MetroHealth

Reciprocal innovation, a model of sustained, multidirectional exchange in which health strategies are adapted, revisited, and refined across contexts, offers a compelling framework to rethink how implementation science can support global health equity by enabling dynamic, multidirectional learning across different contexts. Drawing on the EXTRA-CVD trial, a nurse-led cardiovascular disease prevention intervention designed to extend the HIV treatment cascade in United States (U.S.) HIV clinics, which adapted strategies informed by implementation research in Kenya and the U.S. Veterans Affairs health system, this perspective examines how reciprocal innovation can begin to emerge within existing research structures, as well as where opportunities for deeper exchange remain limited. We identify four operational domains of reciprocal innovation: care delivery strategies, end-user engagement, research methodologies, and research leadership and partnership. Across these domains, we describe how cross-context learning shaped intervention adaptation and site-level implementation in EXTRA-CVD, as well as missed opportunities where more intentional feedback, shared leadership, and methodological exchange could have strengthened multidirectional learning. Taken together, this work highlights both the potential and the practical challenges of reciprocal innovation in implementation research, emphasizing its role in moving beyond unidirectional knowledge transfer toward iterative, context-responsive learning. By embedding structures for iterative feedback, equity-centered governance, and multidirectional learning systems within research and implementation systems, future global partnerships can foster more inclusive, responsive, and sustainable health interventions.

Spinal cord injury typically leads to neurogenic bladder dysfunction, often including detrusor-sphincter dyssynergia. Sacral anterior root stimulation can empty the neurogenic bladder, but this emptying can be impeded by reflex contractions of the urethral sphincter. The sacral sensory roots are typically transected (rhizotomy) to reduce these reflex contractions, but this rhizotomy also impairs desirable reflexes (e.g., sexual function) and sacral sensation, if present. Preclinical experiments have shown that sacral nerve stimulation at 600 Hz can promote bladder emptying while reducing urethral sphincter activity. In this proof-of-concept study, we tested 600-Hz sacral nerve stimulation to limit urethral sphincter activity in individuals with spinal cord injury who were already implanted with a sacral anterior root stimulation device. Bladder pressure, urethral pressure, rectal pressure, anal pressure, and pelvic floor electromyogram were measured in response to stimulation at 20 or 600 Hz. Stimulation was feasible and well-tolerated, and frequency appeared to have an effect on lower urinary tract and bowel function. In one participant, stimulation at 600 Hz produced a significant decrease in urethral pressure compared to 20-Hz stimulation. Further work is needed to explore the potential for this approach to improve bladder emptying efficiency for individuals with spinal cord injury and detrusor-sphincter dyssynergia.

Abstract Background: Latin American (LA) women are more likely to be diagnosed with aggressive early-stage breast cancer (EBC) compared to Non-Hispanic White (NHW) women, yet population-specific tumor biology remains underexplored. Previously, we reported elevated immune gene expression in BluePrint® (BP) Luminal B tumors in LA patients (pts) with EBC and obesity compared to Black and NHW cohorts. Here, we present updated clinical comparisons between LA, NHW and Black pts with EBC and whole transcriptome analysis (WTA) between BP Luminal B and Basal BC in pts with obesity. Methods: Clinical and WT data were analyzed from 15,577 EBC pts self-identified as LA, Black, or NHW enrolled in FLEX (NCT03053193), a prospective observational study with MammaPrint® risk of recurrence and BP molecular subtyping assays, and WT profiles. ImPrint, 53-gene immune signature, results (+/-) were generated for pts with hormone receptor positive (HR+) EBC. Chi-square and t-tests were conducted on clinical groups using arsenal R package. For WT comparisons, 215 obese LA pts with BP Luminal B and 77 with BP Basal EBC were matched to corresponding NHW and Black pts by age, T and N status. Differentially expressed genes (DEGs) were evaluated using limma, and pathway enrichment was performed using gene set enrichment analysis with Hallmark gene sets. Significant results were reported with adjusted p < 0.05. Results: Compared to Black and NHW pts, LA pts were younger and more often premenopausal (Table). Both LA and Black pts had statistically significantly higher rates of obesity compared to NHW pts. Significantly higher rates of MP High Risk 2, BP Basal and ImPrint+ tumors were observed in LA and Black pts vs NHW. WT comparisons among the obese subpopulations revealed that metabolic pathways, including adipogenesis, angiogenesis, epithelial-mesenchymal transition, and oxidative phosphorylation were significantly downregulated in EBC in LA pts vs NHW and Black cohorts. Conversely, immune-related pathways such as allograft rejection and interferon gamma response were enriched among LA pts with Basal cancers compared to NHW and Black groups. These coordinated pathway alterations suggest unique metabolic and immune profiles in LA EBC subtypes with a median absolute fold change of 1.3 among DEGs. Conclusion: The data suggest that signals from metabolic pathway alterations from modest immune-related gene upregulation may contribute to more aggressive tumor behavior in obese LA pts with EBC. Clinical and transcriptomic analyses demonstrated differences in Luminal B and Basal EBC biology among self-identified LA pts compared to NHW and Black cohorts, consistent with prior research. With further research, these findings may offer treatment targets which may enhance outcomes and reflect the importance of including racially and ethnically diverse pts in clinical trials to characterize population-specific differences in EBC outcomes. Citation Format: M. Mazo Canola, A. Santillan, J. Alberty-Oller, E. Dias, V. Kaklamani, A. Elkhanany, K. Hoskins, M. Habibi, R. Hampton, J. L. Barone, N. M. Johnson, N. Gordon, N. Sookhan, T. Bah, P. John, E. Aponte, S. Diab, V. Klimberg, N. Stivers, C. Page, S. Uygun, W. Audeh, J. O'Shaughnessy. Distinct Immune and Metabolic profiles in Latin American breast cancer patients with obesity enrolled in FLEX [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-09-09.

