Does psychological distress predict risk of orthopaedic surgery and postoperative opioid prescribing in patients with hip pain? A retrospective study.

BACKGROUND: Clinicians and public health professionals have allocated resources to curb opioid over-prescription and address psychological needs among patients with musculoskeletal pain. However, associations between psychological distress, risk of surgery, and opioid prescribing among those with hip pathologies remain unclear. METHODS: Using a retrospective cohort study design, we identified patients that were evaluated for hip pain from January 13, 2020 to October 27, 2021. Patients' surgical histories and postoperative opioid prescriptions were extracted via chart review. Risk of hip surgery within one year of evaluation was analyzed using multivariable logistic regression. Multivariable linear regression was employed to predict average morphine milligram equivalents (MME) per day of opioid prescriptions within the first 30 days after surgery. Candidate predictors included age, gender, race, ethnicity, employment, insurance type, hip function and quality of life on the International Hip Outcome Tool (iHOT-12), and psychological distress phenotype using the OSPRO Yellow Flag (OSPRO-YF) Assessment Tool. RESULTS: Of the 672 patients, n = 350 (52.1%) underwent orthopaedic surgery for hip pain. In multivariable analysis, younger patients, those with TRICARE/other government insurance, and those with a high psychological distress phenotype had higher odds of surgery. After adding iHOT-12 scores, younger patients and lower iHOT-12 scores were associated with higher odds of surgery, while Black/African American patients had lower odds of surgery. In multivariable analysis of average MME, patients with periacetabular osteotomy (PAO) received opioid prescriptions with significantly higher average MME than those with other procedures, and surgery type was the only significant predictor. Post-hoc analysis excluding PAO found higher average MME for patients undergoing hip arthroscopy (compared to arthroplasty or other non-PAO procedures) and significantly lower average MME for patients with public insurance (Medicare/Medicaid) compared to those with private insurance. Among those only undergoing arthroscopy, older age and having public insurance were associated with opioid prescriptions with lower average MME. Neither iHOT-12 scores nor OSPRO-YF phenotype assignment were significant predictors of postoperative mean MME. CONCLUSIONS: Psychological distress characteristics are modifiable targets for rehabilitation programs, but their use as prognostic factors for risk of orthopaedic surgery and opioid prescribing in patients with hip pain appears limited when considered alongside other commonly collected clinical information such as age, insurance, type of surgery pursued, and iHOT-12 scores.

The role of O-GlcNAcylation in RNA polymerase II transcription.

Eukaryotic RNA polymerase II (RNAPII) is responsible for the transcription of the protein-coding genes in the cell. Enormous progress has been made in discovering the protein activities that are required for transcription to occur, but the effects of post-translational modifications (PTMs) on RNAPII transcriptional regulation are much less understood. Most of our understanding relates to the cyclin-dependent kinases (CDKs), which appear to act relatively early in transcription. However, it is becoming apparent that other PTMs play a crucial role in the transcriptional cycle, and it is doubtful that any sort of complete understanding of this regulation is attainable without understanding the spectra of PTMs that occur on the transcriptional machinery. Among these is O-GlcNAcylation. Recent experiments have shown that the O-GlcNAc PTM likely has a prominent role in transcription. This review will cover the role of the O-GlcNAcylation in RNAPII transcription during initiation, pausing, and elongation, which will hopefully be of interest to both O-GlcNAc and RNAPII transcription researchers.

Pain-Associated Psychological Distress Is of High Prevalence in Patients With Hip Pain: Characterizing Psychological Distress and Phenotypes.

