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Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.
Objectives/Goals: Chronic stress may accelerate biological aging yet is often overlooked in clinical settings. Many tools to assess stress exist, but a comprehensive measure of cumulative stress across the lifespan is unavailable. This study validates a novel measure of lifetime stress for use as a screening tool in clinical practice. Methods/Study Population: Patients (n > 220) enrolled in brain health research registry at the Washington University St. Louis Knight Alzheimer Disease Research Center completed in-person surveys at baseline and after six months. Baseline measures included the everyday discrimination scale (EDS), total adverse experience (TAE), and demographics. Age and evaluating life course stress experience (ELSE) scores were measured six months later. Ongoing analysis includes age-adjusted correlations of ELSE scores with TAE and EDS scores. We will investigate the correlation with race and ethnicity and sex assigned at birth. We will explore the relationship between ELSE score and multidimensional intersectionality. Results/Anticipated Results: The sample was 87% Black or African American, 8% White, 4% Hispanic, 82% female, and 18% male, with a mean age of 66 ± 10 years. Age-adjusted relationships between patient characteristics and ELSE scores will be analyzed. Additionally, ELSE responses will be compared against age, EDS, and TAE measurements. Intersectionality between race-ethnicity, sex, and gender will be examined. We hypothesize ELSE scores will vary by demographic. Preliminary results indicate the ELSE scale correlates with established life stress measures, accounting for cumulative stress exposure across a lifespan independent of specific stressor topics. Discussion/Significance of Impact: The ELSE scale is a viable tool for clinical screening of chronic stress exposure over a lifespan. Its implementation will allow clinicians to identify patients at high risk for accelerated aging, facilitating targeted interventions and advancing equity in healthcare delivery.
Transdisciplinary sustainability scientists work with many different actors in pursuit of change. In so doing they make choices about why and how to engage with different perspectives in their research. Reflexivity – active individual and collective critical reflection – is considered an important capacity for researchers to address the resulting ethical and practical challenges. We developed a framework for reflexivity as a transformative capacity in sustainability science through a critical systems approach, which helps make any decisions that influence which perspectives are included or excluded in research explicit. We suggest that transdisciplinary sustainability research can become more transformative by nurturing reflexivity.
Technical summary
Transdisciplinary sustainability science is increasingly applied to study transformative change. Yet, transdisciplinary research involves diverse actors who hold contrasting and sometimes conflicting perspectives and worldviews. Reflexivity is cited as a crucial capacity for navigating the resulting challenges, yet notions of reflexivity are often focused on individual researcher reflections that lack explicit links to the collective transdisciplinary research process and predominant modes of inquiry in the field. This gap presents the risk that reflexivity remains on the periphery of sustainability science and becomes ‘unreflexive’, as crucial dimensions are left unacknowledged. Our objective was to establish a framework for reflexivity as a transformative capacity in sustainability science through a critical systems approach. We developed and refined the framework through a rapid scoping review of literature on transdisciplinarity, transformation, and reflexivity, and reflection on a scenario study in the Red River Basin (US, Canada). The framework characterizes reflexivity as the capacity to nurture a dynamic, embedded, and collective process of self-scrutiny and mutual learning in service of transformative change, which manifests through interacting boundary processes – boundary delineation, interaction, and transformation. The case study reflection suggests how embedding this framework in research can expose boundary processes that block transformation and nurture more reflexive and transformative research.
Social media summary
Transdisciplinary sustainability research may become more transformative by nurturing reflexivity as a dynamic, embedded, and collective learning process.
The study objective was to develop and validate a clinical decision support system (CDSS) to guide clinicians through the diagnostic evaluation of hospitalized individuals with suspected pulmonary tuberculosis (TB) in low-prevalence settings.
Methods:
The “TBorNotTB” CDSS was developed using a modified Delphi method. The CDSS assigns points based on epidemiologic risk factors, TB history, symptoms, chest imaging, and sputum/bronchoscopy results. Below a set point threshold, airborne isolation precautions are automatically discontinued; otherwise, additional evaluation, including infection control review, is recommended. The model was validated through retrospective application of the CDSS to all individuals hospitalized in the Mass General Brigham system from July 2016 to December 2022 with culture-confirmed pulmonary TB (cases) and equal numbers of age and date of testing-matched controls with three negative respiratory mycobacterial cultures.
Results:
104 individuals with TB (cases) and 104 controls were identified. Prior residence in a highly endemic country, positive interferon release assay, weight loss, absence of symptom resolution with treatment for alternative diagnoses, and findings concerning for TB on chest imaging were significant predictors of TB (all P < 0.05). CDSS contents and scoring were refined based on the case–control analysis. The final CDSS demonstrated 100% sensitivity and 27% specificity for TB with an AUC of 0.87.
Conclusions:
The TBorNotTB CDSS demonstrated modest specificity and high sensitivity to detect TB even when AFB smears were negative. This CDSS, embedded into the electronic medical record system, could help reduce risks of nosocomial TB transmission, patient-time in airborne isolation, and person-time spent reviewing individuals with suspected TB.
The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis.
Methods
Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use.
Results
In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08–8.43, p = 3.21 × 10−10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use.
Conclusions
Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.
