Citations

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

Objective Epidemiologic estimates for age of systemic lupus erythematosus (SLE) diagnosis are limited, particularly for men and racial and ethnic subpopulations in the United States. Leveraging the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population‐based SLE registries, meta‐analyses were performed estimating age‐specific incidence of SLE by sex, race, and ethnicity. Methods The CDC network of SLE registries includes five state‐based registries, plus a sixth Indian Health Service registry. Incidence periods spanned calendar years 2002‐2018. Registries provided age‐specific incidence of SLE, fulfilling the American College of Rheumatology (ACR) SLE classification criteria, per 100,000 person‐years, stratified by sex, race, and ethnicity for the meta‐analyses. Results Incidence rates among women were highest for those aged 30‐39 (12.7, 95%CI: 9.5‐16.8), while rates among men were highest for those aged 60‐69 (2.1, 95%CI: 1.3‐3.4). Black women aged 20‐39 had the highest SLE incidence rates (23.6, 95%CI: 20.7‐26.8). Among women diagnosed with SLE before age 20, incidence was highest among Asian (6.5, 95%CI: 2.8‐15.2) individuals. Among women diagnosed with SLE after age 60, incidence was highest among American Indian/Alaska Native (9.4, 95%CI: 3.4‐15.4) individuals. Weighted percentages show 10.0% of those with SLE were diagnosed before age 20, while 15.1% were diagnosed after age 60. The largest proportion of individuals with SLE, 22.1%, were diagnosed between 30‐39 years. Conclusions This study provides comprehensive sex‐ and race‐specific estimates of age at SLE diagnosis. The substantial later in life SLE incidence among men and disease burden in pediatric and older populations should raise awareness in considering SLE in the differential diagnosis in previously underrecognized groups.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Background Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. β=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. β=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. β=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.

ABSTRACT Palliative care can be offered concurrently as a treatment option to patients with pulmonary arterial hypertension (PAH) to relieve symptoms and improve quality of life. However, it is infrequently used and is associated with misconceptions. Limited studies have reported patients' perspectives of palliative care as a treatment option for PAH. We conducted a web‐based survey, informed by a brief targeted literature review and input from patients and clinicians, which was completed by adults (≥ 18 years) in the United States (US) with self‐reported PAH. Patients reported demographic and disease variables and their perspectives and experiences with palliative care. Patients self‐reported their Pulmonary Hypertension Functional Class Self‐Report class, EmPHasis‐10, and 6‐min walk test. A total of 200 respondents (86.5% female; mean age 58.5 years) from 42 US states completed the survey between 19 September and 3 October 2023. Most respondents described palliative care as “end‐of‐life care” ( n = 43, 25.7%) and associated it with the need for extra support ( n = 111, 55.5%). Many respondents ( n = 171, 85.5%) had not discussed palliative care services, nor had a palliative care consultation with their healthcare provider (HCP); most had not been offered a consultation ( n = 109/171, 63.7%). Despite this low frequency of discussions, respondents reported feeling comfortable discussing palliative care with their HCPs ( n = 177, 88.5%). The survey results demonstrated that these patients with PAH had limited experiences with palliative care, where palliative care was frequently subject to misinterpretation. These findings emphasize the need for proactive engagement between patients and HCPs to ensure palliative care is optimally used and understood.

