, drove the identification and development of priorities for the pediatric neurocritical care community.

Academic Neurology and the COVID-19 Pandemic: Resilience, Hope, and Solutions.

The SARS-CoV-2 (COVID-19) viral pandemic dramatically affected human health, health care delivery, health care workers, and health care research worldwide. The field of academic neurology was no exception. In this 2022 Presidential Plenary, we discuss the challenges faced by neurologists and neuroscientists professionally and personally. We review the threats posed by the pandemic to neuroscience research activities, materials, productivity, and funding. We then discuss the impact of the pandemic on clinical trials for neurologic diseases. Restrictions to patient enrolment due to limited in-person access to laboratory testing, imaging, and study visits led to delay in both clinical trial enrolment and study completion but also to innovative new means to engage clinical trial participants remotely and to strategies to critically appraise the frequency and design of trial-related patient evaluations. Clinical care was also challenged by initial pandemic prioritization of urgent visit and inpatient care and the rapid pivot to telehealth for most other neurology care encounters. Front-line neurology care teams faced their fears of infection, with the first few months of the pandemic being characterized by uncertainty, inconsistent national health care strategies, limited personal protective equipment, and an alarming rate of human illness and death caused by COVID-19. The personal and societal toll of the pandemic is incalculable. Across research and clinical neurology providers, women and particularly those with young families juggled the impossible balance of career and family care as schools closed and children required home-based education. Shining through this dark time are lessons that should shape a brighter future for our field. We are resilient, and the advances in neuroscience and neurology care continue to advance improved neurologic outcomes. The National Institutes of Health devised multiple support strategies for researchers to help bridge the pandemic. Telehealth, clinical trial designs that are more participant-centric with remote monitoring, and flexible work schedules are strategies to rebalance overworked lives and improve our engagement with our patients. As we re-emerge, we have the chance to reframe our field.

Planning and Implementing Strategically: Year 1 of the NINDS 2021-2026 Strategic Plan.

At the end of 2020, the National Institute of Neurological Disorders and Stroke, an institute of the National Institutes of Health, completed an 18 month-long strategic planning process that involved and engaged diverse internal and external biomedical and general stakeholders. The Institute published and disseminated its 2021-2026 Strategic Plan online in December 2020. Now, 1 year into its implementation, this progress report presents accomplishments to date, new initiatives and opportunities, and a preview of the metrics and benchmarks we will use to gauge the future progress of the strategic plan's implementation.

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo.

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize.

The NINDS 2021-2026 Strategic Plan: Partnership and cross-cutting principles.

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity.

An Article-Based Format for Medical Specialty and Subspecialty Maintenance of Certification.

INTRODUCTION: This article describes an article-based alternative for maintenance of certification that the American Board of Psychiatry and Neurology developed and began pilot testing in 2019. The rationale for and components of the pilot program are presented along with data on participant performance and feedback from the first year of implementation in three primary specialties (neurology, child neurology, and psychiatry) and one subspecialty (child and adolescent psychiatry). METHODS: Evaluation of the pilot program was guided by a widely used validity framework. Data were collected that addressed the five categories of validity evidence: content, response process, internal structure, relation to other variables, and consequences. RESULTS: Enrollment ranged from 66.7% for psychiatrists to 75.3% for child neurologists. For the 2019 cohort, the pass rates ranged from 92.6% for child and adolescent psychiatry to 98.7% for neurology, and very small numbers of diplomates failed or did not complete the process. For psychiatrists, there was a modest, but significant, relationship between performance on previous and subsequent maintenance of certification examinations. Ninety percent or more agreed that: the articles were easy to access and helpful to their practices; the mini-tests were a fair assessment of their understanding of the articles; and their test-taking experience was satisfactory. DISCUSSION: Most eligible diplomates participated in the article-based pilot project, and they strongly preferred this format to the traditional multiple-choice examinations. Most important, the pilot was perceived to be a meaningful and relevant learning activity that had a positive effect on patient care.

Next-generation strategies for gene-targeted therapies of central nervous system disorders: A workshop summary.

The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop titled "Next generation strategies for gene-targeted therapies of central nervous system (CNS) disorders" in September 2019 in Bethesda, MD, USA. The meeting brought together a multi-disciplinary group of experts in the field of CNS-directed gene-targeted therapy delivery from academia, industry, advocacy, and the government. The group was charged with identifying the key challenges and gaps in this evolving field, as well as suggesting potential solutions. The workshop was divided into four sessions: (1) control of level and location, (2) improving delivery and distribution, (3) enhancing models and manufacturing, and (4) impacting patients. Prior to the workshop, NINDS established working groups of key opinion leaders (KOLs) for each session. In pre-meeting teleconferences, KOLs were tasked with identifying the research gaps and key obstacles that delay and/or prevent gene-targeted therapies to move into the clinic. This approach allowed for the workshop to begin with problem-solving discussions and strategy development, as the key issues had been established. The overall purpose of the workshop was to consider knowledge gaps and potential strategies to inform the community around CNS gene-targeted therapies, including but not limited to researchers and funders.

Seeking progress in disease modification in Parkinson disease.

OBJECTIVE: Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. METHODS: The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. RESULTS: Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. CONCLUSIONS: We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

Neurodevelopmental Clues to Neurodegeneration.

Neurodegenerative disorders are characterized by neuronal loss, usually in late life. But recently, abnormalities of proteins implicated in neurodegenerative disorders have been identified in disorders of childhood, raising the possibility that clues to susceptibility to and prevention of neurodegenerative disorders may be identifiable before symptoms of disease arise. This review leverages these new and evolving findings to test our hypothesis, first proposed in 2010, that proteins implicated in neurodegenerative disorders play important roles in brain development by examining evidence in the peer-reviewed literature published in the past five years for the relevance of these proteins in normal and disease-associated brain development.

Programmatic Foci of Women in Academic Leadership Positions at Historically Black Colleges and Universities: Intersectionality and Institutional Mission.

The present studies compare, between Historically Black Colleges and Universities (HBCUs; n=102) and a non-HBCU cohort matched for location, religious and vocational mission, and student enrollment (comparator CUs; n=102), the programmatic foci of women in institutional leadership positions. They demonstrate that, at HBCUs, women are more prevalent in leadership roles with male-dominated foci (e.g., finance), and less prevalent in roles with female-dominated foci (e.g., public relations) than at comparator CUs (p < 0.01). A survey of academic leaders (n=1,053 invited; 111 viewed survey; 83 completed survey) at these institutions indicates that women leaders at HBCUs more frequently fill institutional programmatic gaps than their counterparts at comparator CUs (p < 0.001) or men in any academic setting (p < 0.005). Reasons may include the social purpose of HBCUs; the stereotype threat of the traditional "service" role of women and the unique intersectionality encountered by Black women faculty; and the importance of race over gender in homosociability at HBCUs. This suggests that emphasis on the socioeconomic mission and philosophy of higher education may enhance faculty recruitment diversification efforts in higher education. It also raises the question of whether seeing women in atypical leadership roles influences the career aspirations and attitudes towards women leaders of the students, both men and women, at HBCUs.

PRMT1 promotes neuroblastoma cell survival through ATF5.

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.