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Importance The incidence of human papillomavirus type 16 (HPV16–positive) recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rising. Approved therapies offer a durable response to a minority of patients. Objective To determine the efficacy and safety of a therapeutic HPV16-targeted immunotherapy, PDS0101, in combination with pembrolizumab in participants with HPV16-positive R/M HNSCC, with separate evaluation of immune checkpoint inhibitor (ICI)–naive and ICI-resistant cohorts. Design, Setting, and Participants VERSATILE-002 was a phase 2, open-label, multicenter nonrandomized clinical trial conducted at 26 oncology centers from March 29, 2021, to May 15, 2025, across the US, UK, and Ireland using the Simon 2-stage optimal design. Efficacy analyses were performed on modified intent-to-treat (mITT) population; safety analyses included all participants who received 1 or more doses. Eighty-eight participants with histologically confirmed R/M HPV16-positive HNSCC were enrolled, of whom 87 (98.9%) received treatment and composed the safety population. Seventy five (85.2%) were in the mITT population used for efficacy analyses, of whom 53 (70.7%) were ICI-naive with a programmed cell death ligand 1 combined positive score of 1 or greater and 22 (29.3%) were ICI-resistant. Exposures Pembrolizumab (200 mg, intravenously, every 3 weeks for up to 35 cycles) plus subcutaneous PDS0101 (5 scheduled doses per protocol). Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors , version 1.1, by a masked independent central reviewer. Secondary end points included progression-free survival (PFS), median overall survival (mOS), and safety, with exploratory end points of duration of response, disease control rate, and response rates by programmed cell death ligand 1 status. Results Of the 75 patients in the mITT population, the mean (SD) age was 64.0 (8.3) years; 4 individuals (5%) were female and 71 (95%) were male; and 2 individuals (3%) were Asian, 1 (1%) was Black, 5 (7%) were Hispanic, and 71 (95%) were White. Among 53 ICI-naive participants in the mITT cohort, ORR by the central reviewer was 34.0%, median PFS was 5.3 months (95% CI, 2.10-9.00), and mOS was 39.3 months (95% CI, 23.90 to not evaluable). Among 22 ICI-resistant patients in the mITT cohort, no objective responses were observed and the primary end point (ORR by central reviewer) was not met, but mOS was 14.8 months (95% CI, 8.50-26.00). The treatment was well tolerated, with 13.8% experiencing grade 3 or higher treatment-related adverse events. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that PDS0101 plus pembrolizumab showed antitumor activity in ICI-naive HPV16-positive R/M HNSCC, with favorable safety, response rates, and survival outcomes. The findings support further evaluation in a first-line setting. Trial Registration ClinicalTrials.gov Identifier: NCT04260126

Importance Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition. It is uncertain whether revascularization might be an effective treatment for cognitive impairment in these patients. Objective To test whether any cognitive benefit from revascularization of high-grade, asymptomatic ICA stenosis varies based on the degree of baseline cerebral hemodynamic impairment. Design, Setting, and Participants This substudy was conducted within a multicenter phase 3 randomized clinical trial. Adults (aged 35-86 years) without dementia with eighth-grade education or higher and unilateral asymptomatic ICA stenosis greater than or equal to 70% were enrolled from January 2018 to July 2024 at 61 sites in North America (last follow-up in July 2025). Of 607 participants screened from 2485 in CREST-2, 392 were enrolled. Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery. Intervention Carotid revascularization (endarterectomy or stenting) plus intensive medical management (IMM) vs IMM alone. Main Outcomes and Measures The primary outcome was the difference in composite cognitive z score over 1 year based on 5 cognitive tests. The primary analysis tested for an interaction between treatment group (revascularization vs IMM alone) and degree of baseline hemodynamic impairment among those with reduced baseline cognition (cognitive z score ≤−1.0 SD). Results Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline (25 in the revascularization group and 26 in the IMM alone group). TTP ranged from no interhemispheric TTP delay to a more-than-2-second delay. Mean (SD) cognitive z scores were −1.36 (0.51) at baseline and −1.17 (0.47) at 1 year in the revascularization group and −1.34 (0.83) at baseline and −1.01 (0.97) at 1 year in the IMM alone group. The primary analysis showed no difference in cognition by treatment group over 1 year, adjusting for treatment group × hemodynamic status interaction and other covariates (adjusted difference in cognitive z score, −0.15 SD [95% CI, −0.54 to 0.24]). The interaction was not significant (β estimate = 0.018 [95% CI, −0.025 to 0.061]; P = .40). Conclusions and Relevance In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition, suggesting that revascularization does not improve cognitive dysfunction by restoring flow to the brain in chronic asymptomatic carotid stenosis. Trial Registration ClinicalTrials.gov Identifier: NCT03121209

