Citations

Abstract Aims This study aimed to identify clinical factors associated with AVC in individuals with T2D. Methods and results This cross-sectional study is a pre-specified substudy of the multicentre randomized Steno INTEN-CT trial (Clinical Trials—INTEN-CT). Participants were eligible if they had T2D without ischaemic heart disease and were aged between 55–69 years (men) or 60–74 years (women). All participants underwent non-contrast cardiac computed tomography. AVC was measured in Agatston Units and categorized as 0, 0–300, ≥ 300. Of the 4570 participants, 46% had AVC > 0. With increasing AVC, patients were older, predominantly males, and with significantly more comorbidities. In multivariable ordered logistic regression age (OR per SD 1.54, 95% CI 1.43–1.66), BMI (OR per SD 1.18, 95% CI 1.11–1.25), hypertension (OR 1.21, 95% CI 1.05–1.40), and chronic kidney disease (OR 1.18, 95% CI 1.03–1.36) were associated with higher AVC. Statin use was also associated with higher AVC (OR 1.50, 95% CI 1.27–1.78). Higher LDL cholesterol showed stronger associations with AVC in men than women (OR 1.39, 95% CI 1.24–1.56 vs. OR 1.16, 95% CI 1.02–1.31, P for interaction = 0.025). T2D severity (Haemoglobin A1c, T2D duration, and number of antidiabetic drugs) was not associated with AVC. Conclusion In individuals with T2D without cardiovascular disease, AVC is prevalent in nearly half of all individuals. Higher AVC was associated with T2D-related comorbidities, but not T2D severity.

Donation after circulatory death (DCD) livers increasingly use machine perfusion (MP). This study evaluates MP’s impact on older DCD livers based on data from the United Network for Data Sharing, covering all first adult DCD liver transplants (2016–2025). The cohort, divided into pre-MP and MP eras (separated by the FDA approval of the first normothermic MP platform in 2021), showed accelerated growth in DCD liver transplants during the MP era. Donors ≥60 rose 7.8-fold, including donors ≥70 (a USA first). By 2025, DCD livers accounted for 43.2%, with 61.35% from donors ≥50. Normothermic regional perfusion (NRP) (3.0%–21.7%), NMP (2.3%–35.6%), and sequential NRP-NMP (0.1%–19.2%) increased significantly (p < 0.001). The MP era was associated with a decrease in median waitlist time from 112 to 62 days (p < 0.001). Early graft survival was similar across ages. For ages 50–59, 1- and 3-year survivals were 87.9%/78.4% pre-MP and 90.1%/78.8% in the MP era. For 60–69, survival was 85.0%/80.6% pre-MP and 90.0%/71.3% in the MP era. DCD LTs for ≥70 were limited to the MP era with 87.8% 1-year survival. Multivariable Cox regression showed that static cold storage (HR = 1.19), donor age 50–69 versus 18–49, and recipient age (HR = 1.04) increased the risk of graft loss after adjustment. MP is associated with an increased number of older DCD liver transplants and acceptable early graft survival.