Purpose: To identify common pain-related psychological factors among patients seeking care for athletic hip pain, as well as characterize psychological distress phenotypes and compare hip-specific quality-of-life measures across those phenotypes. Methods: A total of 721 patients were recruited from hip preservation clinics. The Optimal Screening for Prediction of Referral and Outcome-Yellow Flag Assessment Tool (OSPRO-YF) was used to identify the presence or absence of 11 different pain-associated psychological distress characteristics (yellow flags), while the International Hip Outcome Tool-12 (iHOT-12) was used to assess hip-related quality of life. Latent class analysis identified patient subgroups (phenotypes) based on naturally occurring combinations of distress characteristics. An analysis of variance was used to compare demographics, number of yellow flags, and iHOT-12 scores across phenotypes. Results: The median (interquartile range) number of yellow flags was 6 (3-9), with 13.5% of the sample reporting 11 yellow flags. Latent class analysis (L2 = 543.3, classification errors = 0.082) resulted in 4 phenotypes: high distress (n = 299, 41.5%), low distress (n = 172, 23.9%), low self-efficacy and acceptance (n = 74, 10.3%), and negative pain coping (n = 276, 24.4%). Significant differences in mean yellow flags existed between all phenotypes except low self-efficacy and negative pain coping. There were no differences in demographics between phenotypes. The high distress class had the lowest mean iHOT-12 score (mean [SD], 23.5 [17.6]), with significant differences found between each phenotypic class. Conclusions: There was a high prevalence of pain-associated psychological distress in patients presenting to tertiary hip arthroscopy clinics with hip pain. Furthermore, hip quality-of-life outcome scores were uniformly lower in patients with higher levels of psychological distress. Level of Evidence: Level III, retrospective cohort study.

Influence of running on femoroacetabular joint bone-to-bone distances.

There is limited data quantifying the influence of running on hip cartilage mechanics. The goal of this investigation was to quantify changes in hip joint bone-to-bone distance in response to a 3-mile treadmill run. We acquired magnetic resonance (MR) images of the dominant hip of eight young, asymptomatic runners (five males, three females) before and immediately after they ran 3 miles at a self-selected pace on a level treadmill. The femoral heads and acetabula were semiautomatically segmented from the pre- and post-exercise MR images to generate three-dimensional models of each participant's hip that were used to compute changes in the bone-to-bone distances incurred by the running exercise. We observed a significant 3% decrease in bone-to-bone distance from 3.47 ± 0.20 to 3.36 ± 0.22 mm between the femoral head and acetabulum after a 3-mile treadmill run (mean ± 95% confidence interval; p = 0.03). These findings provide new baseline data describing how running impacts the hip joint in young, asymptomatic runners.

Self-assembly of promoter DNA and RNA Pol II machinery into transcriptionally active biomolecular condensates.

Transcription in the nucleus occurs in a concentrated, dense environment, and no reasonable biochemical facsimile of this milieu exists. Such a biochemical environment would be important for further understanding transcriptional regulation. We describe here the formation of dense, transcriptionally active bodies in vitro with only nuclear extracts and promoter DNA. These biomolecular condensates (BMCs) are 0.5 to 1 µm in diameter, have a macromolecular density of approximately 100 mg/ml, and are a consequence of a phase transition between promoter DNA and nuclear extract proteins. BMCs are physically associated with transcription as any disruption of one compromised the other. The BMCs contain RNA polymerase II and elongation factors, as well as factors necessary for BMC formation in vivo. We suggest that BMCs are representative of the in vivo nuclear environment and a more physiologically relevant manifestation of the preinitiation complex/elongation machinery.

Decolonization in Nursing Homes to Prevent Infection and Hospitalization.

