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Abstract Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a rare and aggressive lymphoma with molecular heterogeneity not well characterize. In this study, we performed next-generation sequencing analysis for a large number of DNA and RNA samples from patients with PT-DLBCL. DNA sequencing analysis identified ≥ 3 chromosomes with copy number variations (CNVs) and microsatellite instability as prognostic biomarkers, rather than MYD88 mutations and genetic subtypes. Remarkably, targeted RNA-seq analysis in 195 patients revealed that TP53 mutations with a ≥ 40% variant allele frequency had significantly adverse prognostic impact, and that a 150-gene expression signature subdivided PT-DLBCL into two distinct clusters, termed as testicular lymphoma tumor (TLT) and microenvironment (ME) subtypes. The TLT subtype featured upregulation of genes involved in B-cell receptor signaling, cell cycle, DNA damage and repair, higher frequencies of CNVs and MYD88 mutations, elder ages, larger tumor sizes, and significantly poorer survival. Genomic microRNA profiling analysis identified significantly differentially expressed microRNAs between 113 PT-DLBCL and 180 systemic DLBCL patients, and further subdivided the PT-DLBCL cohort by microRNA signatures. The subcohort with upregulation of 16 microRNAs associated with PT-DLBCL and testicular tissue expression had significantly better survival. This study revealed characteristic genetic, gene expression, and microRNA profiles and heterogeneity in PT-DLBCL.

Importance Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP mAbs) offer effective migraine-specific preventive treatment. However, concerns exist about their potential cardiovascular risks due to CGRP blockade. Objective To compare the incidence of cardiovascular disease (CVD) between Medicare beneficiaries with migraine who initiated anti-CGRP-mAbs vs onabotulinumtoxinA in the US. Design, Setting, and Participants This retrospective, sequential cohort study was conducted among a nationally representative population-based sample of Medicare claims from May 2018 through December 2020. Data analysis was performed from August to December 2023. This study included fee-for-service Medicare beneficiaries aged 18 years or older with migraine who initiated either anti-CGRP mAbs or onabotulinumtoxinA. Beneficiaries who had a history of myocardial infarction (MI), stroke, cluster headache, malignant cancer, or hospice service within a 1-year baseline period prior to treatment initiation were excluded. To minimize channeling bias from new drug introductions and time-related bias due to the COVID-19 pandemic, 5 cohorts were established, representing sequential 6-month calendar intervals based on the initial prescription or date of index anti-CGRP mAbs or onabotulinumtoxinA use. Exposure Anti-CGRP mAbs vs onabotulinumtoxinA. Main Outcomes and Measures The primary outcome was time to first MI or stroke. Secondary outcomes included hypertensive crisis, peripheral revascularization, and Raynaud phenomenon. The inverse probability of treatment-weighted Cox proportional hazards models were used to compare outcomes between the 2 treatment groups. Results Among 266 848 eligible patients with migraine, 5153 patients initiated anti-CGRP mAbs (mean [SD] age, 57.8 [14.0] years; 4308 female patients [83.6%]) and 4000 patients initiated onabotulinumtoxinA (mean [SD] age, 61.9 [13.7] years; 3353 female patients [83.8%]). Use of anti-CGRP mAbs was not associated with an increased risk of composite CVD events (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.44-1.77), hypertensive crisis (aHR, 0.46; 95% CI, 0.14-1.55), peripheral revascularization (aHR, 1.50; 95% CI, 0.48-4.73), or Raynaud phenomenon (aHR, 0.75; 95% CI, 0.45-1.24) compared with onabotulinumtoxinA. Subgroup analyses by age group and presence of established non-MI or stroke CVD showed similar findings. Conclusions and Relevance In this cohort study, despite initial concerns regarding the cardiovascular effects of CGRP blockade, anti-CGRP mAbs were not associated with an increased risk of CVD compared with onabotulinumtoxinA among adult Medicare beneficiaries with migraine, who were predominantly older adults or individuals with disability. Future studies with longer follow-up periods and in other populations are needed to confirm these findings.

