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Abstract Background Stigma associated with tuberculosis (TB) and TB diagnosis is a major social factor in delay of diagnosis and non-adherence to TB treatment among Asian American and Pacific Islander (AAPI) populations. Main sources of stigma include misconceptions regarding TB transmission and lack of knowledge about symptoms or treatment.Figure 1.Respondent demographicsBreakdown of respondent demographics by age, gender, and AAPI subgroup.Figure 2.Demographic breakdown of TB awarenessTB awareness by AAPI subgroup, age, and gender. Methods A cross-sectional survey of 666 AAPI individuals analyzed TB symptom recognition, transmission misconceptions, and awareness in two AAPI community centers. Data were segmented by AAPI subgroup, metropolitan area (Seattle/Tacoma vs. Las Vegas), age, and gender.Figure 3.TB transmission beliefs.Figure 4.TB treatment, curability, and latent TB infection awareness. Results Overall, 76.6% of respondents reported TB awareness, varying by AAPI subgroup. Awareness was highest among Korean (95%) and Filipino (91%) participants, and lowest among Vietnamese (52%) and Cambodian (50%) respondents. Regionally, TB awareness was similar between Tacoma (76%) and Las Vegas (79%). Age and gender significantly impacted awareness. Respondents under 18 had the lowest TB awareness (59%), while those aged 18-34 had the highest (84%). Females reported higher TB awareness (79%) and symptom recognition (61%) than males (74% and 46%, respectively). Symptom knowledge varied. 55% were aware of TB symptoms, but only 16% were able to recognize five common TB symptoms. Misconceptions about transmission also persisted broadly. Out of the 71% of respondents who were aware that TB is transmissible, many incorrectly believed TB spread via shaking hands (35%), sharing food/drinks (50%), or touching items in public areas (37%). The 45-64 and 65+ age groups were most prone to misconceptions about transmission. While 72% of respondents were aware that TB could be treated, only 57% knew TB could be cured. 30% of respondents were aware of latent TB infection. Conclusion Significant disparities in TB awareness exist in AAPI communities. Females demonstrated greater TB awareness perhaps due to cultural differences (“caretaker role”), while TB transmission misconceptions were prevalent among older individuals. Limited knowledge on LTBI and TB treatment represent significant barriers to effective TB control. Tailored educational efforts will be required to improve TB awareness and reduce misconceptions within AAPI communities. Disclosures All Authors: No reported disclosures

Significance: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by reactivating antitumor immunity and improving outcomes across multiple malignancies. Yet, clinical observations and preclinical studies suggest that ICIs may increase long-term cardiovascular disease risk, including hypertension, atherosclerosis, and thrombosis. The underlying mechanisms remain incompletely defined, highlighting the need for focused investigation into the vascular consequences of immune activation. Recent Advances: ICI-induced immune activation disrupts vascular and immune homeostasis through persistent production of reactive oxygen species (ROS), mitochondrial dysfunction, and accumulation of cell-free DNA (cfDNA). Sustained T-cell activation enhances ROS generation, driving DNA damage and senescence in both endothelial and immune cells. ICIs may also promote endothelial-to-mesenchymal transition (EndoMT) through chronic oxidative and inflammatory signaling, contributing to fibrosis, vascular stiffness, and chronic inflammation. Transforming growth factor-beta, although immunosuppressive in many contexts, can drive profibrotic and EndoMT programs within the vasculature. Other cytokines and regulators, including interleukin-17 and regulator of calcineurin 1, have been implicated in vascular remodeling, atherosclerosis, and hypertension. Critical Issues: The relative roles of ROS, mitochondrial dysfunction, cfDNA-driven inflammation, and EndoMT in ICI-associated vascular senescence remain unclear. While inflammation-induced vascular damage is well-recognized, direct ICI-specific mechanisms require stronger evidence. How senescent endothelial and immune cells influence therapy resistance and remodeling of the tumor microenvironment also remains to be defined. Future Directions: Mitochondrial and cytosolic ROS sources—arising from electron leakage during oxidative phosphorylation and NADPH oxidases activity—shape immune signaling and sustain T-cell activation during checkpoint blockade. The DNA damage response kinases ataxia-telangiectasia mutated and ATM- and Rad3-related, activated by oxidative and replicative stress, engage p53-dependent senescence pathways in endothelial and immune cells. Future studies should evaluate biomarkers such as cfDNA and thrombospondin-1 and explore senescence-targeting or redox-modulating interventions that may alleviate cardiovascular toxicity without diminishing antitumor efficacy. This review outlines mechanistic pathways linking ICIs to vascular dysfunction and senescence, integrating preclinical data with emerging clinical insights. It distinguishes established processes from ICI-specific hypotheses and identifies key gaps requiring clinical validation. Antioxid. Redox Signal. 00, 000–000.