ABSTRACT Aim To systematically review and meta‐analyze cohort studies evaluating associations of gingival inflammation, periodontitis, and tooth loss with cognitive decline and incident mild cognitive impairment or dementia. Methods PROSPERO‐registered searches of MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library identified cohort studies from inception through October 10, 2025, with a PubMed update on June 24, 2026. Random‐effects meta‐analyses pooled adjusted hazard ratios (HRs) for dementia/MCI; cognitive function outcomes were summarized qualitatively. Risk of bias (RoB) was assessed using the Newcastle–Ottawa Scale. Results Fifty‐nine studies met inclusion criteria; 28 contributed to dementia/MCI meta‐analyses. Severe periodontitis (HR: 1.16; 95% CI: 1.06–1.27; I 2 = 0%; Q ‐test p = 0.49), periodontitis of unspecified severity (HR: 1.45; 95% CI: 1.21–1.73; I 2 = 98%; Q ‐test p < 0.001), edentulism (HR: 1.26; 95% CI: 1.19–1.33), and low tooth count (HR: 1.27; 95% CI: 1.14–1.42; I 2 = 94%; Q ‐test p < 0.001) were associated with elevated dementia/MCI risk. RoB was low in 31 studies (53%), moderate in 25 (42%), and high in 3 (5%); inadequate confounder adjustment was common. Meta‐regression showed stronger estimates for ICD‐code periodontitis definitions (fold change (FC) = 1.44 95% CI: 1.04–2.01), older cohorts (FC per year = 1.02 95% CI: 1.00, 1.05), and weaker estimates with lower RoB (FC per NOS star = 0.81 95% CI: 0.73–0.92). Follow‐up duration, cohort age, and RoB were not associated with tooth‐count estimates. Conclusion Periodontitis and tooth loss are associated with modestly higher dementia/MCI risk and poorer cognitive function, but heterogeneity, residual confounding, and bias temper causal interpretation. Longitudinal studies with rigorous baseline cognition assessment and intervention studies are needed.

Endocrine therapy remains the cornerstone of treatment for estrogen receptor alpha (ERα)-positive breast cancer, yet the relationship between individual genetic background and molecular response to ERα-targeted therapy remains incompletely understood. Using a well-characterized panel of lymphoblastoid cell lines (LCLs), we performed genome-wide pharmacogenomic expression quantitative trait locus (PGx-eQTL) analysis to identify estradiol (E2)- and tamoxifen (TAM)-induced SNP-gene pairs. PGx-eQTL signals were integrated with previously published breast cancer genome-wide association study datasets to examine their association with clinically relevant breast cancer phenotypes. We identified two ER-mediated PGx-eQTL SNP-gene pairs associated with breast cancer prognosis post-treatment with E2 or TAM. Notable loci included E2-regulated MRPL15 and TAM-regulated SYCP3, which have effects in a genotype-dependent manner, with genotype-dependent survival outcomes, from worse to better relapse-free survival. Similar endocrine-therapy effects on patient survival and breast cancer risk were observed in SIK2, post TAM-treatment, and in LSM4 with E2-treatment. Moreover, qRT-PCR validation in an independent LCL panel confirmed the genotype-specificity of these signals. Overall, we identified ER-mediated PGx-eQTL SNP-gene pairs which represent potential pharmacogenomic tools for identifying patients likely to benefit from ERα-targeted endocrine therapy, offering a foundation for more genotype-informed individualized treatment decisions in breast cancer.

Abstract Background Sarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined. Methods We performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV₁% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis. Results Compared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion (∼2.6%) of this association. Conclusions. The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

Background Studies suggest that hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real‐world populations. Methods We conducted a cross‐sectional study of patients aged ≥18 years seen at the Mayo Clinic in 2022 who underwent echocardiogram and cognitive assessment within 1 year. HF was classified per the 2022 American Heart Association as no HF, HF with preserved ejection fraction (EF), HF with mildly reduced EF, and HF with reduced EF. Cognitive impairment was categorized using the Montreal Cognitive Assessment score as normal (≥26), mild (18–25), and moderate to severe (<18). Linear regression assessed EF–Montreal Cognitive Assessment correlation and logistic regression the association between HF subtypes and cognitive dysfunction, adjusting for age, sex, race, and vascular risk factors. Results A total of 1592 patients met inclusion criteria (mean age, 75.7±13.8 years; 48.5% women). Lower EF was associated with worse cognitive performance (postadjustment β=0.033, P =0.013). Patients with HF with reduced EF and patients with HF with preserved EF had significantly lower Montreal Cognitive Assessment scores than those without HF (17.6±6.2 and 18.9±5.8 versus 19.9±6.0, P <0.001). The prevalence of moderate to severe cognitive impairment was highest in HF with reduced EF (43.3%), followed by HF with preserved EF (34.4%), no heart failure (28.6%), and HF with mildly reduced EF (23.4%) (adjusted trend P =0.032). Conclusions HF, independent of ejection fraction alone, is associated with cognitive impairment. Further studies should confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

