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Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Importance Adjuvant radiotherapy can improve locoregional control and survival in patients with olfactory neuroblastoma (ONB), particularly with advanced-stage and histologic-grade disease. Standard radiotherapy treatment is with intensity-modulated radiotherapy (IMRT). Proton beam radiotherapy (PBRT) provides theoretical advantages in greater sparing of dose to uninvolved organs at risk. Objective To investigate if there are differences in the effectiveness and radiation treatment–related adverse events (RTAEs) between adjuvant IMRT and PBRT for patients with ONB. Design, Setting, and Participants This propensity score–matched cohort study included patients with ONB treated between February 2005 and April 2021 with either IMRT or PBRT at 9 academic tertiary care centers in North America. Patients were matched 1:2 based on age, modified Kadish stage, and Hyams grade. Data were analyzed from July 2024 to January 2025. Exposure Adjuvant IMRT or adjuvant PBRT. Main Outcomes and Measures Local recurrence-free survival (RFS), any RFS, and overall survival (OS). RTAEs, ie, grade 2 events or higher based on Common Terminology Criteria for Adverse Events, were recorded for both modalities. Results Of 54 included patients, 27 (50%) were female, and the mean (SD) age was 46.2 (15.4) years. A total of 18 were treated with PBRT and 36 were treated with IMRT. Most patients had modified Kadish stage C disease (33 of 54 [61%]), and 24 patients (44%) had Hyams grade III or IV disease. The RTAE rate was 20% (8 of 40); IMRT had a rate of 21% (6 of 29), and PBRT had a rate of 18% (2 of 11). The difference in the point estimates for 10-year RFS showed a potential clinical benefit favoring IMRT, although the wide confidence interval indicates uncertainty (10-year RFS: IMRT, 63.3%; 95% CI, 44.6-89.8; PBRT, 37.8%; 95% CI, 14.2-100; difference, 25.5 percentage points; 95% CI, −17.6 to 68.6). There were no clinically meaningful differences in 10-year local RFS (IMRT, 75.6%; 95% CI, 59.8-95.4; PBRT, 72.7%; 95% CI, 45.2-100; difference, 2.9 percentage points; 95% CI, −35.9 to 41.7) or 10-year OS (IMRT, 61.8%; 95% CI, 42.8-89.1; PBRT, 57.1%; 95% CI, 24.3-100; difference, 4.7 percentage points; 95% CI, −49.2 to 58.6), although wide confidence intervals indicate considerable uncertainty. Conclusions and Relevance Due to the imprecision of estimates, no definitive conclusions can be made regarding the comparative effectiveness of IMRT vs PBRT for patients with ONB. These preliminary data may inform the design of appropriately powered prospective studies evaluating the efficacy of PBRT vs IMRT in this population.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Abstract Introduction The rapidly ageing population and multimorbidity are associated with increased emergency department (ED) visits by older adults. In the ED, older adults have higher risk of hospitalization, functional and cognitive decline, and mortality. Boarding, holding admitted patients in the ED awaiting a hospital bed, exacerbates these negative outcomes, which disproportionately affect older adults. Methods We conducted a cross-sectional analysis to investigate US boarding trends by age using clinical administrative data from 5 health systems and publicly available NHAMCS data from 2018 to 2024. Results Boarding ≥3 h in the ED has increased across diverse hospital types, with oldest adults (85+) facing the greatest risk (System 4: IRR [95% CI] = 1.18 [1.15-1.20], System 5: IRR [95% CI] = 1.20 [1.17-1.23], System 3 [Community Hospital]: IRR [95% CI] = 1.25 [1.19-1.33]). These results were recapitulated at the national level in NHAMCS (IRR [95% CI] = 1.30 [1.05-1.61]). Discussion The trend of increased boarding has serious implications for patients, caregivers, and health systems. The 2025 CMS Age-Friendly Hospital Measure offers opportunities to improve processes and procedures to mitigate the negative effects of hospital boarding on older patients. We highlight opportunities to address this challenge, including ongoing quality improvement initiatives, bed prioritization algorithms, and alternate admission pathways.

