Citations

Abstract Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

ABSTRACT Objectives Lasers are integral to contemporary endourologic stone surgery; however, reported institutional practices regarding laser access, personnel requirements, and safety protocols vary. We sought to characterize respondent‐reported laser access models, operational requirements, safety practices, and perceived barriers to care. Materials and Methods A cross‐sectional, web‐based 25‐item survey was distributed between October 2024 and March 2025 through social media, professional organizations, and departmental contacts. The survey assessed practice characteristics, laser access, physician and technician responsibilities, institutional safety requirements, and perceived barriers to care. Responses were self‐reported, collected anonymously, and summarized using descriptive statistics. Results A total of 187 respondents completed the survey; 85.6% identified as endourologists and 61.5% practiced in academic settings. Most respondents reported institution‐owned laser equipment (70.1%), while 9.6% reported contracted equipment and 20.3% combination models. Among respondents addressing contracted equipment availability ( n = 58), 55.2% reported ready access after regular business hours and 46.6% on weekends. Among 182 evaluable responses, 65.4% reported that physicians could operate lasers without a technician present. Fifty‐two respondents perceived that technician availability could affect patient care; among these, 40 reported potential delays in definitive treatment and 33 reported potential multiple or staged procedures. Staff laser safety goggles could be deferred according to 78.4% of evaluable responses, and 18.3% reported a prior institutional laser safety incident. Conclusion This survey identified substantial respondent‐reported variation in laser access, staffing requirements, and safety practices. The findings describe perceived institutional practices and barriers and do not establish effects on treatment delays, workflow efficiency, patient outcomes, or comparative safety. Future studies should directly compare institutional models using objective measures of access, workflow, treatment delays, and safety outcomes.

ABSTRACT Aims Religiosity and spirituality (R/S) are generally associated with a more favourable cardiovascular risk profile, but longitudinal evidence is limited. We examined whether multidimensional R/S predicts its future behavioural and biological components. Methods This prospective cohort study analysed 6,844 adults aged ≥50 (56% women; mean R/S score 2.1; 20% weekly attenders; 81% Christian) from waves 4–7 of the English Longitudinal Study of Ageing (ELSA). Behavioural outcomes included smoking, exercise, alcohol intake, and fruit and vegetable consumption; biological outcomes included blood pressure (BP), haemoglobin A1c (HbA1c), and the inflammatory risk markers C-reactive protein (CRP) and fibrinogen. R/S was assessed with four items from the Santa Clara Strength of Religious Faith Questionnaire. Hierarchical linear and logistic regressions adjusted for age, sex, wealth, education and ethnicity; biomarker models also adjusted for health behaviours and body mass index. Results Greater spirituality ( B =−0.019; 95%CI[−0.036,−0.003]), daily prayer/meditation ( B =−0.017; 95%CI[−0.032,−0.002]), participation in organized religion ( B =−0.017; 95%CI[−0.032,−0.002]), and importance of religious faith ( B =−0.017; 95%CI[−0.033,−0.002]) were independently associated with lower fibrinogen levels. Daily prayer/meditation also independently predicted higher fruit and vegetable intake ( B =0.004; 95%CI[0.000,0.008]). However, frequent attendance (OR=0.846; 95%CI[0.730,0.982]), the significance of faith (OR=0.935; 95%CI[0.879,0.994]), and religious purpose (OR=0.939; 95%CI[0.884,0.997]) independently reduced the odds of meeting exercise recommendations. Similarly, frequent attendance was associated with higher HbA1c ( B =0.002; 95%CI[0.000,0.005]). There were no independent associations with CRP or blood pressure. Conclusion R/S showed mixed prospective associations with the cardiovascular risk profile: favourable for fibrinogen and fruit and vegetable intake, unfavourable for physical activity and HbA1c. LAY SUMMARY We examined whether religious and spiritual involvement was related to later heart-related health behaviours and blood measurements in more than 6,800 English adults aged 50 and over. The associations ran in both directions, and the study cannot show that religion or spirituality causes these changes. Stronger religious and spiritual involvement was associated with lower fibrinogen, a blood protein linked to clotting. Daily prayer or meditation was associated with eating more fruit and vegetables. Regular attendance at religious services was associated with less physical activity and higher blood sugar. GRAPHICAL ABSTRACT