INTRODUCTION: Spondyloarthritis (SpA), the most common extraintestinal manifestation of inflammatory bowel disease (IBD), is reported in up to 39% of patients with IBD. Despite this high prevalence, risk factors of developing SpA in patients with IBD are not well described. In this study, we aimed to determine the factors associated with SpA symptoms and their prevalence in an IBD cohort. METHODS: Two validated screening questionnaires for the detection of SpA in IBD (DETAIL = DETection of Arthritis in Inflammatory boweL diseases, IBIS-Q = IBD Identification of Spondyloarthritis Questionnaire) were administered to patients with IBD without a prior diagnosis of SpA in 6 US academic medical centers. Demographic data, IBD characteristics, and medication history were recorded. RESULTS: Screening questionnaires were completed by 588 patients (220 ulcerative colitis, 349 Crohn's disease, and 19 IBD-unclassified), with a median age of 40 years (interquartile range 30–53) and median disease duration of 12 years (interquartile range 6–22). The number of positive screens was 130 (22%) for DETAIL, 196 (33%) for IBIS-Q, and 204 (35%) for either DETAIL or IBIS-Q. Age, female sex, history of smoking, prior bowel surgery, and history of any biologic or targeted small molecule exposure were associated with a positive screen on univariate analysis. After multivariate analysis, female sex (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.41–2.93), older age (OR 1.02, 95% CI 1.01–1.04), history of smoking (OR 1.67, 95% CI 1.04–2.69), and history of any biologic or targeted small molecule exposure (OR 2.27, 95% CI 1.34–3.84) were independently associated with positive screens. Higher number of biologic exposures was associated with higher risk of positive screens, with the highest risk seen with 3 or more exposures (OR 3.25, 95% CI 1.75–6.03). DISCUSSION: A substantial number of patients with IBD screen positive for SpA symptoms, indicating a potentially high burden of undiagnosed illness. Factors associated with SpA symptoms include older age, female sex, and more severe disease (based on increased number of advanced therapies or prior surgery), whereas IBD phenotype does not independently increase the risk of a positive SpA screen. Further studies are needed to confirm these findings and better characterize SpA in IBD.

AbstractBackgroundUFMylation is an understudied ubiquitin‐like post‐translational modification (PTM). Like ubiquitin, UFM1 is conjugated to substrates via a catalytic cascade involving a UFM1‐specific E1 (UBA5), E2 (UFC1), and an E3 ligase complex (UFL1, DDRGK1 and CDK5RAP3). UFMylation is reversible, and this is mediated by UFSP2. UFMylation plays essential roles in several biological processes including the DNA damage response, endoplasmic reticulum homeostasis, unfolded protein response, autophagic functions, and immune response. Importantly, UFMylation is also crucial for healthy brain development. Alzheimer’s disease (AD), a complex neurodegenerative disorder, is characterized by the accumulation of pathologic tau and beta‐amyloid proteins and has been associated with abnormalities in the aforementioned processes. Intriguingly, the potential link between AD and UFMylation has not been investigated yet. Considering that pathological tau plays a critical role in AD, and tau also plays an important role for the DNA damage response in neurons under physiological conditions, we speculated that tau itself could be modified with UFM1.MethodWe performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2 and other UFMylation pathway components in RIPA‐soluble and insoluble fraction in human post‐mortem frontal cortex. To test whether tau can be modified by UFM1, we performed co‐immunoprecipitation (Co‐IP), Proximity Ligation Assays (PLA) and liquid chromatography‐tandem mass spectrometry (LC‐MS/MS).ResultWe found a significant reduction of soluble UFSP2, but an increase of soluble total UFM1 in AD compared to controls. We found that tau interacts with UFL1 and DDRGK1. In addition, using immunoprecipitation of denaturing lysates we found that tau can indeed be covalently modified by UFM1 when overexpressed. We detected strong signal of HA‐UFM1‐tau in neurons but not in negative controls using PLA. Furthermore, we immunoprecipitated denatured UFM1 from human autopsy brain, and detected two specific UFM1‐tau bands with tau antibodies. Together, this data strongly indicates that tau is UFMylated under endogenous conditions. Using LC‐MS/MS, we identified 17 UFMylation sites in tau proteins.ConclusionUFMylation is dysregulated in AD; tau protein can be modified by UFM1 both in vitro and in vivo, which enables a more comprehensive understanding of tau PTMs.

AbstractBackgroundThe Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks.MethodWe applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs.ResultModel fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91).ConclusionThe harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.