Abstract Background Isolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF). Method We included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests. Result Compared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance ( T = 2.0, p < 0.05, Figure 2). Conclusion Our study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

Abstract Hereditary hemorrhagic telangiectasia (HHT) causes severe recurrent epistaxis, chronic gastrointestinal bleeding, solid organ arteriovenous malformations, and significant anemia. Although it is the second most common inherited bleeding disorder worldwide, no approved therapies exist. The multicenter, US randomized, controlled PATH-HHT trial demonstrated efficacy of short-term pomalidomide treatment of epistaxis in HHT. However, questions regarding long-term safety, effectiveness, and utility for HHT-associated gastrointestinal bleeding remain. The PATH-HHT ATLAS (after trial longitudinal assessment study) was a multicenter US longitudinal observational study evaluating patients enrolled in PATH-HHT who continued pomalidomide after PATH-HHT through a poststudy drug access program, with ongoing close monitoring per PATH-HHT protocol and as mandated by the US Food and Drug Administration. Sixty-two patients treated with pomalidomide for HHT for up to 4.4 years were included. Significant, durable improvements in mean epistaxis severity score (5.55 points [baseline] to 2.80 points [month 12]; P&lt; .0001) and mean hematologic support score (9.11 red cell unit equivalents [RUEs] during 6 months pretreatment to 5.73 RUEs [months 7-12]; P = .0056) were observed. Pomalidomide was less effective for gastrointestinal bleeding than for epistaxis, particularly in patients with high red blood cell transfusion requirements. Thirty-one patients (50%) underwent dose reduction from 4 mg daily, primarily due to neutropenia, but most maintained effectiveness at 2 or 3 mg daily. Over 105.2 patient-years of pomalidomide treatment, 0 patients developed peripheral neuropathy, 1 developed venous thromboembolism, and 5 developed serious infections. In conclusion, pomalidomide was effective for HHT-associated epistaxis over extended durations, albeit with nontrivial potential toxicities, and may be considered for certain patients with HHT. This trial was registered at www.clinicaltrials.gov as NCT07018401.

BACKGROUND AND OBJECTIVES: Minimum clinically important differences (MCIDs) for patient-reported outcome metrics (PROMs) in patients with cervical spondylotic myelopathy (CSM) lack consensus on the most appropriate calculation method. This retrospective study aimed to identify the optimal MCIDs for commonly used PROMs in CSM. METHODS: The CSM database from the Quality Outcomes Database SpineCORe Study Group was analyzed. Baseline, 3-month, and 24-month PROM values for Neck Disability Index (NDI), 5-dimension Euro-quality of life (EQ-5D) in quality-adjusted life years, modified Japanese Orthopaedic Association (mJOA) score, and neck/arm pain numeric rating scale (NRS) were collected. MCIDs were calculated for each PROM using previously validated techniques. MCID values were compared using the area under the curve (AUC) with the North American Spine Society satisfaction scale as an anchor. RESULTS: A total of 1141 patients with CSM undergoing surgery were included in this analysis. Improvement of ≥30% from baseline was the optimal MCID for NDI and neck/arm NRS. At 24 months, the optimal percentage cutoff MCID for these instruments resulted in AUCs of 0.76, 0.72, and 0.67, similar to the 30% improvement method, with AUCs of 0.73, 0.71, and 0.67, respectively. Numeric cutoffs (0.065 at 3 months; 0.149 at 24 months) were the superior MCIDs for EQ-5D. For mJOA score, a severity-adjusted MCID outperformed other methods, yielding an AUC of 0.67 at 24 months. MCIDs were achieved in 63% of patients for NDI, 59% for neck pain NRS, 61% for arm pain NRS, 52% for EQ-5D, and 59% for mJOA score at 24 months. CONCLUSION: Using the Quality Outcomes Database SpineCORe data set, we defined optimal MCIDs for key PROMs in CSM. A ≥30% improvement from baseline was optimal in NDI and arm/neck NRS. An absolute numeric cutoff was superior for EQ-5D (0.149 at the 24-month follow-up). A severity-adjusted MCID performed best for mJOA score. These redefined benchmarks better capture the treatment impact and guide care decisions for patients with CSM.

