Citations

Abstract Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation’s effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.

ABSTRACT Background Treating Mycobacterium avium complex (MAC) infection pre‐lung transplant (LT) can be challenging to treat, given prolonged therapy and side effects. The impact of pre‐transplant MAC treatment on recurrence and outcomes post‐LT remains unclear, especially in patients with interstitial lung disease (ILD) who have a median survival of less than 2 years. Methods We performed a retrospective cohort study of adult LT patients at the Mayo Clinic who had positive MAC sputum cultures pre‐LT. The cohort was stratified and compared based on the type of treatment (complete, partial, or no treatment) for MAC pulmonary infection. The primary outcome was MAC recurrence post‐LT, and secondary outcomes were mortality, FEV‐1, and FVC at 1‐year post‐LT. Results Among the cohort of 47 patients, 9 (19.1%) were partially treated and 11 (23.4%) were completely treated for MAC infection pre‐LT. Post‐transplant MAC pulmonary infection recurrence occurred in eight (17%) of the total cohort, with four (14.8%) in the non‐treated, four (44.4%) in the partially‐treated, and none (0%) in the completely treated patients ( p = 0.026). There was no difference in mortality in patients who had MAC recurrence post‐transplantation (13% vs. 9.7%, p > 0.9) and those who were completely or partially treated, compared to non‐treated (0% vs. 13% vs. 13%, p > 0.9). The FEV1 and FVC at 1‐year post‐LT did not differ by the pre‐transplant treatment or post‐transplant MAC recurrence status. Conclusion The role of treatment for MAC infection pre‐transplant is questionable, especially in patients with diseases like ILD who may not have enough wait time to complete therapy.

Introduction/Background: CHIP is a risk factor for cardiovascular (CV) disease, cancer, and all-cause mortality. Previous work has shown that CHIP, and particularly larger CHIP clones, are associated with adverse CV outcomes, yet the molecular pathways through which CHIP impacts CV risk are poorly defined. Hypothesis/Research Question: We hypothesize that the integration of whole blood transcriptomics and methylomics will provide novel insights into the pathophysiology of CHIP. Methods/Approach: Whole blood DNA methylation profiling, transcriptomics, and whole exome sequencing with CHIP calling for variant allele frequencies (VAF) of ≥2% (CHIP) and ≥10% (large CHIP) were performed for 507 ISCHEMIA and ISCHEMIA-CKD participants with moderate-severe ischemia. We identified transcriptomic and methylomic differences between participants with CHIP and large CHIP vs no CHIP using DESeq2 and limma, adjusted for age, sex, and race/ethnicity. Gene set enrichment analysis (GSEA) and probe set enrichment analysis (PSEA) were performed to identify pathway-level alterations in transcription and methylation, respectively. Results/Data: Clinical characteristics of study participants are described in Fig 1A . Compared to no CHIP (n=391), transcriptomics identified 6 differentially expressed genes (DEGs) in CHIP (n=116) and 27 DEGs in large CHIP (n=35) (p-adj<0.05; abs(logFC)>0.25) (Fig 1B) . Compared to no CHIP, methylation identified no differentially methylated probes in CHIP and 6 in large CHIP (padj<0.20, abs(logFC)>0.03). GSEA identified 137 pathways significantly different in both CHIP and large CHIP vs. no CHIP (padj<0.05), while PSEA identified 724 and 2356 pathways (padj<0.20), respectively. Given its stronger relationship with methylation and transcription, downstream analyses focused on large CHIP. Integrating these data, we found 58 pathways to be both hypomethylated and transcriptionally upregulated in large CHIP, including azurophil granule-related pathways implicated in neutrophil degranulation (Fig 1C) . Further investigation into the gene-probe pairs driving the azurophil granule pathway enrichment in large CHIP revealed hypomethylation and increased transcription of genes implicated in neutrophil extracellular trap formation, including ELANE, PTRN3, AZU1, and CTSG (Fig 1D) . Conclusions: Integration of the methylome and transcriptome suggests large CHIP is linked to neutrophil-mediated immune pathways in patients with stable coronary artery disease.