IntroductionUnilateral sphenoid sinus opacification on computed tomography is caused by a variety of pathologies including inflammatory and infectious sinusitis, benign and malignant tumors, and encephaloceles. The purpose of this study was to report craniofacial pain locations and outcomes in inflammatory unilateral sphenoid sinusitis (USS) patients who underwent endoscopic sinus surgery (ESS).MethodsA multi‐institutional retrospective cohort study was conducted on all adult patients who had ESS for USS from 2015 to 2022. Patient demographics, presenting symptoms and nasal endoscopy findings, extent of surgical dissection, and craniofacial pain locations and outcomes were recorded. Exclusion criteria included age <18 years, non‐inflammatory etiology, immunodeficiency, invasive fungal sinusitis, lack of follow‐up, lack of preoperative pain location, and neoplasia. Descriptive statistics were calculated.ResultsOf 57 patients with USS, 44 (77.2%) reported craniofacial pain at one or more locations. Retrobulbar (n = 19, 43.2%) was the most common pain location followed by frontal (n = 17, 38.6%) and occipital (n = 10, 22.7%). Surgical intervention resulted in pain resolution in 33/44 patients (75%), with a mean follow‐up of 83.7 (±97.8) days. There were no significant associations between presenting symptoms, imaging findings, endoscopy, surgical extent, or final pathology and the presence or resolution of facial pain (p > 0.05).ConclusionIn USS patients, the most common craniofacial pain locations were retrobulbar, occipital, and frontal, with a minority being vertex. Based on short‐term follow‐up, ESS resolved the craniofacial pain in 75% of cases. There were no clinical variables that predicted the presence or resolution of craniofacial pain.Level of Evidence4 Laryngoscope, 135:1915–1919, 2025

ObjectiveSpondyloarthritis (SpA) is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). The application of screening tools to detect SpA in patients with IBD may lead to earlier recognition of SpA and affect treatment decisions.MethodsA combination of two previously described SpA screening questionnaires, the Detection of Arthritis in Inflammatory Bowel Disease (DETAIL) and IBD Identification of Spondyloarthritis Questionnaire (IBIS‐Q), was administered to consecutive patients with IBD attending IBD specialty clinics in six US academic medical centers. Demographic data, IBD, and rheumatology history were extracted by chart review.ResultsA total of 669 patients were analyzed. The median age was 40 years (interquartile range [IQR] 30–54) with a median disease duration of 12 years (IQR 6–22) and moderate to severe IBD based on medication exposure and history of bowel surgery. A total of 81 patients (12%) carried a diagnosis of an inflammatory rheumatic disease, whereas 75 (11%) had consulted a rheumatologist during the previous year. Using published cutoffs, 180 out of 669 patients (27%) screened positive with DETAIL, 266 (40%) with IBIS‐Q, and 275 (41%) with either questionnaire. Axial symptoms were more frequently reported than peripheral musculoskeletal complaints. Notably, 189 out of 275 (69%) screen‐positive patients had neither a documented inflammatory rheumatic disease diagnosis nor a visit with a rheumatologist within the past year.ConclusionA substantial proportion of patients with IBD have symptoms suggestive of SpA, and many of these may have undiagnosed SpA. The IBIS‐Q questionnaire appears to identify more potential SpA cases than DETAIL. Strategies are needed to prioritize rheumatology consultations for those patients with IBD who are most likely to benefit.