BACKGROUND: Nursing home residents are at high risk for infection, hospitalization, and colonization with multidrug-resistant organisms. METHODS: We performed a cluster-randomized trial of universal decolonization as compared with routine-care bathing in nursing homes. The trial included an 18-month baseline period and an 18-month intervention period. Decolonization entailed the use of chlorhexidine for all routine bathing and showering and administration of nasal povidone-iodine twice daily for the first 5 days after admission and then twice daily for 5 days every other week. The primary outcome was transfer to a hospital due to infection. The secondary outcome was transfer to a hospital for any reason. An intention-to-treat (as-assigned) difference-in-differences analysis was performed for each outcome with the use of generalized linear mixed models to compare the intervention period with the baseline period across trial groups. RESULTS: Data were obtained from 28 nursing homes with a total of 28,956 residents. Among the transfers to a hospital in the routine-care group, 62.2% (the mean across facilities) were due to infection during the baseline period and 62.6% were due to infection during the intervention period (risk ratio, 1.00; 95% confidence interval [CI], 0.96 to 1.04). The corresponding values in the decolonization group were 62.9% and 52.2% (risk ratio, 0.83; 95% CI, 0.79 to 0.88), for a difference in risk ratio, as compared with routine care, of 16.6% (95% CI, 11.0 to 21.8; P<0.001). Among the discharges from the nursing home in the routine-care group, transfer to a hospital for any reason accounted for 36.6% during the baseline period and for 39.2% during the intervention period (risk ratio, 1.08; 95% CI, 1.04 to 1.12). The corresponding values in the decolonization group were 35.5% and 32.4% (risk ratio, 0.92; 95% CI, 0.88 to 0.96), for a difference in risk ratio, as compared with routine care, of 14.6% (95% CI, 9.7 to 19.2). The number needed to treat was 9.7 to prevent one infection-related hospitalization and 8.9 to prevent one hospitalization for any reason. CONCLUSIONS: In nursing homes, universal decolonization with chlorhexidine and nasal iodophor led to a significantly lower risk of transfer to a hospital due to infection than routine care. (Funded by the Agency for Healthcare Research and Quality; Protect ClinicalTrials.gov number, NCT03118232.).

Longitudinal analysis of serum-derived extracellular vesicle RNA to monitor dacomitinib treatment response in EGFR-amplified recurrent glioblastoma patients.

Background: Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor (EGFR) amplified and ~50% also are EGFRvIII mutant positive. In a previously reported multicenter phase II study, we have described the response of recurrent GBM (rGBM) patients to dacomitinib, an EGFR tyrosine kinase inhibitor (TKI). As a continuation of that report, we leverage the tumor cargo-encapsulating extracellular vesicles (EVs) and explore their genetic composition as carriers of tumor biomarker. Methods: Serum samples were longitudinally collected from EGFR-amplified rGBM patients who clinically benefitted from dacomitinib therapy (responders) and those who did not (nonresponders), as well as from a healthy cohort of individuals. The serum EV transcriptome was evaluated to map the RNA biotype distribution and distinguish GBM disease. Results: Using long RNA sequencing, we show enriched detection of over 10 000 coding RNAs from serum EVs. The EV transcriptome yielded a unique signature that facilitates differentiation of GBM patients from healthy donors. Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration. Conclusion: This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.

Prediction of Resistance to 177Lu-PSMA Therapy by Assessment of Baseline Circulating Tumor DNA Biomarkers.

177Lu-PSMA-617 and 177Lu-PSMA I&T (collectively termed 177Lu-PSMA) are currently being used for the treatment of selected metastatic castration-resistant prostate cancer (mCRPC) patients with PSMA PET-positive disease, but biomarkers for these agents remain incompletely understood. Methods: Pretreatment circulating tumor DNA (ctDNA) samples were collected from 44 mCRPC patients receiving 177Lu-PSMA treatment. Prostate-specific antigen responders and nonresponders were assessed relative to the ctDNA findings at baseline. Results: The ctDNA findings indicated that nonresponders were more likely to have gene amplifications than were responders (75% vs. 39.2%, P = 0.03). In particular, amplifications in FGFR1 (25% vs. 0%, P = 0.01) and CCNE1 (31.2% vs. 0%, P = 0.001) were more likely to be present in nonresponders. CDK12 mutations were more likely to be present in nonresponders (25% vs. 3.6%, P = 0.05). Conclusion: Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for 177Lu-PSMA-treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions.

Extrinsic and intrinsic preanalytical variables affecting liquid biopsy in cancer.

