Citations

Abstract Background Partial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited. Methods This trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared: proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR). Results Between 2013 and 2023, 1041 women with early-stage breast cancer were treated with PBI. Of these, 1026 patients were included in the analyses. The median age was 66 years; 22.51% had ductal carcinoma in situ (DCIS), and 97.56% were estrogen receptor positive. With median follow-up of 38.2 months, the rate of IBR in the overall group was 3.05% (95% confidence interval [CI] = 1.99% to 4.65%) at 3 years. After IPW, compared with photon PBI, the hazard ratio for IBR for proton PBI was 2.11 (95% CI = 0.70 to 6.33) and for brachytherapy, 3.86 (95% CI = 1.39 to 10.69). Compared with proton PBI, the hazard ratio for IBR for brachytherapy was 1.83 (95% CI = 0.88 to 3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the hazard ratio for IBR for brachytherapy was 7.64 (95% CI = 1.64 to 35.58) and 3.59 (95% CI = 1.22 to 10.56) relative to photons and protons, respectively. Conclusion PBI with applicator-based brachytherapy was associated with higher IBR than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.

Abstract Introduction Benign prostatic hyperplasia (BPH) is an age-related condition affecting many men. Emerging evidence highlights a strong relationship between BPH, lower urinary tract symptoms (LUTS) and sexual dysfunction, including erectile dysfunction (ED), reduced sexual desire, hormonal imbalances, and ejaculatory dysfunction, warranting a comprehensive approach to diagnosis and management. Objectives This report aims to provide recommendations for identifying and managing sexual dysfunction associated with BPH and LUTS. Methods Based on guidelines from the International Consultation on Sexual Medicine, a literature review was conducted. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system. Results The association between BPH, LUTS, and sexual dysfunction is significant, with ED, ejaculatory dysfunction, and hypogonadism being common complications. Lifestyle modifications, medical therapies, minimally invasive surgical therapies, prostate artery embolization, and surgeries (eg, Transurethral resection of the prostate, HoLEP, Aquablation) are among the recommended treatments. Each intervention carries varying risks of sexual dysfunction, requiring specific tailored treatment plans. Conclusions BPH/LUTS significantly affect sexual health, emphasizing the need for a multidisciplinary approach to management. Future research should refine diagnostic criteria and develop treatments that minimize sexual side effects. Enhanced education for patients and their partners could improve quality of life and coping mechanisms.

Abstract Valvular heart disease (VHD) remains significantly underdiagnosed and undertreated. This review examines an artificial intelligence (AI)-enhanced ‘spoke–hub–node’ care model designed to improve the early detection, risk stratification, and treatment of VHD. In this model, AI tools—such as automated ECG interpretation, digital stethoscopes, and point-of-care ultrasound—facilitate decentralized screening and referral for cardiac imaging at the community level. During the transition from outpatient settings to tertiary care centres, AI-integrated echocardiography, cardiac tomography, and magnetic resonance imaging facilitate advanced diagnostic evaluation and inform procedural planning. We review emerging innovations that can enhance this model of care delivery—including unsupervised machine learning to uncover novel VHD phenotypes, generative AI for automated reporting, the use of digital twins to simulate interventions, and the integration of multiple AI agents to support heart team meetings. These advances are followed by the emerging use of AI in robotic transoesophageal and intracardiac echocardiography, as well as in fusion fluoroscopy imaging, to guide valve interventions. While outlining the challenges inherent in this rapidly evolving field, the review’s central contribution is its vision to connect the continuum—from AI-enabled community screening to personalized, image-guided therapies at tertiary care centres—offering a scalable and equitable model for VHD care.

Background: Whether there are sex and obesity differences in fat oxidation and free fatty acid (FFA) mobilization during low-intensity exercise is unclear. Methods: We studied 21 (nine females) participants without and 24 (16 females) with obesity during 5 h of treadmill walking (~2 mph). We measured energy expenditure (EE) and substrate oxidation (indirect calorimetry) and FFA-palmitate kinetics and oxidation with isotopic palmitate infusions ([U- 13 C]palmitate and [1- 14 C]palmitate or [9,10- 3 H]palmitate). Skeletal muscle samples were collected at 1.5 and 5 h of exercise and 24 h after exercise. We calculated fatty acid (FA) oxidation, palmitate rate of disappearance (Rd), and intramyocellular triglyceride-derived palmitate fractions during exercise. Results: At rest, EE was 1.24 ± 0.23 kcal/min, with FA oxidation contributing 49 ± 13% of total EE. During exercise, FA oxidation accounted for 73 ± 8% of EE, and was not different between males and females ( P = 0.34). Plasma FFA-palmitate concentrations were greater in females than males ( P = 0.003), mean palmitate Rd and plasma palmitate clearance were not different ( P = 0.32 and 0.14, respectively). Plasma FFA-palmitate Rd was correlated with EE ( r = 0.49, P = 0.001), with a proportionally greater Rd response in females ( P < 0.001). Although absolute plasma FFA-palmitate oxidation rates were comparable between sexes, the percent contribution of FFA-palmitate oxidation to EE was greater in females ( P = 0.001). During exercise, intramyocellular triglyceride-palmitate fraction amounts remained stable. Conclusions: Lipid oxidation during low-intensity exercise is similar in males and females, independent of obesity, although next-day values were greater in participants with normal weight. EE correlates with plasma palmitate disappearance rates, but is proportionally greater in females. The contribution of plasma palmitate oxidation is greater in females than in males during low-intensity exercise.