Abstract Background Decreased kidney function, indicated by a lower estimated glomerular filtration rate (eGFR), may affect interpretation of Alzheimer's disease (AD) blood biomarkers, including phosphorylated tau ( p ‐tau) and amyloid‐beta (Aβ) peptides, due to altered clearance. However, there is limited data available to determine the influence of eGFR on these biomarkers and whether it differs by biomarker or assay type, especially in racially diverse studies of community‐based older adults. Methods We used data from 557 participants in the Mayo Clinic Study of Aging (Rochester, MN n = 182; age 79±8 years; 36.3% Female, White participants) and the UMMC MIND Center‐Mayo Clinic Study of Aging (Jackson, MS n = 375; age 69±8 years; 73% Female 27% Black participants). eGFR was determined using the 2021 CKD‐EPI Creatinine equation. Plasma biomarkers were measured using the Lumipulse immunoassays for p ‐tau217, Aβ42, and Aβ40 (Fujirebio Diagnostics; n = 420); or the mass spectrometry‐based PrecivityAD2 assay (C2N Diagnostics; n = 253) for p ‐tau217, np‐tau217, Aβ42, and Aβ40. Common ratio values were calculated. Aβ42/40 measures were inverted so higher values are worse for all biomarkers. Log base‐2 transformed regression analysis related eGFR to each single analyte and ratio; coefficients (95% CI) reflect estimated doubling in biomarker per doubling in eGFR. Group specific [MN White ( n = 182), MS White ( n = 224), MS Black ( n = 151) participants] estimates are reported, as the distribution of social determinants of health can vary across populations and locations. Results Lower eGFR was associated with higher (worse) AD‐plasma biomarkers, and group stratified estimates were mostly consistent (Figure 1). Ratios of biomarkers diminished but did not entirely alleviate associations with eGFR. For example, MN White participants’ C2N p ‐tau217 association of ‐1.47 (‐1.94, ‐1.00), was attenuated to ‐0.67 (‐1.11, ‐0.22), when using p ‐tau217/np‐tau217. Conclusions Kidney function may be associated with AD‐plasma biomarker values, even with common ratio corrections. There was not strong evidence for highly differential associations of eGFR by race/site categories, though sample sizes are currently limited. The implications for diagnosis and risk classification need to be explored further to support health equity. Optimal consideration of comorbidities on blood biomarker concentrations must continue to be informed by investigation in large, racially and ethnically diverse, community‐based studies.

Abstract Background Plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration provide a non‐invasive method to assess brain pathology associated with dementia and cognitive decline. However, it remains unclear whether these biomarkers are differentially associated with changes in specific cognitive domains or how they relate to subsequent cognitive change in participants with or without cognitive impairment. Methods Plasma biomarkers were assayed in a subset of ARIC participants using Quanterix SiMoA technology on stored specimens collected in midlife (visit 3: 1993‐95, mean age: 59) and late‐life (visit 5: 2011‐13, mean age: 77). Biomarkers included amyloid‐β 42 to amyloid‐β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Factor scores for global cognition and cognitive domains (memory, language, executive function) were calculated from ten neuropsychological tests administered at visits 5 (2011‐13), 6 (2016‐17), 7 (2018‐19), 8 (2020), and 9 (2021‐22). Linear mixed effects models with multiple imputation of pre‐death cognitive change estimated the association between biomarkers in midlife and late‐life, and biomarker change from midlife to late‐life, with 5‐year change in late‐life global and domain‐specific cognition, adjusting for demographics, lifestyle and cardiovascular risk factors, and APOE‐ε4 status. Exploratory analyses examined effect modification of the biomarker‐global cognition associations by visit 5 adjudicated cognitive impairment. Results Among 1515 participants with plasma biomarkers (60.7% female, 25.5% identified as Black), 39% had late‐life cognitive impairment (Table 1). Higher midlife NfL and GFAP were associated with faster 5‐year declines in global cognition and language during late‐life (Table 2). Only midlife NfL was associated with faster late‐life memory decline. No midlife biomarkers were associated with executive function. In late‐life, lower Aβ42:Aβ40 and higher p ‐Tau 181, NfL, and GFAP were associated with faster declines in global cognition, memory, and language. Midlife to late‐life changes in p ‐Tau 181, NfL, and GFAP were associated with declines in global cognition and language. No consistent effect modification by cognitive impairment was observed (Figure 1). Conclusions Plasma biomarkers of AD pathology, neuronal injury, and astrogliosis, measured at different life epochs (midlife vs. late‐life) show distinct association patterns with subsequent changes in cognitive function across domains.