Liquid biopsy, through isolation and analysis of disease-specific analytes, has evolved as a promising tool for safe and minimally invasive diagnosis and monitoring of tumors. It also has tremendous utility as a companion diagnostic allowing detection of biomarkers in a range of cancers (lung, breast, colon, ovarian, brain). However, clinical implementation and validation remains a challenge. Among other stages of development, preanalytical variables are critical in influencing the downstream cellular and molecular analysis of different analytes. Although considerable progress has been made to address these challenges, a comprehensive assessment of the impact on diagnostic parameters and consensus on standardized and optimized protocols is still lacking. Here, we summarize and critically evaluate key variables in the preanalytical stage, including study population selection, choice of biofluid, sample handling and collection, processing, and storage. There is an unmet need to develop and implement comprehensive preanalytical guidelines on the optimal practices and methodologies.

Development and Evaluation of an Enhanced Recovery Protocol to Reduce Length of Stay following Elective Endovascular Aneurysm Repair.

BACKGROUND: Elective endovascular abdominal aortic aneurysm repair (EVAR) can be performed safely with a short postoperative length of stay (LOS). We aimed to develop and assess the impact of an enhanced recovery protocol (ERP) on LOS after elective EVAR. METHODS: Pre-ERP development single center retrospective review of elective EVAR procedures from January 2012 to December 2019. ERP was developed by targeting factors associated with prolonged LOS (>2 days) elucidated from semistructured interviews and Bayesian additive regression tree analysis. Post-ERP development, a subsequent retrospective review of elective EVAR performed from January 2018 to June 2021 was performed to evaluate LOS before and after ERP. Primary outcome was LOS. RESULTS: Two hundred sixteen patients underwent elective infrarenal EVAR from 2012 to 2019. Periprocedural factors identified as associated with LOS >2 days included noncommercial insurance (43.6% vs. 26.5%; P = 0.01), preoperative anemia (hemoglobin 12.56 g/dL vs. 13.57 g/dL; P = 0.001), worse renal function (creatinine 1.31 mg/dL vs. 1.01/dL; P = 0.004), open femoral access (74.4% vs. 26.5%; P < 0.001), intensive care unit (ICU) stay (2.7 days vs. 0.9 days; P < 0.001), postoperative anemia (9.8 g/dL vs. 11.9 g/dL; P < 0.001), postoperative creatinine (1.55 mg/dL vs. 0.97 mg/dL; P < 0.001), and beta blocker need on discharge (45.5% vs. 25%; P = 0.003) as significant between patients with short and prolonged LOS groups. Semistructured interviews revealed postoperative day 1 complete blood count/chemistry, postoperative physical therapy evaluation, ICU admission, urinary retention, patient expectations, and unavailability of transportation home as modifiable factors that delayed early discharge. A 14-component ERP was created to target the factors identified from combined qualitative and quantitative results. Post-ERP development, 74 elective EVAR patients were reviewed from 2018 to 2021 (37 pre-ERP and 37 post-ERP). Following ERP development, the mean LOS was reduced from 2.6 (standard deviation: 1.9) to 1.3 days (standard deviation: 1.3); P < 0.01. There were no significant differences in 30-day readmission, postoperative complications, emergency room visits, or 90-day mortality before and after the ERP was used. CONCLUSIONS: Practice and procedural factors can be modified through an informed and safe process to reduce LOS after elective EVAR. LOS following elective EVAR was safely reduced following the use of a systematically developed ERP.

Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide.

BACKGROUND: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide. METHODS: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort. RESULTS: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035). CONCLUSIONS: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity.

Toxicokinetics of metformin overdose treated with CVVHDF.

A 53-year-old man died following a reported ingestion of 80 g of his metformin tablets resulting in severe, refractory shock and metformin-associated lactic acidosis. His peak serum metformin concentration was 53 µg/mL (therapeutic range 1-2 µg/mL), peak lactic acid concentration was 49.7 mmol/L, and arterial pH nadir was 7.06. He died despite vasopressors and renal replacement therapy [RRT; both intermittent hemodialysis (IHD) and continuous venovenous hemodiafiltration (CVVHDF)]. Serial metformin concentrations during CVVHDF suggested a half-life of 33-h. Similar to previous reports of RRT for metformin toxicity, CVVHDF appears to provide first-order elimination of metformin.