Abstract Rationale Inflammatory bowel disease (IBD) is increasingly recognized as a systemic disorder, with extraintestinal manifestations (EIMs) involving multiple organ systems. Pulmonary involvement, particularly interstitial lung disease (ILD), remains an underrecognized manifestation of IBD. Its prevalence, clinical characteristics, and risk factors in IBD remain poorly defined. Methods We conducted a retrospective study of adults (≥18 years) with IBD who had at least one encounter in our health system between January 1, 2013 and December 31, 2023. IBD, and ILD cases were identified using ICD-9/ICD-10 codes, with ILD diagnoses confirmed by thoracic radiologists. Demographic, clinical, pulmonary, smoking, medication, and surgical data were abstracted. Associations between patient characteristics and ILD were evaluated using both a cohort design and a matched case-control design (1:3 ratio). Mortality was assessed using a Cox proportional hazards model with ILD as a time-dependent covariate. Results Among 875 patients with IBD, 109 (12%) had ILD. Radiographic patterns included nonspecific interstitial pneumonia (NSIP, 27%), indeterminate (26%), definite/probable UIP (24%), hypersensitivity pneumonitis (15%), and organizing pneumonia (8%). Pulmonary function testing demonstrated predominantly restrictive physiology and impaired diffusion capacity. In multivariable analysis, higher BMI (OR 1.04), bronchiectasis (OR 2.65), ex-smoking (OR 2.15), and use of adalimumab (OR 2.04) or infliximab (OR 2.14) were independently associated with ILD. The matched case-control design confirmed these findings and also identified older age (OR 1.04) as a significant factor. ILD was strongly associated with mortality (HR, 3.78; 95% CI, 2.50-5.72; p < 0.001). Conclusions ILD occurs in a meaningful subset of patients with IBD and is associated with older age, higher BMI, prior smoking, bronchiectasis, and TNF inhibitor use. ILD confers a markedly increased risk of death, highlighting the importance of early recognition and close monitoring in this population. This abstract is funded by: None

Abstract Rationale Type-1 inflammation in asthma leads to significant airway level changes independent of Type-2 inflammation and may underlie the severity seen in combined Type1/2 high disease. As IFNs can cause airway epithelial injury and impaired repair, we applied a novel interpretable machine learning algorithm, SLIDE, to analyze the transcriptome of airway epithelial brushings of mild-moderate (MMA) and severe asthma (SA) participants in the Immune Mechanisms in Severe Asthma (IMSA) cohort to identify latent/hidden factors of disease that associate with disease severity. Methods The expression of genes identified by SLIDE as part of a co-expression program was assessed in the full IMSA cohort by severity and in an independent cohort of the NHLBI Severe Asthma Research Program (SARP). We also examined associations of these genes with clinical asthma outcomes in both cohorts. Results SLIDE identified aberrant increased expression of membrane-tethered mucin genes, MUC1 and MUC4. MUC1 appeared in each of 5 significant latent factors associated with greater severity and MUC4 in 2/5. Standard DGE analysis also identified the gene CEACAM5 as a predictor of severity. Pathway analysis of latent factor genes revealed airway keratinization which may contribute to airway remodeling and worsening obstruction over time. Expression of MUC1, MUC4, and CEACAM5 were increased in SA compared to HC in both the full IMSA and separate SARP cohorts (p < 0.001 for all genes in both cohorts). Expression in MMA was consistently lower than in SA in both cohorts, reaching significance in IMSA (p < 0.01) but not consistently in SARP (MUC1 p = 0.04, MUC4 p = 0.27, CEACAM5 p = 0.27). Protein analysis of endobronchial biopsies by immunofluorescence staining showed a trend towards increased MUC1 protein content with evidence of secretion. MUC1, MUC4 and CEACAM5 were negatively correlated with FEV1 % predicted in both cohorts (IMSA: MUC1 r=-0.47, p < 0.01, MUC4 r=-0.47, p < 0.01, CEACAM5 r=-0.62, p < 0.01; SARP: MUC1 r=-0.19, p = 0.05, MUC4 r=-0.29, p < 0.01, CEACAM5 r=-0.51, p < 0.01). All three genes positively correlated with prospective exacerbations in both cohorts (IMSA: MUC1 r = 0.345, p = 0.01, MUC4 r = 0.216, p = 0.08, CEACAM5 r = 0.368, p < 0.01; SARP: MUC1 r = 0.22, p = 0.02, MUC4 r = 0.32, p < 0.01, CEACAM5 r = 0.38, p < 0.01). Conclusions The expression of MUC1, MUC4 and CEACAM5 increased with asthma severity in the airway epithelium and correlated with both prospective exacerbations and obstruction. As pathway analysis of genes in the significant latent factors were associated with airway keratinization aberrant expression of these mucins (with known signaling functions) may contribute to maladaptive repair and airway remodeling that drives obstruction over time, contributing to worse asthma outcomes. This abstract is funded by: NIH