Abstract Background: Treatment approaches for early-stage breast cancer (EBC) have advanced significantly in recent decades, with the addition of HER2-targeted therapies, immunotherapy, and personalized chemotherapy. However, despite these advances, many questions related to treatment cannot be practically or ethically addressed in prospective, randomized clinical trials. The required extended follow-up in EBC treatment trials may delay the dissemination of practice-changing results. Additionally, many EBC trials have poor representation of less common tumor subtypes (such as invasive lobular carcinoma, ILC) and limited enrollment of patients of diverse racial/ethnic backgrounds. In this context, observational registry Real-World Data clinical trials, such as FLEX, which analyze clinical and pathologic data, treatment history, outcomes, and other metadata such as whole transcriptomics can provide actionable evidence that can inform clinical practice. The ongoing, multi-center, FLEX study (NCT03053193) seeks to enroll 30,000 EBC patients to create a large-scale, diverse, population-based registry of whole transcriptome data matched with clinical data with 10 years of follow-up to investigate new gene expression signatures of prognostic and/or predictive value in a real-world setting. Efforts are focused on enriching enrollment of diverse racial/ethnic minorities, historically underrepresented groups, and uncommon EBC tumor histologies. An additional objective is supporting investigator-initiated sub-studies to address clinically relevant questions in EBC with up to 10 years of follow-up. Methods: FLEX is a large prospective, observational trial that enrolls patients (male or female) who are ≥ 18 years old with stage I-III breast cancer. Patients who receive standard of care MammaPrint® (70-gene signature risk of recurrence), with or without BluePrint® (80-gene signature molecular subtype) on their primary breast tumor and consent to clinically annotated whole transcriptome data collection are eligible for enrollment. Within 7 years of trial initiation, FLEX has enrolled over 20,000 patients across 102 sites in the US, 3 sites in Canada, and 1 site each in Greece and Israel. Of the total FLEX population, 9495 (47%) have reached 3 years of follow-up, and 4047 (20%) have reached 5 years of follow-up. To address racial/ethnic disparities in clinical trials, a concerted effort has led to the inclusion of 1892 Black/African American, 1722 Latin American/Hispanic, and 490 Asian American/Pacific Islander EBC patients of self-reported racial/genetic ancestry, making FLEX a highly diverse study of EBC patients. Similarly, FLEX represents one of the largest cohorts of ILCs, composed of 2196 ILC and 649 mixed ILC/ductal histology tumors. Studies from FLEX have led to 3 peer-reviewed publications, with 3 submitted in 2025 currently under review. Fourteen FLEX investigator-initiated sub-study abstracts have been presented in 2025. Additionally, over 53 FLEX abstracts have been accepted at congresses internationally (2018-2025), including 11 presentations focused on therapy selection, 12 on differences in tumor biology and clinical outcomes by race/ethnicity, and 2 on ILC, among others. Data generated from FLEX include important new findings in EBC management. Among these findings are the prediction of absolute chemotherapy benefit in genomically high-risk patients, prediction of survival benefit from adjuvant anthracyclines, associations of genomic signatures that predict resistance to CDK4/6 inhibition, and overrepresentation of aggressive ER+ basal-type tumors in Black/African American patients. Citation Format: L. P. Gold, L. Samiian, K. Hoskins, S. Diab, L. Lee, V. K. Gadi, E. A. Brown, J. R. Ramadurai, J. A. Elayoubi, R. E. Kaczynski, R. E. Fine, T. Bah, L. Matt-Amaral, B. J. Lieblong, W. Audeh, J. O'Shaughnessy. Flex: from genomic profiling to real-world insights in 30,000 patients with early-stage breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-19.

This cohort study examines the association between cataract surgery and progression of age-related macular degeneration in adults 60 years or older.