Objective: Pulmonary involvement is commonly observed in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), presenting with manifestations such as diffuse alveolar hemorrhage, inflammatory infiltrates, pulmonary nodules, and tracheobronchial disease. We aimed to identify distinct subgroups of tracheobronchial disease patterns in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using latent class analysis (LCA), and to evaluate their clinical characteristics and outcomes. Methods: We conducted a retrospective cohort study using electronic medical records of patients aged >18 years diagnosed with AAV and tracheobronchial disease between 1 January 2002 and 6 September 2022. Patients with follow-up <6 months were excluded. LCA was employed to identify disease subtypes based on 10 pre-defined indicators. Maximum likelihood estimation with 10 repetitions per model ensured robustness in model selection, guided by the Akaike information criterion (AIC). Patient and disease characteristics were summarized and compared across predicted classes. Statistical analyses included Kruskal–Wallis and Fisher’s exact tests for continuous and categorical variables, respectively. The primary outcome was time to relapse of the tracheobronchial inflammation after starting immunosuppressive medication, analyzed using the Kaplan–Meier method and log-rank tests. Secondary outcomes included severity of pulmonary disease on pulmonary function tests, endoscopic interventions, tracheostomy, or mortality during follow-up. Results: Among 136 identified AAV patients assessed for tracheobronchial involvement, 111 (81.6%) were included after excluding 25 without tracheal or bronchial disease. Predominant findings included subglottic stenosis (91.0%), lower tracheal stenosis (16.2%), and bronchial stenosis (17.1%). LCA identified a three-class model as optimal: tracheal predominant (n = 94), tracheobronchial (n = 12), and bronchial predominant (n = 5). Tracheal predominant patients showed reduced risk of ear, eye, and lower respiratory manifestations, with milder obstruction on pulmonary function testing (PFT). Tracheobronchial-class patients were prone to saddle nose deformity (50%), extensive lower respiratory involvement (91.7%), and renal disease (66.7%). Bronchial predominant patients exhibited severe obstructive disease (median forced expiratory volume in 1 s (FEV1)% predicted: 58, IQR 34–66; FEV1/forced vital capacity (FVC) ratio: 56.9, interquartile range (IQR) 43–63.3) but lacked systemic AAV manifestations. LCA classes did not predict outcomes such as endoscopic intervention, tracheostomy, recurrent tracheobronchial narrowing, or mortality. Conclusion: LCA shows promise in subtype stratification of AAV patients, yet its utility in predicting outcomes and guiding treatment remains limited based on our analysis. Future studies with enhanced phenotypic data and larger cohorts are warranted to improve predictive accuracy.

ABSTRACT Background and Purpose In idiopathic normal pressure hydrocephalus (iNPH) patients, cerebrospinal fluid (CSF) flow is typically evaluated with a cardiac‐gated two‐dimensional (2D) phase‐contrast (PC) MRI through the cerebral aqueduct. This approach is limited by the evaluation of a single location and does not account for respiration effects on flow. In this study, we quantified the cardiac and respiratory contributions to CSF movement at multiple intracranial locations using a real‐time 2D PC‐MRI and evaluated the diagnostic value of CSF dynamics biomarkers in classifying iNPH patients. Methods This study included 37 participants: 16 iNPH, 10 Alzheimer's disease (AD), and 11 cognitively unimpaired (CU) controls. Anatomical and real‐time (non‐gated) PC images were acquired in a 3T Philips scanner. CSF flow was assessed at the foramen magnum, fourth ventricle, Sylvian fissure, lateral ventricle, and cerebral aqueduct. We calculated three CSF dynamics biomarkers: mean velocity amplitude, cardiac signal power, and respiratory signal power. Biomarkers from each location were evaluated for classifying iNPH versus AD and CU using support vector machine (SVM). A p ‐value of 0.05 or less was considered statistically significant. Results The velocity amplitude and cardiac signal power were significantly reduced in iNPH compared to CU ( p < 0.005) and AD ( p < 0.05) at the lateral ventricle. The SVM model using biomarkers from the lateral ventricle performed significantly better at classifying iNPH than the other locations in terms of accuracy ( p < 0.005) and diagnostic odds ratio ( p < 0.05). Conclusion Evaluation of CSF movement beyond the cerebral aqueduct may aid in identifying patients with and understanding the pathophysiology of iNPH.

ABSTRACTObjectivesThis study aimed to compared Patient‐Reported Outcomes Measurement Information System (PROMIS) anxiety, depression, and anger item bank among Korean, US and Dutch general population.MethodsBetween December 2021 and January 2022, we surveyed representative Korean participants (N = 2699). Then we compared the mean T‐scores of PROMIS anxiety, depression, and anger full items bank among Korean, US (N = 1696) and the Dutch (N = 1002) populations. Differential item‐functioning (DIF) analyses were also performed. We also compared each score by age group, sex, presence of comorbidities, and general health status.ResultsIn Korean, the mean T‐scores for anxiety, depression, and anger were 45.3 (standard deviation [SD] = 11.6), 48.4 (SD = 11.2), and 44.9 (SD = 12.6), respectively. Among the general population in Korea, patients aged 35–44 years and those with comorbidities had higher anxiety, depression, and anger scores. In the DIF analyses between the US and Korean populations, 28%, 32%, and 45% were flagged for uniform or non‐uniform DIF in anxiety, depression and anger, respectively.ConclusionsConsidering the cultural differences, we recommend using a harmonized approach that includes country‐specific reference values while retaining a standardized core set of items to enable cross‐country comparability.