Abstract Background Plasma biomarkers show promise as a noninvasive method for measuring Alzheimer's disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late‐life brain morphology in community‐dwelling populations requires further investigation. Method Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received an adjudicated cognitive diagnosis and underwent 3 Tesla magnetic resonance imaging scans. Whole‐brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993‐95, mean age 59.0 years) and late‐life (2011‐13, mean age 76.8 years) from a subsample of 1,515 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid‐β (Aβ)42/40, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of plasma biomarkers from midlife, late‐life, and the change from midlife to late‐life with cortical thickness in late‐life. Interactions and effect modification by age were examined in exploratory analyses. Result The sample (Table 1) included 920 (60.7%) women, 387 (25.5%) Black participants, 513 (33.9%) participants with mild cognitive impairment, and 85 (5.6%) participants with dementia. The average age in late‐life was 76.8 (5.3 SD) years and the average cortical thickness was 2.27 (0.11 SD) millimeters. Cortical thickness was lower in individuals with adjudicated mild cognitive impairment or dementia compared to individuals without cognitive impairment (2.25 mm versus 2.29 mm, p <0.0001). In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p ‐Tau181 and increases from midlife to late‐life in NfL and GFAP were associated with lower cortical thickness in late‐life (Table 2). Concurrent measures of plasma biomarkers in late‐life were associated with lower cortical thickness (Table 2) and exhibited a stronger association among participants ≥75 years compared to <75 years (Table 3). Conclusion Plasma biomarkers of Alzheimer's disease pathology and neurodegeneration obtained in midlife and late‐life were associated with late‐life differences in cortical thickness. Additional longitudinal research is needed to determine whether plasma biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.

Abstract Background There is growing interest in artificial intelligence (AI) models for predicting future breast cancer. We performed a systematic review of studies of mammography-based AI models for future breast cancer risk prediction to summarize current evidence, identify knowledge gaps, and inform future research directions. Methods We searched 6 databases for studies from January 1, 2012, to February 28, 2025, that evaluated mammography-based AI models for future breast cancer risk prediction. We extracted study design, participants’ race and ethnicity, geographic origin, mammogram type, vendor, prediction time frame, breast cancer type predicted, external validation, and exclusion of cancers diagnosed on the index screening mammogram. Areas under the receiver operating curve (AUCs) were summarized overall and by study characteristics. Results A total of 41 studies met our inclusion criteria. All studies were retrospective, and most used 2D mammograms (n = 37 studies) acquired using Hologic equipment (n = 25) and performed in the United States (n = 17); White, non-Hispanic women were most represented. Nearly all (n = 40) studies assessed discrimination performance with a median AUC of 0.71 for no longer than 2-year risk prediction, 0.72 for 3-4 years, and 0.71 for 5 years or more prediction. Median AUC was 0.75 for studies including index cancers vs 0.68 when excluded. Six studies reported model calibration performance ranging from good to overestimation of risk. Conclusion Future studies should evaluate models using digital breast tomosynthesis, examine performance for aggressive or advanced breast cancer, include diverse populations, and evaluate both discrimination and model calibration. Prospective evaluations are needed to determine the clinical utility of mammography-based AI models for personalized risk-based breast cancer screening before implementation.

Background: Neck lacerations sustained while playing ice hockey are rare but potentially fatal. Neck laceration protectors (NLPs) have been around for decades but only lately are becoming required by leagues given recent fatalities. Purpose: To outline the relevant neck anatomy at risk, describe rink-side evaluation and management techniques, review historical and contemporary NLP mandates, and conclude with evidence-based recommendations. Study Design: Narrative review; Level of evidence, 5. Methods: A review of the literature regarding neck lacerations in ice hockey was utilized for content collection. Google Scholar and PubMed were queried for peer-reviewed articles relevant to the topic. Keywords including “ice hockey,” “neck lacerations,” “neck laceration protector,” and combinations thereof were used to identify relevant literature. Results: Neck lacerations are rare but can be fatal given that they often damage zone II neurovascular structures. While numerous international leagues require mandates for NLPs, notable holdouts include the National Hockey League and the National Collegiate Athletic Association. Numerous materials and builds for NLPs are capable of withstanding penetration from a skate slash, although they possess differences in comfort and neck range of motion. Conclusion: NLPs have the capacity to prevent significant and potentially fatal laceration injuries in ice hockey. Based on the available data, implementing NLP mandates appears to be in the interest of player safety.