Abstract Objective. Four-dimensional CT (4DCT) enables visualization of dynamic wrist joint pathology but may be compromised by motion artifacts. Deep learning (DL)-assisted motion correction has the potential to enhance wrist 4DCT quality, but model development is hindered by scarce training data. To address this, we developed a model-based motion simulation framework that generated realistic 4DCT data with paired static ground truth images to demonstrate wrist motion correction using a physics-informed DL model trained with simulated data. Approach. Wrist motion was simulated by synchronizing rotational and translational movements of carpal bones and connective tissues. Elastic deformation guided by analytically-derived motion vector fields was applied to static wrist scans at neutral positions to create artifact-free images at multiple angular positions. Virtual motion-corrupted 4DCT images were produced via forward projection and reconstruction with synchronized gantry and wrist motion. Experimental data from 4DCT cadaver scans were collected to validate simulation quality. Low-intensity region score (LIRS), positivity, and entropy were used to assess simulated motion artifacts. A physics-informed motion correction network was adapted exclusively using simulated training data and subsequently deployed on simulated, real cadaveric, and in vivo 4DCT scans. LIRS and structural similarity index (SSIM) were used to evaluate motion correction quality. Wilcoxon signed-rank tests were conducted ( α = 0.05). Results. The simulation method created realistic motion artifacts compared to real scan reference ( p > 0.05). Motion artifacts were effectively mitigated across testing cases demonstrating generalizability. In simulated scans, LIRS improved from 0.55 ± 0.12–0.75 ± 0.04 and SSIM from 0.87 ± 0.08–0.95 ± 0.03 at bone regions (each p < 0.01). In experimental cadaveric scans, LIRS improved from 0.05 ± 0.01–0.31 ± 0.17 in marker regions and from 0.58 ± 0.19–0.77 ± 0.14 in bone regions (each p < 0.01). Significance. Our simulation method facilitates training DL-assisted motion correction algorithms by providing high-quality training data, effectively supporting 4DCT image quality enhancement.

Background Competition for urgent and emergent operating-room access is a significant challenge in many hospitals. Evidence-based benchmarks for early intervention are well established for emergencies like acute appendicitis or hip fracture. In contrast, laparoscopic cholecystectomy for acute cholecystitis or symptomatic cholelithiasis is often delayed. The purpose of this study was to evaluate the clinical and economic impact of delays in laparoscopic cholecystectomy across the US. Methods The Nationwide Readmissions Database was queried for patients aged ≥18 years admitted between 2021 and 2022 undergoing urgent or emergent laparoscopic cholecystectomy. Patients were stratified based on operative timing (<3 vs ≥ 3 days). The primary outcome was 30-day readmission. Secondary outcomes included VTE, SSI, and total cost. Propensity score matching (1:1) was performed using 46 covariates. Linear regression assessed the cost associated with each additional hospital day prior to surgery, with a subgroup analysis of safety-net hospitals. Results Among 136,893 patients, 24,496 (17.9%) experienced delayed laparoscopic cholecystectomy. After matching (n = 48,992), delays were associated with increased odds of readmission (9.5%; OR 1.22 [1.15-1.29], P < 0.001) and VTE (1.5%; OR 1.51 [1.30-1.77], P < 0.001). SSI (0.2%) was not significantly different. The mean total cost was $25,957 ± $21,609 for delayed patients vs $20,784 ± $20,027 for early surgery. Linear regression revealed an incremental cost of $1,695 per additional hospital day prior to surgery, rising to $2071 per day in safety-net hospitals ( P < 0.001). Discussion Delays in laparoscopic cholecystectomy have significant clinical and economic impacts, underscoring the urgent need for national benchmarks to standardize operative timing and reduce disparities for patients in safety-net hospitals.

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.