Introduction: Higher mtDNA-CN reflects better mitochondrial function, while lower levels indicate mtDNA release and increased inflammation. Although mtDNA-CN serves as a marker of cardiovascular health, the importance and mechanism of risk associated with mtDNA in high-risk individuals with chronic coronary artery disease (CAD) remains poorly understood. To address this gap, we leveraged the ISCHEMIA Biorepository to: (1) evaluate the association between mtDNA-CN and all-cause death (ACD); and (2) define a transcriptomic profile associated with high mtDNA-CN and ACD risk for high-risk patients with CAD. Hypothesis: Higher mtDNA-CN is associated with reduced ACD risk and inflammation in high-risk patients enrolled in the ISCHEMIA Biorepository. Methods: Low pass whole genome sequencing and whole blood RNA-Seq were performed on 594 ISCHEMIA and ISCHEMIA-CKD participants with moderate-severe ischemia. Data were processed using the NYU deciphEHR pipeline and mtDNA was quantified using mitoAnalyzer. mtDNA-CN was median split, with samples having values ≤ median classified as the 'low' group and those > median as the 'high' group. Unadjusted group differences were assessed using Chi-squared tests. Survival analysis was performed using Cox proportional hazard models, adjusted for age, sex, diabetes, eGFR, dialysis status, ischemia severity, and left ventricular ejection fraction. Adjusted differential gene expression (DGE) and gene set enrichment analysis (GSEA) were performed to explore molecular mechanisms underlying mtDNA-CN. Results: Median age was 67 (IQR: 57–78); 19% were female, 84% white, and 6% Hispanic. Hypertension (84%), diabetes (43%), and obesity (45%) were common; 26% had eGFR <60 mL/min/1.73 m 2 . Median mtDNA-CN was 153 counts per sample. After multivariate adjustment , mtDNA-CN > median was associated with a 48% reduction in ACD (aHR = 0.52, 95% CI: 0.30–0.90; P = 0.020) (Figure 1A) . DGE revealed downregulation of inflammatory genes in the mtDNA-CN group, including S100A9 (FC=-.41, p=3.32e-10) and S100A12 (FC=-.56, p=3.32e-10). Inflammatory pathways such as the inflammasome complex (NES=-2.17, p=9.32e-03) and interleukin-1 production (NES= -2.02, p=6.60e-03) were downregulated among participants in the high mtDNA-CN ( Figure 1B) . Conclusion: Higher mtDNA-CN is associated with lower risk of ACD and reduced inflammasome activity, suggesting that enhanced mitochondrial health may mitigate inflammasome-related pathology linked to ACD in patients with CAD.

ABSTRACT As artificial intelligence (AI) continues to rapidly reshape health care, there is a critical need for clear frameworks for clinicians to ensure ethical, equitable, and effective integration and use of AI in patient care. Key integrations of AI include enhancing health communications, patient engagement, clinicians' training, pharmaceutical advertising, clinical decision‐making, and automation of clinical operations and workflow. However, there are growing concerns related to regulatory gaps, the spread of misinformation, security threats, patient and data privacy leaks, and widening health disparities gaps. These concerns are exacerbated by limited institutional infrastructure and limited AI literacy of clinicians and patients. Recent policy developments reflect efforts to guide responsible AI development and use. While progress has been made, the lack of standardized human oversight remains a critical gap, particularly as policies may not fully consider the challenges and complexities at institutional, societal, technical, and individual levels. Thus, herein, the Drug Information Practice and Research Network (DI PRN) of the American College of Clinical Pharmacy (ACCP) : (1) explores current and emerging multifaceted challenges, a call to action, and opportunities of AI integration in health care including examination of the regulatory, ethical, operational, and health equity implications; and (2) provides practical recommendations for responsible use of AI through DI PRN‐developed example case‐based approaches and best practices infographics to enhance AI literacy for diverse learners including clinicians, trainees, and patients. This DI PRN opinion paper highlights the importance of proactive governance frameworks and equips and empowers diverse learners with practical AI literacy tools to confidently engage with AI technologies in patient care.

ABSTRACT Background The impact of psychosocial health and socioeconomic status (SES) on long‐term lung transplant survival remains unclear. Methods We conducted a single‐center, retrospective 2:1 matched case‐control study of adult lung transplant recipients (1999–2019). Cases survived ≥6 years post‐transplant; controls survived <6 years. Matching was based on transplant year (±5 years) and indication. Psychosocial health and SES were assessed using the Psychosocial Assessment of Candidates for Transplant (PACT) score, Mayo Clinic Housing‐Based Socioeconomic Status (HOUSES) index, and Area Deprivation Index (ADI). Secondary covariates included insurance, marital status, employment, caregiver relationship, and proximity to the transplant center. Conditional logistic regression adjusted for age and gender was used. Results Among 189 patients (63 cases, 126 controls), PACT score, HOUSES index, and ADI were not significantly associated with long‐term survival. Patients with non‐family caregivers had lower odds of survival compared to those with a spouse or partner (OR = 0.16, p = 0.022). Regional residents had lower odds of long‐term survival compared to local recipients (OR = 0.55, p = 0.001). Conclusions Pre‐transplant psychosocial and SES measures were not significantly associated with long‐term survival. Caregiver relationships and geographic proximity may have a greater impact on outcomes, highlighting the importance of support systems and access to care.

BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

Abstract The sections in this article are: Vascular Anatomy and Fluid Phase Conduit Vessels to Bone Capillaries of Bone Fluid Transport Physiological Implications Bone Tissue Turnover Bone Remodeling Cells of Bone Mineral Phase Bone Repair Transport of Ions and Molecules in Bone Movement Into Bone From Bulk Extracellular Fluid (Influx) Efflux Methodology Indicator‐Dilution Methods Steady‐State Techniques (Volume of Distribution) Blood Flow Summary and Conclusions

Abstract Disclosure: E.M. Lewiecki: Amgen Inc, Kyowa Kirin, Ultragenyx, Angitia, Radius Health, Inc, Ascendis. E. Kapoor: Fresenius Kabi USA Inc., Astellas Pharma, Estetra SRL, WellFound Inc., Exeltis. S. Hurtado: None. V.M. Navarro: Bayer, Inc. M. Torres: Bayer, Inc. J. Beau: Bayer, Inc. I. Gkioni: Syneos Health LLC (providing service to Bayer), AstraZeneca. K. Genga: Bayer, Inc.. Background: The neuropeptide substance-P and its receptor neurokinin-1 (SP-NK1R pathway) play a role in bone metabolism and remodelling. Pre-clinical evidence also points to a role of this pathway in energy homeostasis. NK-1R antagonists have been proposed as potential therapies in obesity and musculoskeletal disorders like osteoporosis. Elinzanetant (EZN) is a dual neurokinin-1 and -3 receptor antagonist in late-stage development for vasomotor symptoms (hot flashes) associated with menopause. This post hoc analysis evaluates potential benefits of EZN on the skeleton, body weight, and body composition in postmenopausal women. Methods: Data were gathered from exploratory endpoints of the 52-week (wk), placebo (PL)-controlled, OASIS-3 Phase 3 EZN efficacy and safety trial. Mean percentage (%) change in total bone mass (kg) (measured indirectly by bioelectrical impedance analysis at baseline (BL), wks 4, 8, 12, 18, 24, 36, 52); mean % change in bone mineral density (BMD, measured directly by dual-energy X-ray absorptiometry at BL, wks 24 and 52) in femoral neck, total hip, and lumbar spine; and mean % change in key bone turnover markers osteocalcin (OC) and procollagen 1N-terminal propeptide (P1NP) at BL, wks 4, 8, 12, 18, 24, 36, 52 were evaluated. Weight, body mass index (BMI: weight/height2), waist circumference (WC), fat mass index (FMI; fat mass/height2), lean mass index (LMI; lean mass/height2) and body water were measured to monitor body composition at BL and wks 4, 8, 12, 18, 24, 36, 52. A sub-analysis was performed based on FMI at baseline (FMI ≤9 normal fat mass; &gt;9 excess fat mass). Descriptive statistics were used to evaluate all parameters and trends. Results: From BL to wk 52, increasing trends in bone mass were observed with EZN (mean [SD]: 2.81 [1.02] to 2.95 [1.96]) but not PL (mean [SD]: 2.87 [1.09] to 2.87 [1.13]). In parallel, lower BMD reductions were seen in EZN vs PL at all skeletal sites [EZN vs PL, mean % change from BL: femoral neck (0.00% vs -1.22%), total hip (-0.70% vs -1.37%), and lumbar spine (-0.57% vs -1.22%), with considerable variability in both groups (SD range 3.01 - 4.70)]. Lower levels of circulating OC and P1NP were consistently observed over 52 wks of EZN treatment, suggesting a lower rate of bone resorption with EZN vs PL. Trending reductions in weight, BMI, and WC, along with increases in LMI and body water were observed with EZN vs PL. Trends of higher LMI in patients with excess fat, or lower FMI in patients with normal fat at BL were observed with EZN, suggestive of a positive body re-composition with EZN. Conclusions: These data expand on EZN safety profile and further point to novel potential benefits for the skeleton and body composition of postmenopausal women. Further research is warranted to provide conclusive evidence of the benefits of EZN specifically in post-menopausal women with obesity/overweight status or osteoporosis. Sponsorship: Bayer U.S., Whippany, NJ, USA Presentation: Monday, July 14, 2025