Abstract Background Inflammatory bowel disease (IBD) can lead to a hypercoagulable state, particularly at initial diagnosis. Consequently, venous thromboembolism (VTE) represents a serious complication associated with IBD. For children, the risk of VTE near the time of IBD diagnosis has not yet been quantified, and guidance for VTE prophylaxis remains unclear. Methods This multisite matched case-control study examined pediatric patients with a new diagnosis of IBD from 2019-2024. Cases were those who developed VTE ≤30 days prior or ≤90 days post IBD diagnosis. Controls were newly diagnosed IBD patients without VTE. Each case was matched to 2-6 controls based on IBD subtype and age at IBD diagnosis. Demographics, laboratory values, prothrombotic risk factors and treatments were compared between matched cases and controls using conditional logistic regression stratified, by case sets. Results Study subjects included 15 cases and 52 controls, resulting in 70 matched pairs. Factors associated with early VTE included lower hemoglobin (P = .003), lower albumin (P = .002), corticosteroids use (P = .01), central line (P = .002), and any surgery ≤90 days post IBD diagnosis (P = .001). No association with VTE was detected for platelets, C-reactive protein, fecal calprotectin, family history of IBD or body mass index. Conclusions Albumin, hemoglobin, steroid use, central line, and any surgery ≤90 days post IBD diagnosis were associated with early VTE. These risk factors may be used in a future prediction model to stratify newly diagnosed pediatric IBD patients by their risk for early VTE development.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P &amp;lt; .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Background Takayasu arteritis (TA) is a rare large-vessel vasculitis that can involve pulmonary arteries, potentially leading to pulmonary hypertension (PH). Noninvasive evaluation by echocardiography is often used, but its reliability in confirming and characterizing PH in TA is unclear. We investigated the role of invasive hemodynamic testing in TA patients with suspected PH. Methods We retrospectively identified 10 patients with TA meeting 2022 ACR criteria and suspected PH based on symptoms and/or echocardiography; all underwent echocardiography followed by right heart catheterization (RHC).PH was defined as mean pulmonary artery pressure (mPAP) &gt;20 mmHg. PH was classified as pre-capillary (pulmonary artery wedge pressure [PAWP] ≤15 mmHg), post-capillary (PAWP &gt;15 mmHg), or combined (PAWP &gt;15 mmHg with elevated pulmonary vascular resistance). Echocardiographic parameters were collected where available, along with invasive hemodynamics, cardiac biomarkers (BNP/NT-proBNP), inflammatory markers (ESR, CRP), NYHA functional class, and outcomes. Results Median age was 44 years (range 18-58), and 90% were female. Based on invasive hemodynamics, pre-capillary PH was present in 5 patients, combined pre-/post-capillary PH in 3, and isolated post-capillary PH in 2. Median mPAP was 38 mmHg (IQR 30-55), median pulmonary vascular resistance 3.5 Wood units (IQR 2.3-8.7), and median PAWP 15 mmHg (IQR 8-24). Echocardiography frequently underestimated disease severity. Several patients with absent or low tricuspid regurgitation velocity (≤1.0 m/s), where measurable, demonstrated severe pre-capillary PH on RHC, including pulmonary vascular resistance &gt;6 Wood units. Among patients with available data, NT-proBNP levels ranged from 59 to 51,968 pg/mL, and inflammatory markers varied widely (CRP &lt;0.3 to 107.9 mg/L). Among patients with available NYHA data, most were class II-III. Conclusions In this TA cohort, RHC was essential to confirm and phenotype PH, which was present in the majority of those with suspected PH. Echocardiography alone often underestimated or misclassified PH in TA - in one case missing severe pre-capillary PH due to an absent TR signal, and in another failing to discern elevated left-heart filling pressure. Invasive assessment prevented missed diagnoses and misclassification, ensuring appropriate management of TA-associated PH This abstract is funded by: None

Abstract BACKGROUND Remote, smartphone‐based cognitive testing may improve access to cognitive assessments for Alzheimer's disease and related dementias. We evaluated the feasibility, reliability, and validity of unsupervised smartphone‐based cognitive tests in a registry‐based cohort. METHODS Adults without a record of cognitive impairment ( N = 1815; ages 18–92) were recruited from the University of California, San Francisco (UCSF) Brain Health Registry to complete three unsupervised smartphone cognitive testing sessions within 2 weeks. Reliability was assessed with correlations between sessions. Linear regression models tested associations of smartphone tasks with demographics, self‐ and informant‐rated cognitive concerns, and web‐based cognitive testing (Cogstate Brief Battery). RESULTS Adherence was high (82.2%) and usability favorable. Test–retest reliability was moderate to strong ( ρ ’s = 0.61–0.85, all p ’s < 0.001). Lower smartphone scores were associated with older age, lower education, cognitive concerns, and worse Cogstate performance. DISCUSSION Findings support the feasibility, reliability, and validity of remote digital assessments in adults without a record of cognitive impairment.

Summary Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26/28) of patients ( P = 3.2x10 -5 ) and accurately identified 83% (10/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.