Clinical and molecular determinants of PSA response to bipolar androgen therapy in prostate cancer.

BACKGROUND: Bipolar androgen therapy (BAT) is a novel therapy known to be effective in a subset of men with metastatic castrate resistant prostate cancer (mCRPC). A better understanding of responders and nonresponders to BAT would be useful to clinicians considering BAT therapy for patients. Herein we analyze clinical and genetic factors in responders/nonresponders to better refine our understanding regarding which patients benefit from this innovative therapy. METHODS: mCRPC patients were assessed for response or no response to BAT. Patients with PSA declines of greater than 50% from baseline after 2 or more doses of testosterone were considered to be responders. Whereas, nonresponders had no PSA decline after 2 doses of testosterone and subsequently manifest a PSA increase of >50%. Differences between these two groups of patients were analyzed using clinical and laboratory parameters. All patients underwent genomic testing using circulating tumor DNA (ctDNA) and germline testing pre-BAT. RESULTS: Twenty five patients were nonresponders and 16 were responders. Baseline characteristics between nonresponders and responders varied. Responders were more likely to have had a radical prostatectomy as definitive therapy and were more likely to have been treated with an androgen receptor (AR) antagonist (enzalutamide or apalutamide) immediately before BAT (compared to abiraterone). Duration of prior enzalutamide therapy was longer in responders. Nonresponders were more likely to have bone-only metastases and responders were more likely to have nodal metastases. Assays detected ctDNA AR amplifications more often in responding patients. Responders trended toward having the presence of more TP53 mutations at baseline. CONCLUSIONS: BAT responders are distinct from nonresponders in several ways however each of these distinctions are imperfect. Patterns of metastatic disease, prior therapies, duration of prior therapies, and genomics each contribute to an understanding of patients that will or will not respond. Additional studies are needed to refine the parameters that clinicians can utilize before choosing among the numerous treatment alternatives available for CRPC patients.

A novel image-based method for simultaneous counting of Lactobacillus and Saccharomyces in mixed culture fermentation.

Mixed microorganism cultures are prevalent in the food industry. A variety of microbiological mixtures have been used in these unique fermenting processes to create distinctive flavor profiles and potential health benefits. Mixed cultures are typically not well characterized, which may be due to the lack of simple measurement tools. Image-based cytometry systems have been employed to automatically count bacteria or yeast cells. In this work, we aim to develop a novel image cytometry method to distinguish and enumerate mixed cultures of yeast and bacteria in beer products. Cellometer X2 from Nexcelom was used to count of Lactobacillus plantarum and Saccharomyces cerevisiae in mixed cultures using fluorescent dyes and size exclusion image analysis algorithm. Three experiments were performed for validation. (1) Yeast and bacteria monoculture titration, (2) mixed culture with various ratios, and (3) monitoring a Berliner Weisse mixed culture fermentation. All experiments were validated by comparing to manual counting of yeast and bacteria colony formation. They were highly comparable with ANOVA analysis showing p-value > 0.05. Overall, the novel image cytometry method was able to distinguish and count mixed cultures consistently and accurately, which may provide better characterization of mixed culture brewing applications and produce higher quality products.

Clinical and Genetic Analysis of Metastatic Prostate Cancer to the Central Nervous System: A Single-Institution Retrospective Experience.

BACKGROUND: Prostate cancer (PC) rarely metastasizes to the central nervous system (CNS). In this retrospective single-institution study at a tertiary cancer center, we aimed to evaluate the clinical and genetic characteristics of advanced PC patients with CNS metastases. PATIENTS AND METHODS: Between January 2010 and March 2020, 12 out of 579 patients with extracranial metastatic PC were identified to have CNS metastases based on imaging, including six patients with brain metastases (BMs), five patients with dural metastases, and one unknown. These patients were followed up through March 2022. Clinical data were compared to the overall cohort of patients evaluated at our cancer center during that decade. Genetics information was also analyzed for the patients with available data via cell-free DNA (cfDNA) blood samples. RESULTS: Median time from development of extracranial metastatic disease to development of CNS metastases was 5.5 years (95% CI, 1.8-7.0). Median overall survival (mOS) from diagnosis of CNS metastases was 6.1 months (95% CI, 5.8-8.2). Notably, there was no significant difference in mOS after development of extracranial metastases in patients with CNS metastases (6.4 years; 95% CI, 4.6-7.9) compared to the patients without known CNS metastases (5.2 years; 95% CI, 4.6-5.7) (P = .91). For the cohort with CNS metastases, nine patients had germline testing and seven patients had somatic testing via cfDNA. CONCLUSION: PC patients with CNS metastases did not often die from a neurological cause. With advancing therapies, the overall prognosis of metastatic PC continues to improve, and CNS metastases will become more common.