Assessing balance is crucial in neurological rehabilitation, yet while wearable sensors enable real-world monitoring, identifying reliable digital biomarkers remains challenging. This study utilized a high-fidelity instrumented walkway to determine which gait parameters best predict balance impairment, providing robust targets for future wearable applications. We analyzed 49 steady-state gait metrics from 140 individuals with diverse neurological conditions. Using statistical analysis and machine learning, we evaluated these parameters against objective force plate sway scores and clinical fall-history labels. Group analysis identified 16 parameters significantly distinguishing fallers from non-fallers, and a neural network classified fallers with an area under the curve of 0.75. Across all analytical approaches, overall gait variability, e.g., Stride Width S.D. and the Gait Variability Index, emerged as a universal predictor of balance impairment and fall risk. Furthermore, while traditional linear models emphasized spatial postural control, machine learning classification uniquely identified inter-limb asymmetry as a premier driver of fall prediction. These findings indicate that instrumented gait analysis effectively identifies digital biomarkers for balance deficits. Isolating these specific metrics provides a clear blueprint for meaningful metrics required for continuous objective monitoring and future development of personalized, adaptive rehabilitation strategies.

ABSTRACT Purpose This study assesses the association between colorectal cancer (CRC) screening and a validated, housing-based measure of individual-level socioeconomic status (SES, called HOUSES hereafter) within rural communities and determines whether HOUSES-integrated geospatial analysis can be used to tailor interventions. Methods We used CRC screening data from a subset of Mayo Clinic Midwest patients living in cities without ready access to routine care in the Mayo Clinic Health System in 2019 to represent rural communities. At the individual level, we assessed the association between CRC screening rates and the HOUSES index, adjusting for age, sex, race/ethnicity, comorbidity, distance from home address to clinic, and area deprivation index, using a multilevel mixed-effects logistic regression model. Additionally, we conducted geospatial analysis to examine the correlation between hotspots of 1) lower CRC screening rates and 2) lower SES of the subject population (HOUSES quartile 1). Findings Among 34,489 individuals (median age 64.0 years, 52.4% female), those with the lowest SES (HOUSES Q1) had 37% lower odds of being CRC screening adherent than those with the highest SES (HOUSES Q4) (adj. OR [95% CI]: 0.63 [0.58-0.69]). In the 14 identified HOUSES Q1 hotspots, there was a significant correlation in counts of HOUSES Q1 and low CRC screening (correlation coefficient=0.81). Conclusion Lower SES was significantly associated with lower CRC screening among rural populations. HOUSES-enabled geospatial analysis identified geographic hotspots with lower CRC screening rates for targeted interventions to address disparities in CRC screening in rural communities. HOUSES may be a useful digital tool for cancer preventive care and research.

Abstract Background Central nervous system (CNS) involvement by mycosis fungoides (MF) is an uncommon but serious manifestation of advanced disease. Large-cell transformation (LCT) is associated with aggressive clinical behavior and increased risk of extracutaneous dissemination; however, CNS involvement remains rare and is infrequently confirmed by molecular studies. Case Presentation: We report a 77-year-old man with a 13-year history of MF who presented with progressive generalized weakness, gait instability, and weight loss. Brain magnetic resonance imaging demonstrated multiple bilateral enhancing intraparenchymal lesions concerning for primary CNS lymphoma. Cerebrospinal fluid cytology and flow cytometry were nondiagnostic. Stereotactic biopsy of a right frontal lesion revealed diffuse infiltration of brain parenchyma by large atypical lymphoid cells with a predominantly perivascular distribution. By immunohistochemistry, the lymphocytes express CD3, TCRβF1, CD30, and demonstrate diffuse p53 overexpression, complete loss of p16, and a high proliferative index (70–80%). Comparison with a prior skin biopsy which showed typical MF morphology with limited CD30 expression (< 10% of atypical lymphocytes). Polymerase chain reaction–based T-cell receptor gene rearrangement studies performed on both CNS and skin specimens demonstrated similar clonal rearrangements, confirming CNS dissemination of the original MF clone with large-cell transformation. Discussion CNS involvement in MF is rare and may occur years after the initial diagnosis, particularly in the setting of transformation. This case highlights several important features, including multifocal intraparenchymal CNS disease, nondiagnostic cerebrospinal fluid studies, and molecular confirmation of clonal relatedness between skin and CNS lesions. These findings underscore the limitations of cerebrospinal fluid-based diagnostic studies and emphasize the importance of tissue biopsy and molecular analysis in establishing the diagnosis. Conclusion We describe a rare case of MF with large-cell transformation presenting as multifocal intraparenchymal CNS disease. Molecular demonstration of identical T-cell receptor rearrangements in skin and brain lesions provided definitive evidence of metastatic dissemination. Recognition of this rare complication is essential, as new neurologic symptoms in patients with MF should prompt evaluation for CNS involvement regardless of the extent of active cutaneous disease.