Objectives. Allergic rhinitis (AR) can substantially compromise daily functioning and well-being, and many patients require more than a single agent to obtain satisfactory symptom control. This study examined whether adding montelukast to antihistamine could manage AR symptoms and quality-of-life outcomes effectively.Methods. A review was performed in PubMed, Embase, Medline, Scopus, the Cochrane Library, and Google Scholar to identify eligible studies reported through April 2025. Eligible studies compared combination therapy with montelukast plus antihistamine against antihistamine monotherapy and reported nasal symptoms or rhinoconjunctivitis quality of life questionnaire (RQLQ) scores. Treatment effects were further examined by antihistamine class.Results. Fifteen studies including 2,882 subjects were analyzed. Combination therapy significantly improved daytime nasal symptoms (standardized mean difference [SMD] [95% CI], 0.44 [0.21–0.67]), nighttime nasal symptoms (0.12 [0.01–0.23]), and RQLQ scores (0.14 [0.00–0.27]) versus monotherapy. Individual nasal or ocular symptoms, sneezing, nasal obstruction, and rhinorrhea improved significantly, while nasal itching and ocular symptoms did not. Combinations with desloratadine and levocetirizine showed greater benefits than those with loratadine or fexofenadine.Conclusion. Montelukast–antihistamine combination therapy reduced overall symptoms and improved quality of life versus antihistamine monotherapy. The magnitude of benefit appears to vary depending on the specific antihistamine used, highlighting the possible value of individualized treatment strategies in the treatments of AR.

ABSTRACT Objectives Multicenter research of geriatric emergency department (GED) care remains limited. Our objectives were to: 1. Prospectively collect data prioritized by the Geriatric Emergency care Applied Research (GEAR) network, a transdisciplinary taskforce for GED care, and create a multicenter GED research repository of prospective and electronic health record (EHR) data, 2. Assess concordance between prospective and EHR data. Methods The GEAR Standardization Study (GEARSS) is a multicenter, prospective study of older emergency department (ED) patients (65+) focusing on the 4Ms of age‐friendly care (mobility, medication safety, mentation, what matters) and elder mistreatment. Demographic and clinical data were collected via interviews by trained research assistants (RA) on Days 0, 4, 30, and 90 and linked to EHR. Prevalence of chronic comorbidities and incident delirium were measured and reported using descriptive statistics. Prospective and EHR data concordance was assessed with Cohen's Kappa. Results 999 participants were recruited from 5 EDs (3/25/2021–6/30/2022) across 3 institutions: Grady Health System, Northwestern Memorial Hospital, and Yale New Haven Health. The cohort was 57.0% female, 55.2% White, 39.1% Black, and 3.4% Hispanic, and the mean age was 75.1 years. For rheumatologic disease, peptic ulcer disease, diabetes, renal disease, and cancer, prevalence differed between prospective and EHR data by > 10%. About two‐thirds of participants were at risk for falls. Concordance between prospective and EHR data was good for ethnicity ( K = 0.73); excellent for sex ( K = 1.00), age ( K = 1.00), and race ( K = 0.98); fair for disposition ( K = 0.53); slight for ED observation status ( K = 0.33) and dementia diagnosis ( K = 0.24); poor for delirium presence ( K = 0.07). Conclusion In GEARSS, demographic variables aligned strongly between prospective and EHR data, while diagnosis, disposition, and mentation factors did not. This multicenter data source provides preliminary findings for common geriatric syndromes and conditions. Choice of measures using these data should be driven by GED research questions.

Abstract Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell–associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. Significance: T cell–engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542

Objectives: Novel biomechanics of the exhalation delivery system can deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard nasal sprays. This study aimed to evaluate the effectiveness of EDS-FLU in treating chronic rhinosinusitis (CRS). Methods: Studies were retrieved from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases up to April 2024. We analyzed 5 studies that compared EDS-FLU with a control group (exhalation delivery system with placebo) on various outcomes, including the 22-item Sinonasal Outcome Test (SNOT-22), nasal symptom scores (congestion, facial pain, olfactory dysfunction, and rhinorrhea), nasal polyp scores, surgical indication rate, and the incidence of adverse effects. Results: Five studies with 2129 patients were included. EDS-FLU significantly improved SNOT-22 score (−20.9657 [−23.5639; −18.3674]) and the polyp score (−1.5099 [−1.7810; −1.2388]) after 6 months. The incidence of epistaxis was significantly higher in the treatment group compared to the control group (OR = 5.7954 [2.1004; 15.9909]). Effects of EDS-FLU on polyp score (−0.6497 [−0.8186; −0.4807]), responder rate (OR = 2.1755 [1.2784; 3.7020]), complete responder rate (OR = 2.0423 [1.0109; 4.1262]), surgical indication rate (OR = 0.7313 [0.5459; 0.9797]), and SNOT-22 score (−6.1513 [−11.3054; −0.9972]) were significantly higher in the treatment group than in the control group. Conclusions: This study demonstrated that EDS-FLU (372 µg twice daily) produced statistically significant improvements compared to EDS-placebo in multiple subjective and objective outcomes, although some adverse effects, such as epistaxis, may occur.

