Citations

Abstract The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534

ABSTRACTBackgroundIdiopathic inflammatory myopathies, beyond inclusion body myositis (IBM), have demonstrated an increased risk of adverse cardiovascular outcomes, particularly myocardial infarction (MI). This study evaluated the risk of cardiovascular disease in IBM.MethodsWe conducted a non‐concurrent cohort study utilizing the expanded Rochester Epidemiologic Project, including 50 patients with IBM, matched 1:6 to age‐, sex‐, and calendar year‐matched referents without IBM. Baseline cardiovascular risk factors were recorded. Differences in baseline covariates were adjusted by the inverse probability of treatment weighting method. Participants were followed from the index date forward to determine relative risks (RR) and hazard ratios (HR) for the development of cardiovascular outcomes including MI, ischemic stroke, cardiomyopathy, congestive heart failure (CHF), and peripheral vascular disease (PVD).Results50 patients with IBM and 294 matched population referents were included. Baseline cardiovascular risk factors were similar between groups. Aspirin use was more common (28% vs. 18%, p = 0.03) and statin use less common (26% vs. 38%, p = 0.04) in IBM versus referents. Patients with IBM had an increased hazard of MI compared to referents [HR: 5.79, 95% CI (2.51, 13.36)]. The risk of MI remained consistently elevated across all models, after accounting for potential confounders. For PVD, 16/50 IBM patients versus 16/287 referents were excluded due to pre‐existing PVD at index (p < 0.001). Among remaining participants, RR for PVD was 2.38 (0.82, 6.9). IBM was not associated with an increased risk of ischemic stroke, cardiomyopathy, or CHF.ConclusionsIBM is associated with increased risk of MI compared to population referents. Heightened cardiovascular monitoring and prevention strategies are needed in IBM.

Objective: To evaluate the safety and efficacy of recombinant human prourokinase (rhPro-UK) administered via intravenous (IV) and intra-arterial (IA) routes in acute ischemic stroke (AIS) patients compared with standard treatments. Methods: A comprehensive search was conducted in accordance with PRISMA guidelines across Scopus, Web of Science, and PubMed until 11 December 2024. Randomized controlled trials (RCTs) assessing rhPro-UK’s efficacy and safety were included. Outcomes included the modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), mortality, and adverse events (AEs). Data analysis used risk difference (RD) with 95% confidence intervals (CIs). Results: Six RCTs (n = 3993) met the inclusion criteria. IV rhPro-UK showed comparable efficacy to the comparator for the mRS 0–1 at 90 days (RD: 0.00, 95% CI: [−0.04, 0.04]) and the mRS 0–2 (RD: −0.01, 95% CI: [−0.03, 0.01], P = 0.23). IA rhPro-UK significantly improved the mRS 0–1 (RD: 0.13, 95% CI: [0.01, 0.26], P = 0.04). The NIHSS reduction was significant for IV rhPro-UK (MD: −0.83, 95% [CI: −1.36, −0.29]). IV rhPro-UK did not significantly reduce the risk of systemic bleeding (RD: −0.10, 95% CI: [−0.24, 0.03], P = 0.12), serious AEs (RD: −0.01, 95% CI: [−0.04, 0.02], P = 0.53), or mortality (RD: 0.01, 95% CI: −0.01, 0.02). IA rhPro-UK significantly increased hemorrhage with neurological deterioration (RD: 0.08, 95% CI: [0.01, 0.14], P = 0.02). Conclusions: IV rhPro-UK provides non-inferior efficacy to both alteplase and standard care with a better safety profile at 35 mg, while IA rhPro-UK enhances functional outcomes in middle cerebral artery occlusions, albeit with safety concerns. Further trials are needed to confirm long-term outcomes, optimal dosing, and broader applicability.