The COVID-19 pandemic highlighted gaps in infection control knowledge and practice across health settings nationwide. The Centers for Disease Control and Prevention, with funding through the American Rescue Plan, developed Project Firstline. Project Firstline is a national collaborative aiming to reach all aspects of the health care frontline. The American Medical Association recruited eight physicians and one medical student to join their director of infectious diseases to develop educational programs targeting knowledge gaps. They have identified 5 critical areas requiring national attention.
Being married may protect late-life cognition. Less is known about living arrangement among unmarried adults and mechanisms such as brain health (BH) and cognitive reserve (CR) across race and ethnicity or sex/gender. The current study examines (1) associations between marital status, BH, and CR among diverse older adults and (2) whether one’s living arrangement is linked to BH and CR among unmarried adults.
Method:
Cross-sectional data come from the Washington Heights-Inwood Columbia Aging Project (N = 778, 41% Hispanic, 33% non-Hispanic Black, 25% non-Hispanic White; 64% women). Magnetic resonance imaging (MRI) markers of BH included cortical thickness in Alzheimer’s disease signature regions and hippocampal, gray matter, and white matter hyperintensity volumes. CR was residual variance in an episodic memory composite after partialing out MRI markers. Exploratory analyses stratified by race and ethnicity and sex/gender and included potential mediators.
Results:
Marital status was associated with CR, but not BH. Compared to married individuals, those who were previously married (i.e., divorced, widowed, and separated) had lower CR than their married counterparts in the full sample, among White and Hispanic subgroups, and among women. Never married women also had lower CR than married women. These findings were independent of age, education, physical health, and household income. Among never married individuals, living with others was negatively linked to BH.
Conclusions:
Marriage may protect late-life cognition via CR. Findings also highlight differential effects across race and ethnicity and sex/gender. Marital status could be considered when assessing the risk of cognitive impairment during routine screenings.
The fundamentals of cubic norm structures and Jordan algebras are laid out in the first two sections of the chapter. We then derive elementary principles of building up “big” cubic norm structures out of “smaller” ones before we proceed to study cubic Jordan matrix algebras, the most important “hands-on” examples of cubic Jordan algebras. Next we turn to elementary idempotents, which will be used to present a special version of the Jacobson Coordinatization Theorem. Proceeding to Freudenthal algebras, we show that they exist only in ranks 1, 3, 6, 9, 15, and 27, with those of rank 27 being (finally!) called Albert algebras. We define the notion of a split Freudenthal algebra and prove, in analogy with composition algebras, that all Freudenthal algebras are split by some faithfully flat extension, though not always by an étale cover. After having investigated isotopies and norm similarities, with an important characterization of isotopes in Jordan matrix algebras over LG rings as its central result, we study reduced Freudenthal algebras over fields by exhibiting various classifying quadratic form invariants, particularly those pertaining to the invariants mod 2 of Albert algebras.
This chapter is devoted to a short excursion into the theory of alternative algebras over commutative rings. We prove Artin’s theorem, according to which alternative algebras on two generators are associative. We study in detail McCrimmon’s theory of homotopes, which plays a strong role in this book and therefore merits greater emphasis here than one might find in other discussions of alternative algebras.
This chapter provides an in-depth study of composition algebras over commutative rings, which we carry out in the more general framework of conic algebras (called quadratic algebras or algebras of degree 2 by other authors). We present the Cayley–Dickson construction and define composition algebras as unital nonassociative algebras that are projective as modules and allow a non-singular quadratic form permitting composition. We use this construction to obtain first examples of octonion algebras more general than the Graves–Cayley octonions and to derive structure theorems for arbitrary composition algebras. Specializing, it is shown that all composition algebras of rank at least 2 over an LG ring arise from an appropriate quadratic étale algebra by the Cayley–Dickson construction. Other examples of octonion algebras are obtained using ternary hermitian spaces. We address the norm equivalence problem, which asks whether composition algebras are classified by their norms and has an affirmative answer over LG rings but not in general. After a short excursion into affine (group) schemes, we conclude the chapter by showing that arbitrary composition algebras are split by étale covers.
This chapter is concerned with the two Tits constructions of cubic Jordan algebras over commutative rings, which we present for the first time in book form. The key feature of the first Tits construction is that it starts out from cubic alternative algebras rather than cubic associative ones; the key notion that keeps the construction going is that of a Kummer element. Similar statements apply to the second Tits construction, where Kummer elements are replaced by étale elements. Such elements are available in abundance over residually big LG rings. It follows that all Albert algebras over such rings or over arbitrary fields may be obtained from the second Tits construction. The chapter concludes with an application to cubic Jordan division algebras over fields. We show that they are either purely inseparable field extensions of characteristic 3 or Freudenthal algebras of dimension 1, 3, 9, or 27. In each of these dimensions, we construct examples over appropriate fields and conclude the section by showing that over the “standard” fields (the complex numbers, the real numbers, finite, local and global ones), Albert division algebras do not exist.
In most of this book, we have studied Albert and octonion algebras. In this chapter, we connect those with the theory of semi-simple affine group schemes, especially those of type E6, F4, and G2. As part of this effort, we give an introduction to non-abelian flat cohomology and its applications to descent. We leverage this together with known results about affine group schemes such as Gross’s mass formula to classify the Albert algebras over the integers, a recently discovered result.