Citations

ABSTRACT Supplemental oxygen (hyperoxia), often provided to premature infants, can disrupt lung growth and contribute to development of neonatal and pediatric lung diseases, necessitating understanding of underlying mechanisms. We previously showed that even moderate hyperoxia (< 60% O 2 ) induces detrimental cellular senescence in 18–22 weeks human fetal airway smooth muscle (fASM), a key cell type in airway contractility and remodeling. In this study, we examined the ability of senotherapeutics Fucoidan and Dasatinib (D) + Quercetin (Q) (D + Q) to mitigate adverse effects of hyperoxia and assessed the preventive effect of mitochondrial antioxidants (MitoQ). fASM cells exposed to normoxia (21% O 2 ) or hyperoxia (50% O 2 ) were treated with Fucoidan [100 μg/mL], D + Q [250 nM + 375 nM] or MitoQ [100 nM] and assessed for senescence markers, senescence‐associated secretory profile (SASP), extracellular matrix (ECM) deposition, and cell viability. Our results showed that moderate hyperoxia increases senescence markers and SASP. Fucoidan decreased p21 expression and inhibited SASP release without inducing cell death, while D + Q decreased β‐galactosidase (β‐Gal) activity, p21 and plasminogen activator inhibitor‐1 (PAI‐1) expression, and caused cell death without affecting SASP in hyperoxia‐induced senescent fASM. MitoQ prevented increases in senescence markers and SASP in hyperoxia‐exposed fASM. These findings demonstrate distinct and viable strategies to counter hyperoxia‐induced fASM senescence. Fucoidan (senomorphic), D + Q (senolytic), and MitoQ (prophylactic antioxidant) represent promising, mechanistically different approaches to alleviate detrimental effects of moderate hyperoxia in developing airways towards limiting perinatal lung disease.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Background Recent studies have disputed the association between bisphenol A (BPA) and endometriosis. This updated meta-analysis was conducted to investigate the impact of BPA exposure on endometriosis. Methods This study evaluated BPA exposure and endometriosis risk, analyzing studies from Web of Science, PubMed, Embase, Cochrane Library, and Chinese databases (CNKI, CBM, Wanfang, VIP) through August 2025. Methodological quality was assessed via the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality Tool (AHRQ). Heterogeneity was quantified using I 2 statistics. Pooled odds ratios (ORs) and 95% CIs were calculated using fixed- or random-effects models according to heterogeneity. Subgroup analysis, sensitivity analysis, and publication bias assessment were supplemented to validate the overall finding. Results Seven studies comprising 2,488 participants were included in quantitative synthesis. The meta-analyses demonstrated that BPA exposure was associated with a statistically significant increase in endometriosis risk (OR = 1.36, 95% CI = 1.13–1.63, p = 0.008). Additionally, subgroup analysis indicated that BPA exposure may further elevate endometriosis risk in cases with different regions, populations, and measurement methods. Sensitivity analysis confirmed that the results of these meta-analyses were relatively robust. No publication bias was detected. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251019552 , identifier PROSPERO (CRD420251019552).

Abstract INTRODUCTION Naturalistic driving provides real‐world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in‐vehicle sensors with points of interest (POIs) to quantify daily environmental engagement among older adults who were cognitively normal at enrollment. METHODS Data from 438 participants enrolled in the Driving Real‐world in‐Vehicle Evaluation System Project were used to generate daily POI share vectors and model latent engagement patterns using a logistic‐normal hidden Markov model (HMM). Thirteen latent states described distinct modes of environmental interaction. From each participant's inferred state sequence, we derived mobility features – state occupancy, dwell time, transition entropy, and self‐transition probability – and examined their differences across clinical status groups and associations with Preclinical Alzheimer's Cognitive Composite (PACC) performance. RESULTS Transition entropy and several state‐specific occupancy and dwelling metrics differed across clinical groups, but none of the mobility features were significantly associated with PACC scores. DISCUSSION Mobility‐derived behavioral features differentiate clinical status groups and may reflect early functional changes preceding cognitive decline.

