Citations

Abstract Clinical syndromes of frontotemporal dementia present both distinct and overlapping neuroimaging abnormalities and, consequently, domains of impairment. The aim of this study was to determine how well covariance patterns from multiple neuroimaging modalities discriminate across clinical frontotemporal dementia syndromes. Four-hundred participants with a clinical frontotemporal dementia diagnosis, including behavioral variant of frontotemporal dementia, semantic variant of primary progressive aphasia, right temporal variant of frontotemporal dementia, primary progressive aphasia, apraxia of speech with agrammatic aphasia, primary progressive apraxia of speech, progressive supranuclear palsy and corticobasal syndrome, and 109 cognitively unimpaired participants underwent extensive neurological and neuropsychological assessments, structural MRI, flortaucipir-PET for tau and [18F] fluorodeoxyglucose-PET. Multimodal imaging covariance was investigated at the voxel-level using principal component analysis after adjusting for age and sex effects. Linear regression models were fit to investigate the relationship between principal components and clinical scores. Multinomial logistic regression models investigated the ability of imaging principal components to discriminate across syndromes. The first principal component, which describes the largest source of variability in the data, was a pattern of widespread cortical atrophy (21% variability explained) and of frontoparietal and temporal hypometabolism (21%): scores were lowest in behavioral variant of frontotemporal dementia and correlated with general cognitive impairment. On tau-PET, the first principal component (43% variability) was not significantly different among syndromes and captured a widespread cortical tau uptake, with a focus on the temporal lobe. In all three modalities, the second principal component captured temporal lobe imaging abnormalities, contrasting the motor and semantic clinical syndromes. Subsequent components described smaller variability. On cross-validation, the classifiers based on principal components from MRI (multiclass area under the receiver operating characteristic: 0.76) and [18F]fluorodeoxyglucose-PET (0.79) outperformed tau-PET (0.71), while combining all three modalities did not significantly improve the classifier performance. On cross-validation, the sensitivity of the image-based classifiers was heterogeneous across syndromes and modalities, with highest values for progressive supranuclear palsy and semantic variant of primary progressive aphasia and lowest for primary progressive aphasia and corticobasal syndrome. Our study found that the covariance components of structural and molecular neuroimaging underlying frontotemporal dementia clinical syndromes exist both as a continuum and with syndrome-specific patterns. More than one imaging model was able to correctly classify several frontotemporal dementia clinical syndromes with good specificity and sensitivity, highlighting the value of imaging in aiding patient diagnosis.

PURPOSE Detection of bone marrow disease has been a major component of rhabdomyosarcoma (RMS) staging with bilateral bone marrow aspirates/biopsies (BMAB) from the iliac crests considered the diagnostic gold standard. This study's goal was to determine if 2- 18 F-labeled fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) or PET/magnetic resonance imaging (MRI) may replace BMAB in RMS staging. METHODS Patients were recruited in Europe and North America. Medical records, FDG PET/CT or FDG PET/MRI (PET), and BMAB reports were collected retrospectively. Images were re-reviewed by nuclear medicine physicians at the patients' home institutions if PET reports indicated increased FDG uptake at bone/bone marrow sites or if tumor cells were detected in bone marrow samples. RESULTS PET imaging and BMAB were performed before chemotherapy and tumor resection in 301 patients with FDG-avid RMS. Bone marrow metastases were detected by PET and BMAB in 54, by PET only in 24, and by BMAB only in one of 301 patients with FDG-avid primary tumors. Absence of bone marrow metastases was confirmed by PET and BMAB in 222 of 301 patients. These observations translated into 98% sensitivity and 90% specificity for PET in detecting bone marrow metastases when BMAB was considered as gold standard. FDG-avid marrow disease was patchy (1-5 foci) in one third of cases. Patients with marrow disease indicated by PET and BMAB had more FDG-avid bone marrow foci, more metastatic sites, and lower survival than those with marrow disease indicated by PET only, suggesting more advanced disease stages. CONCLUSION Bone marrow sampling may be omitted in patients without evidence of FDG-avid bone marrow disease by PET. If there are FDG-avid bone marrow lesions, further investigation by MRI and/or biopsy should be considered.

Abstract Background Immigrant women experience disproportionate psychosocial stress driven by acculturation, socioeconomic hardship, discrimination, and transnational responsibilities. Despite evidence supporting culturally tailored stress‑management interventions, limited formative research has examined program preferences across diverse immigrant communities. Methods Using a community‑based participatory research (CBPR) approach, we conducted three language‑concordant focus groups (Somali, Spanish, English; n = 18) and a mixed‑methods survey (n = 88) with immigrant women in southeast Minnesota. Qualitative data were analyzed using constant comparative methods; quantitative data were summarized descriptively. Results Participants described intersecting stressors including caregiving burdens, financial insecurity, immigration‑related fears, bicultural identity strain, and transnational obligations (e.g., “Every day you are being told of problems back at home”). Barriers to discussing stress included stigma, limited culturally concordant care, religious norms discouraging emotional disclosure, and structural constraints such as lack of insurance (e.g., “How are you gonna pay for a therapist if you don't have health insurance?”). Coping strategies varied culturally but consistently emphasized social support, spirituality, and practical stress‑reduction techniques. Survey findings indicated strong preference for education on stress, stigma reduction, culturally and linguistically aligned support groups, and flexible delivery formats (in‑person, hybrid). Conclusions Immigrant women experience multifaceted stress shaped by minority stress processes and structural inequities. Findings highlight the need for culturally responsive, community‑informed stress‑management interventions that integrate education, social support, and flexible delivery modalities. These results directly inform adaptation of a stress‑management program for Somali, Spanish‑, and English‑speaking immigrant women.