SLC26A9 is a Cl - channel and electrogenic Cl - -HCO 3 ‑ exchanger found in several human epithelia, including the lung, intestine / GI tract, and kidney. SLC26 proteins are defined by a C-terminal, cytoplasmic sulfate transporter / anti-σ-domain (STAS). In mammals, several STAS domains have protein-protein interactions with the regulatory-region of CFTR (R-CFTR), the Cl - channel associated with cystic fibrosis. However, the functional consequences, i.e., regulatory effects (up/downregulation), of STAS-to-R-CFTR binding seem to differ by SLC26 member. Our prior work showed that the SLC26A9:CFTR interaction decreases SLC26A9 channel and exchange activity. If SLC26A9-STAS was replaced with SLC26A6-STAS, no inhibition of SLC26A9 conductance occurred when interacting with R-CFTR (PMID 19643730). Complete deletion of SLC26A9-STAS removed Cl - conductance. Thus, we hypothesized that a disordered loop within STAS is the likely interaction area, and therefore deleted this STAS-disordered loop (ΔLoop) to test this region’s functionality. We used a voltage clamp to measure Cl - currents (IV; conductance G calculated) in Xenopus laevis oocytes (n=10 / construct) injected with cRNA of ΔLoop and subcomponent areas of SLC26A9. Each construct contained a 3xFLAG tag such that stained oocytes from these constructs allowed determination of membrane expression. ΔLoop has three subregions: K/R rich, Middle, S/T rich. Both ΔLoop and ΔLoop(K/R) increase Cl - currents (and conductance) by 5x greater comparted to wild-type SLC26A9. Five amino acid extension of ΔLoop (N- or C-terminal) produces Cl - currents equivalent to ΔLoop deletion. However, 10 amino acid extension of ΔLoop (N- or C- direction) produces currents equivalent to WT-SLC26A9. Membrane localization indicates that ΔLoop and regional deletion constructs have similar membrane abundance to WT, while boundary deletions inhibit channel trafficking to the membrane. As ΔLoop(S/T) slightly increased conductance, the ordered S/T-rich motif [T 620 SVSYITFS 628 ] was examined for possible phosphorylation effects by serial alanine substitution. Each alanine substitution in the S/T-rich motif decrease SLC26A9 Cl - conductance vs WT-SLC26A9. However, for S623A the conductance decrease was due to minimal plasma membrane expression rather than apparent change of channel activity. Together these data suggest that the disordered loop is multifaceted and can maintain low conductance (autoinhibition) or by potential phosphorylation. As cystic fibrosis (CF) results from loss-of-function, trafficking or degradation mutations, the robust Cl - conductance from elimination of SLC26A9 autoinhibitory, disordered loop, presents an opportunity to supplement or replace Cl - conductance in CF tissues and potentially patients. R25-DK101405 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Objective Allergic fungal rhinosinusitis (AFRS) is characterized by type I immunoglobulin E (IgE)‐mediated hypersensitivity reactions to fungal antigens. This systematic review and meta‐analysis assessed the efficacy of biologics in the management of refractory AFRS. Data Sources PubMed, SCOPUS, Embase, Web of Science, and Cochrane. Review Methods Changes in Sino‐Nasal Outcome Test (SNOT)‐22 scores, endoscopic findings, serum eosinophil count, and total IgE levels were assessed in patients with refractory AFRS after receiving biologic therapy. Subgroup analyses were conducted to evaluate the individual efficacy of each biologic agent, including dupilumab, mepolizumab, and omalizumab. Results A total of 60 patients from 6 studies were analyzed. Biologics showed a significant improvement in SNOT‐22 scores (standard mean difference 1.1607 [95% CI 0.5549; 1.7664]), endoscopic scores (2.1953 [1.4181; 2.9725]), serum eosinophil count (1.1649 [0.7735; 1.5563]), and total IgE level (1.0700 [0.4052; 1.7348]). Dupilumab, mepolizumab, and omalizumab all enhanced SNOT‐22 and endoscopic scores. Additionally, dupilumab significantly reduced total IgE levels (1.2981 [0.4063; 2.1900]), whereas both dupilumab (0.9274 [0.1592; 1.6957]) and mepolizumab (1.2324 [0.9215; 1.5433]) significantly lowered the serum eosinophil counts. Conclusion The agents significantly improved nasal symptoms, laboratory findings, and endoscopic scores. These findings support the potential role of biologics as a therapeutic option for patients with AFRS who are unresponsive to conventional treatments.