ABSTRACT Purpose To validate a custom smartphone application for at‐home visual acuity (VA) measurement in children. Methods A total of 452 children aged 3–17.5 years participated. Certified examiners measured in‐office test–retest VA (logMAR) using gold‐standard Amblyopia Treatment Study HOTV (3‐to‐6‐year‐olds, younger cohort) or electronic Early Treatment of Diabetic Retinopathy Study (7‐to‐17.5‐year‐olds, older cohort) protocols at 3–4.5 m and app‐based VA at 1.5 m. Caregivers measured at‐home app‐based VA at 1.5 m. Results Comparing at‐home app‐based with gold‐standard VA, in eyes 20/40 or better, 95% (143/151) and 93% (91/98) of the younger and older cohorts were within 2 lines, respectively (mean differences: younger = −0.03, older = −0.04; 95% limits‐of‐agreement half‐width (LOA): younger = ±0.26, older = ±0.22). In eyes 20/50 or worse, 66% (42/64) and 75% (76/101) of the younger and older cohorts were within 2 lines, respectively (mean differences: younger = 0.11, older = 0.13, LOA: younger = ±0.50, older = ±0.51). Comparing in‐office app‐based VA with gold‐standard VA, in eyes 20/40 or better, 98% (160/164) and 94% (99/105) of the younger and older cohorts were within 2 lines, respectively (mean differences: younger = −0.03, older = −0.03; LOA: younger = ±0.22; older = ±0.24). In eyes 20/50 or worse, 85% (60/71) and 91% (101/111) of the younger and older cohorts were within 2 lines, respectively (mean differences: younger = 0.04; older = 0.04; LOA: younger = ±0.39; older = ±0.24). For gold‐standard test–retest, in eyes 20/40 or better, 99% (163/164) and 99% (104/105) of the younger and older cohorts had retest within 2 lines, respectively (mean differences: younger = 0.00; older = 0.01; LOA: younger = ±0.17; older = ±0.11). For 20/50 or worse, 92% (66/72) and 100% (111/111) in the younger and older cohorts were within 2 lines, respectively (mean differences: younger = 0.01; older = 0.02; LOA: younger = ±0.35; older = ±0.15). Conclusions Our app demonstrated good concordance with the gold standard at home and in the office for eyes with VA of 20/40 or better. However, concordance decreased considerably for eyes with VA 20/50 or worse, particularly at home.

Abstract INTRODUCTION Sleep and circadian rest–activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS‐associated AD continuum remain uncharacterized. METHODS We analyzed 7‐day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group‐specific associations. RESULTS DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

Poststenotic dilatation in renal artery stenosis, evaluated at abdominal CT, might be related to stenotic kidney damage and inflammation, particularly to monocyte chemoattractant protein-1 release.

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Abstract The hallmark of heparin-induced thrombocytopenia (HIT) is the presence of immunoglobulin G (IgG) antibodies against platelet factor 4/heparin (PF4/H) complexes, typically detected by PF4/H enzyme-linked immunosorbent assay (ELISA); thus, negative ELISA results are commonly used to exclude this diagnosis. Here, we report a prevalent yet previously unrecognized subset of antibodies that are undetectable by PF4/H ELISA (ELISA−) but activate platelets in the PF4-dependent P-selectin expression assay (PEA+). In 11 patients with clinically confirmed HIT who tested positive in both PF4/H ELISA and platelet activation assays, ELISA−PEA+ antibodies accounted for 65% ± 19% of total platelet-activating IgG activity and coexisted with ELISA+PEA+ antibodies. Consistent with this finding, single-cell cloning from 7 patients with HIT identified 23 PEA+ antibody-producing B-cell clones, of which 17 were ELISA−, outnumbering the ELISA+ clones. Functionally, ELISA−PEA+ antibodies closely resembled ELISA+PEA+ antibodies: platelet binding and activation required exogenous PF4 and were inhibited by FcγRIIA blockade, high-dose heparin, or Fab fragments made from ELISA+PEA+ antibodies. Importantly, these antibodies induced thrombocytopenia in a humanized mouse model of HIT. Despite lacking PF4/H reactivity in ELISAs, they recognize PF4 on platelets and showed no appreciable binding to neutrophil-activating peptide-2, interleukin-8, or PF4 alone. Structurally, these antibodies were heterogeneous, with a subset sharing heavy-chain features with ELISA+PEA+ antibodies. Collectively, our findings demonstrate that ELISA−PEA+ antibodies are a common, previously unrecognized feature of HIT, with functional relevance, supporting the possibility that they play an important, perhaps even central, role in HIT pathogenesis. Defining their prevalence, kinetics, and clinical impact deserves high priority for further investigation.

ABSTRACT The novel HLA‐DQB1*02:02:01:28Q shows a point mutation in the intron 3 splice site.