Black Patients with Metastatic Castrate-Resistant Prostate Cancer Have a Shorter Time Interval Between PSA and Clinical Progression on Novel Hormonal Therapies plus Avelumab.

BACKGROUND: Black men are at higher risk for prostate cancer death. Previous studies showed a benefit of different therapies, including immune-based therapy, for Black men with metastatic prostate cancer. We sought to explore the efficacy of the PD-L1 inhibitor avelumab in Black men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after abiraterone or enzalutamide. METHODS: This pilot phase II study enrolled self-identified Black patients who developed mCRPC on next-generation hormonal therapies (NHTs) abiraterone acetate or enzalutamide (NCT03770455). Enrolled patients received avelumab 10mg/kg IV every 2 weeks while remaining on the same NHTs. The primary endpoint of our study was ≥ 50% reduction in prostate specific antigen (PSA) at ≥8 weeks. RESULTS: A total of eight patients were enrolled. The median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). The median time to initiate avelumab was 8 days (3-14). With a median follow-up of 196 days, no patients achieved the primary endpoint. The median time to PSA progression was 35 days (95 CI%, 0-94.8) and the median time to radiographic and/or clinical progression was 44 days (95 CI%, 0-118.5). The study was closed prematurely due to safety concerns related to the rapid clinical progression observed in the patients enrolled on study. CONCLUSION: In conclusion, the addition of avelumab to NHT did not demonstrate clinical activity in Black men with new mCRPC. The unexpected short interval between PSA and radiographic and/or clinical progression observed in this study has potential clinical implications.ClinicalTrials.gov Identifier: NCT03770455 (IND number 139559).

MYC: a complex problem.

The MYC protooncogene functions as a universal amplifier of transcription through interaction with numerous factors and complexes that regulate almost every cellular process. However, a comprehensive model that explains MYC's actions and the interplay governing the complicated dynamics of components of the transcription and replication machinery is still lacking. Here, we review the potency of MYC as an oncogenic driver and how it regulates the broad spectrum of complexes (effectors and regulators). We propose a 'hand-over model' for differential partitioning and trafficking of unstructured MYC via a loose interaction network between various gene-regulatory complexes and factors. Additionally, the article discusses how unstructured-MYC energetically favors efficient modulation of the energy landscape of the transcription cycle.

"Nothing Is Gonna Change If We Don't Care for Everyone": A Narrative Inquiry Alongside Urban Indigenous Youth in an Afterschool Physical Activity Wellness Program.

In the fall of 2013, the authors received funding to help develop and implement an afterschool wellness program alongside Indigenous youth aged 6-10 years old in the North Central neighborhood of Regina, Saskatchewan, Canada. The Growing Young Movers (GYM) afterschool program was funded, in part, as a corrective response to a broader social trend in which Indigenous youth in this neighborhood reported declining health and wellness outcomes, as well as multiple other barriers to social inclusion. This article discusses the reflections of three senior high school Indigenous youth (16-18 years old) who participated in the afterschool program as peer-mentors over a 2-year period from 2015 to 2017. Our inquiry reveals how these youth viewed the program-and their role(s) within it-in far more complex, active, and even political terms, than the program's initial framing as a physical activity-based "intervention" had anticipated. Our analysis (re)positions youth according to their own personalized voice and narratives as: cultural leaders, knowledge holders, and as agents of change in their community.