Abstract Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and alveolar macrophage pneumonia (AMP) are two rare but closely related conditions within the spectrum of smoking-related interstitial pneumonias. Both share characteristic histopathologic features, including the accumulation of pigmented alveolar macrophages alongside varying degrees of interstitial inflammation and fibrosis. RB-ILD is typically a localized, bronchiolocentric process often found in smokers, whereas AMP represents a more diffuse and clinically significant disease that may arise not only from tobacco smoke but also from other causes such as occupational exposures, autoimmune diseases, and drug reactions. This review highlights the clinical presentation, imaging findings, histopathology, and treatment of both entities, emphasizing their overlapping features as well as key distinctions. We further discuss the pathogenic mechanisms driven by cigarette smoke—including oxidative stress, immune activation, and fibrosis—that underlie these diseases. A clear understanding of the similarities and differences between RB-ILD and AMP is essential for accurate diagnosis, effective management, and prognostication, particularly in patients with a history of smoking and diffuse parenchymal lung involvement.

Adults with congenital heart disease (CHD) constitute a growing population with challenges related to cardiovascular and neurological health. Many individuals born with CHD experience neurodevelopmental delays in childhood. Ongoing neurocognitive and psychological concerns impact education, employment, and quality of life. Despite this, interventions to address these issues are largely unexplored. Collaborations among multidisciplinary experts and patient partners culminated at a 2‐day Adult Congenital Heart Disease (ACHD)/Neuro Conference (April 2024) to review the current state of knowledge and guide future directions for research and clinical care. Three working groups separately focused on genetics and brain health, characterizing outcomes, and interventions among patients with ACHD. This article focuses on the work of the interventions group. A consensus statement was created to synthesize current knowledge, identify key gaps, and recommend next steps around 5 critical questions designed to guide research and clinical care for interventions with ACHD: (1) What interventions are effective for improving neurocognitive functioning? (2) What interventions are effective for improving psychological wellbeing? (3) What evidence do we have about safety and efficacy of psychotropic medications? (4) What interventions can improve health literacy? (5) What are modifiable facilitators and barriers to accessing high‐quality neurocognitive and psychological interventions? Limited research and fragmented health systems hinder interventions in ACHD. Efforts from pediatric congenital heart disease could inform the ACHD community. Although interventions are costly and resource intensive, neglecting neurocognitive and psychological needs could lead to lower quality of life and higher health care costs. By ultimately shifting to prevention and intervention, the ACHD community could facilitate positive outcomes.

Abstract Background Heavy ion radiotherapy offers distinct advantages over conventional treatments due to its superior dose distribution and enhanced biological effectiveness. However, the microdosimetric characteristics of high linear energy transfer (LET) ions, particularly near the Bragg peak, remain poorly characterized. Most experimental microdosimetry has been conducted at lower LETs, leaving a critical gap in high‐LET microdosimetric data. Purpose This study aims to extend microdosimetry to several different high‐LET ions (700–2500 keV/µm) using the novel ENCORE detector. Methods Microdosimetry was performed at the Florida State University John D. Fox Accelerator Laboratory using the ENCORE detector, a multi‐sampling ionization chamber filled with low‐pressure tissue‐equivalent gas capable of resolving energy deposition from approximately 200 keV to 3 MeV. 12 C, 16 O, and 28 Si beams were accelerated to 17–55 MeV and delivered to the segmented detector. Energy deposition patterns near the Bragg peak were recorded, and microdosimetric spectra were reconstructed. Monte Carlo was used to model the experimental setup. From each measured and simulated spectra, dose‐mean lineal energy () was calculated and compared. Results The 16 strips of the ENCORE corresponded to a tissue‐equivalent thickness of 17.6 µm, enabling resolution of energy deposition immediately proximal and distal to the Bragg peak. In six measurement configurations, the ion beam stopped within this range, allowing precise mapping of the profile around the peak; in the remaining configurations, the beam fully traversed the detector. Across all beams, difference between measured and simulated averaged 12%, based on one measurement per strip. Peak measured reached 920 ± 220, 1240 ± 206, and 2460 ± 620 keV/µm for 12 C, 16 O, and 28 Si beams, respectively. Conclusion This study demonstrated that ENCORE can resolve microdosimetric spectra with high spatial and LET resolution across a range of ion energies. Measured values reasonably agreed with Monte Carlo simulations, validating the potential of ENCORE for position‐resolved microdosimetry and model benchmarking in particle therapy.