Abstract The use of natural killer (NK) cells for the treatment of solid tumors such as cholangiocarcinoma has been hindered by challenges related to cell production, persistence and trafficking, as well as by reduced efficacy within an immunosuppressive tumor microenvironment. Antitumor immunity can be reduced by the interaction of NK cell expressed programmed cell death protein 1 (PD1) with ligands on tumor and other cells within the tumor microenvironment. The antitumor effect of NK cells is enhanced in cells engineered to express a truncated PD1 without an intracellular domain. The cytolytic potential and therapeutic efficacy of extracellular vesicles (EVs) derived from human NK cells expressing truncated PD1 was evaluated as a cell-free therapeutic to overcome some limitations faced by cell therapies. We demonstrate the feasibility of efficient expansion, production and isolation of therapeutic vesicles from human NK cell lines and from engineered NK92 cells expressing truncated PD1. The cytotoxic efficacy of these therapeutic vesicles was validated in both monolayer tumor cell cultures and in multicellular tumor spheroids. Concomitant administration of gemcitabine upregulated NKG2D ligands on tumor cells and increased susceptibility to NK cell and to NK cell derived EV mediated killing. These findings position engineered NK cell derived-EVs as a scalable and promising cell-free immunotherapeutic for cholangiocarcinoma.

ABSTRACT Background Bile acid (BA) malabsorption (BAM) is a common cause of chronic diarrhoea and may occur in some patients due to abnormalities of the gut microbiota. Effects of probiotics on faecal secretory BAs, particularly the primary BA, chenodeoxycholic acid, are unclear. Aim/Methods We conducted a randomized, double‐blind, placebo‐controlled trial of the De Simone formulation 8‐strain probiotic in 24 patients previously diagnosed with BAM. Patients were randomized to 3 weeks of the probiotic (900 billion bacteria) or placebo (maltose), both administered three times daily. Symptoms, serum 7 α C4, faecal primary BAs, intestinal permeability by 13 C‐mannitol‐lactulose test (0.1 and 1 g of the sugars respectively) over 24 h, faecal short chain fatty acids (SCFA), microbiome, and metabolome were assessed at baseline and post‐intervention. Results Data from 22 patients were included. Probiotic supplementation was associated with a significant decrease in % faecal primary BAs (chenodeoxycholic acid and cholic acid) with median change from baseline −5.7 [IQR −10.3, 0.9]% compared to 9.8 [IQR 0.2, 20.6]% on placebo ( p = 0.012). The faecal microbiome was significantly different in the probiotic group after intervention, driven by probiotic‐specific species. There were no significant differences in symptoms, intestinal permeability, or SCFA. However, there was a numerical difference in the changes from baseline in 0‐2 h 13 C‐mannitol excretion −1.9 [−13.9, 4.2] mg for the probiotic and 1.0 (−0.5, 12.7) mg for placebo ( p = 0.084). Conclusions The De Simone formulation probiotic induced significant microbiome and metabolome changes in patients with BAM, ultimately leading to a decrease in % faecal primary BAs and possible reduction in intestinal permeability. Clinical Trials.gov registration NCT #06609148, January 2, 2025.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Abstract Technological advancements have increased the number of human spaceflights, including the advent of space tourism and deep space travel. The structure and function of the pulmonary system are gravitationally dependent, highlighting the importance of understanding functional changes within the pulmonary system during transient and sustained microgravity exposure. This systematic review and meta-analysis provide an overview of effects of microgravity (0G) on various functional outcome measures of the human lungs relative to Earth gravity (1G). Twenty-eight studies comprising parabolic flights (~20 seconds), short- (≤30 days) and long-duration spaceflight (>30 days) were assessed. Outcome measures reported in 1G (before flight) and 0G (in-flight) were extracted. Fixed effects models showed microgravity caused a reduction in elastic work and carbon dioxide production, and increases in pulmonary diffusion capacity, compliance, and pulmonary capillary blood volume. Despite this, the effect sizes were small and likely have little clinical significance in healthy individuals. However, they could impact space tourists who have lower health requirements for space travel, and those with underlying obstructive respiratory disorders. The results demonstrate how traditional functional pulmonary testing provides essential physiological benchmarks that complement high-throughput data collection methods, enabling an integrated understanding of how molecular changes translate into functional respiratory outcomes in microgravity.

Abstract Improved understanding of how chimeric antigen receptor (CAR) and endogenous T‐cell phenotypes associate with progression‐free survival (PFS) is needed to individualize and improve immunotherapy outcomes in multiple myeloma (MM). We characterized and investigated the prognostic value of immune dynamics defined with multidimensional and computational flow cytometry in 258 bone marrow aspirates from 107 MM patients treated with idecabtagene vicleucel in the KarMMa trial. At screening, there was an association between longer PFS and increased percentages of PD1 + cytotoxic T cells and ICOS − TIGIT + Tregs. At Month 1 after infusion, the presence of >1% CAR‐T cells, a CD4/CD8 CAR‐T‐cell ratio >0.09, and greater abundance of non‐activated non‐cytolytic CAR‐T cells identified patients with longer PFS. Notably, 47 of the 115 endogenous T‐cell clusters were prognostic at the latest assessment performed after CAR‐T infusion. Lower percentages of ICOS + TIGIT − Tregs showed the strongest association with longer PFS. Altogether, this large dataset of dynamic immune profiling throughout treatment with anti‐B‐cell maturation antigen (anti‐BCMA) CAR‐T cells uncovered that the T‐cell composition prior to apheresis as well as CAR‐T and endogenous T‐cell phenotypes after infusion associates with PFS. These findings have potential for translation into routine laboratory practice for improved understanding of response and resistance to CAR‐T cells in relapsed/refractory MM.