AbstractIntroductionActive learning engages learners in constructing knowledge through interactive strategies such as simulation, small‐group discussion, and peer instruction. Although recognized as a superior approach to traditional passive learning, its adoption has been inconsistent. Barriers include reliance on traditional lectures, lack of training, and limited time to develop materials. Simulation educators have a unique skill set that may inform and support active learning initiatives.MethodsFifteen emergency medicine simulation experts convened to define the unique skill set of simulation educators and identify transferable simulation‐based medical education (SBME) skills and concepts to promote effective active learning beyond the simulation lab. Workgroup members are simulation education directors who have undergone specialized training in SBME. During biweekly meetings over 6 months, workgroup members reviewed primary literature in SBME and active learning, along with relevant simulation educator training materials. Objectives were achieved through iterative review, group conceptualization, and expert consensus.Unique treatmentThe increasing prevalence of SBME in medical education, along with the growth of simulation fellowships, has produced a group of education experts with shared competencies. Simulation educators acquire expertise in psychological safety, facilitation, communication, and debriefing, through specialized training and extensive experience. These skills are critical for active learning environments where learners benefit from structured, engaging, and psychologically safe experiences.Implications for educatorsKey transferable SBME topics were identified for use in active learning environments outside of the simulation lab: (1) psychological safety, (2) facilitation strategies, and (3) communication techniques. Transferable tools and concepts were identified to promote efficacy and learner engagement during active learning in diverse environments. Simulation educators’ expertise is an underutilized resource for faculty development initiatives aimed at advancing active learning. This work advocates for leveraging simulation educators’ skills to close the active learning implementation gap, enhance learner outcomes, and meet the evolving needs of contemporary medical education.

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

Takayasu arteritis is a chronic, large vessel vasculitis that typically affects the aorta and its main branches. We present a case of a 33-year-old male patient who was diagnosed with Takayasu arteritis after being admitted for acute cardiogenic shock requiring inotropes. Initial transthoracic echocardiography demonstrated severe biventricular dysfunction. Computed tomography imaging of his chest showed pulmonary infarcts. Patient subsequently developed sudden lower extremity weakness and bowel incontinence, and urgent magnetic resonance imaging of his spine demonstrated thoracolumbar vascular myelopathy. Transesophageal echocardiography revealed diffuse symmetrical thickening of the walls of the aorta; findings suggestive of aortitis. Patient was initiated on intravenous corticosteroid and systemic anticoagulation. Subsequent computed tomography angiography demonstrated irregular luminal contour of the aortic arch, and complete occlusion of the left subclavian artery, abdominal aorta, superior mesenteric artery, and left renal artery. He underwent an emergent aortoiliac thrombectomy. He was transitioned to oral prednisone, tocilizumab, and azathioprine with excellent recovery.

ABSTRACTIntroduction/AimsPacinian corpuscles are end organs of the sensory nervous system. The size and superficial location of Pacinian corpuscles allows them to be visualized with high‐resolution ultrasound. This pilot study sought to assess the reliability of Pacinian corpuscle counting in the hand using ultrasound.MethodsTwo healthy participants underwent ultrasound evaluation by three ultrasonographers using a scanning protocol developed for this study. The ultrasound protocol used anatomic landmarks to identify and trace digital nerves in the palms and the adjacent Pacinian corpuscles. The ultrasonographers used morphologic features to identify and count Pacinian corpuscles at two sites in each hand for each participant using a 10–22 MHz linear‐array transducer. The procedure was repeated at 2 time points. Inter‐rater and intrarater reliabilities were determined using intraclass correlation coefficients (ICCs).ResultsPacinian corpuscles were identified in the second–third and fourth–fifth intermetacarpal spaces. The ultrasound appearance of Pacinian corpuscles is of a hypoechoic, rounded structure without a hyperechoic rim. A clustered appearance and septate internal structure are distinct features of Pacinian corpuscles, but these features are not always present. The mean number at each site was between 10.71 and 11.71. Inter‐rater and intrarater reliability both resulted in ICC values over 0.8, indicating “good” inter‐rater and intrarater reliabilities.DiscussionPacinian corpuscles can be reliably counted in the hand using high‐resolution ultrasound. The reliability data from this pilot study may facilitate further ultrasound studies of Pacinian corpuscles, which may be decreased in number or undergo other changes in polyneuropathies.