British anatomical physiology in the early 19th century evolved from the work of William Harvey, Thomas Willis, and William Hunter, who emphasized cerebral functional localization, integrating physiology and anatomy. This novel perspective was championed by Herbert Mayo (1796–1852). A student of Charles Bell at the Middlesex Hospital in London, Mayo subsequently became a surgeon there in 1818 and later a professor of anatomy and surgery. His experiments on the motor functions of the seventh cranial nerve and sensorimotor functions of the fifth cranial nerve brought him renown. Mayo, inspired by Johann Christian Reil, also conducted the first accurate brainstem dissections, developed innovative tissue preservation methods, and provided detailed descriptions of key fiber tracts. Mayo’s 1822–1823 Anatomical and Physiological Commentaries and 1827 A Series of Engravings Intended to Illustrate the Structure of the Brain and Spinal Chord in Man accurately depicted the corona radiata, cerebellar peduncles, and uncinate fascicle. In his 1842 book, The Nervous System and Its Functions , Mayo discussed the localization of higher brain functions. His dissections remained unmatched until Josef Klingler’s work in 1934. Despite the quality of his work, Mayo has been largely neglected, possibly because of his tumultuous relationship with Bell and later professional difficulties. Nevertheless, Mayo significantly contributed to white matter anatomy and led the search for cerebral localization, subsequently impacting neurosurgery. This article examines his life and work.

Introduction Male circumcision (MC) has been shown to decrease transmission of HIV and is a critical strategy to decrease its incidence in countries with high rates of heterosexually transmitted HIV. Early infant MC (EIMC), with single-use MC devices, could increase rates of MC in Sub-Saharan Africa. Our objective was to determine the safety, efficacy and satisfaction of ShangRing EIMC in resource-constrained environments. Methods Healthy male infants aged 1–60 days underwent ShangRing EIMC performed by non-physician clinicians in 14 sites in Kenya, Tanzania and Uganda. The primary outcomes were the safety and efficacy of ShangRing EIMC. Secondary outcomes were pain related to the procedure, wound healing and parental satisfaction. Male infants were assessed at discharge and on postoperative days 7 and 28 for wound healing and complications. This trial is registered with Clinical.Trials.gov, NCT03338699 , and is complete. Results From the 1697 participants enrolled from February to November 2020, 1691 (99.6%) underwent ShangRing EIMC. Median duration of the procedure was 10 min (IQR 6–13). The mean Neonatal Infant Pain Scale 20 min postprocedure was 0.3 (SD 0.8), indicating no pain. At the time of discharge, 1679 (99.0%) participants had a normal-appearing wound and 1574 (93.1%) demonstrated complete wound healing at 28 days. A total of 17 (1.0%) AEs were reported, most related to bleeding. A total of 1635 (99.1%) of parents were satisfied with the appearance of the circumcised penis at 28 days. Conclusion ShangRing EIMC is a simple and successful MC method that non-physician clinicians can perform safely, with low AE rate, satisfactory wound healing and high satisfaction rate among parents. This indicates that the ShangRing EIMC can be considered a long-term strategic approach to accelerate the scale-up of MC in Sub-Saharan Africa. Trial registration number NCT03338699 .