Introduction: Mass casualty incident (MCI) simulation scenarios are developed based on detailed review and planning by multidisciplinary trauma teams. This study aimed to assess the feasibility of using generative artificial intelligence (AI) in developing mass casualty trauma simulation scenarios. The study evaluated a range of mass casualty trauma simulation scenarios generated from a public generative artificial intelligence platform based on publicly available data with a validated objective simulation scoring tool. Methods: Using a large language model (LLM) platform (ChatGPT4, OpenAI, San Francisco, CA, USA), 10 complex MCI trauma simulation scenarios were generated based on publicly available US reported trauma data. Each scenario was evaluated by two Advanced Trauma Life Support (ATLS) certified raters based on the Simulation Scenario Evaluation Tool (SSET), a validated scoring tool out of 100 points. The tool scoring is based on learning objectives, tasks for performance, clinical progression, debriefing criteria, and resources. Two publicly available mass casualty trauma scenarios were similarly evaluated as controls. Revision and recommended feedback was provided for the scenarios, with review time recorded. Post-revision scenarios were evaluated. Interrater reliability was calculated based on Intraclass Correlation Coefficients (2, k) (ICCs). For the scenarios, scores and review times were reported as medians with interquartile range (IQR) as 25th and 75th percentiles. Results: Ten mass casualty trauma simulation scenarios were generated by an LLM, producing a total of 62 simulated patients. The initial LLM-generated scenarios demonstrated a median SSET score of 78.5 (IQR 74–82), substantially lower than the median score of 94 (IQR 93–95) observed in publicly available scenarios. The interrater reliability ICC for the LLM-generated scenarios was 0.965 and 1.00 for publicly available scenarios. Following secondary human revision and iterative refinement, the LLM-generated scenarios improved, achieving a median SSET score of 94 (IQR 93–96) with an interrater reliability ICC of 0.7425. Conclusions: The feasibility study suggests that a structured, collaborative workflow combining LLM-based generation with expert human review may enable a new approach to mass casualty trauma simulation scenario creation. LLMs hold promise as a scalable tool for the development of MCI training materials. However, consistent human oversight, quality assurance processes, and governance frameworks remain essential to ensure clinical accuracy, safety, and educational value.

Abstract Background Subglottic stenosis (SS) is a type of laryngotracheal stenosis defined by a location of less than 1.5 cm below the glottis or the vocal cords. Approximately 20% of cases are idiopathic. Objective We performed a systematic literature review of idiopathic subglottic stenosis (ISS) complicating pregnancy. Search Strategy PubMed, Scopus, and clinicaltrials.gov databases were queried from inception through August 10, 2023 with the following terms: idiopathic subglottic tracheal stenosis, subglottic stenosis, subglottic stenoses, tracheal stenosis, tracheal stenoses, and pregnancy. This systematic review was conducted according to the methods described in the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) guidelines for reporting systematic reviews. Selection Criteria Studies detailing cases of ISS affecting pregnancy were included and studies reporting SS in pregnancy from a known etiology were excluded. Data Collection and Analysis Our search identified 31 peer‐reviewed published cases of ISS complicating pregnancy that met the inclusion criteria. We also included two additional cases from our institution. Publication bias was checked by the Joanna Briggs Institute critical appraisal tools. Descriptive statistical analyses were performed using Excel. Main Results A majority of patients (26/33, 79%) were diagnosed with ISS during the reported pregnancy. Prior to pregnancy, 20/33 (61%) patients had a working diagnosis or reported symptoms of airway obstruction. Of these patients, 9/20 (45%) carried a diagnosis of asthma, and 6/20 (30%) carried a diagnosis of ISS. Specific symptoms prior to pregnancy were reported in 10/33 (30%) patients. The most common symptoms in these patients were dyspnea (10/10, 100%) and stridor (4/10, 40%). During pregnancy, all patients experienced worsening respiratory symptoms, with dyspnea (31/33, 94%), stridor (18/33, 55%), cough (13/33, 39%), hoarseness (7/33, 21%), and wheeze (5/33, 15%) being the most common symptoms. A total of 22/33 (67%) patients required medical and/or surgical management with dilation and/or excision during pregnancy. Postpartum outcomes were reported in 27/33 (82%) patients, and 1/27 (3.7%) required a tracheostomy immediately postpartum. The majority (18/27, 67%) of these patients required intervention postpartum, while 9/27 (33.3%) were asymptomatic. Conclusion ISS should be considered in pregnant patients with worsening respiratory symptoms despite medical management of asthma. If high clinical suspicion for upper airway obstruction exists, an otolaryngology referral for evaluation with bronchoscopy is recommended.

BACKGROUND: Chronic aortic regurgitation (AR) is associated with significant cardiac remodeling, but the prevalence and prognostic impact of extravalvular cardiac damage remain unexplored. METHODS: Adults with moderate or greater chronic AR identified on echocardiogram between January 2008 and July 2024 were included. Exclusion criteria were acute AR, hypertrophic and infiltrative cardiomyopathies, prior cardiac surgery, and valve stenosis. Cardiac damage was classified into hierarchical stages: no cardiac damage (stage 0), left ventricular damage (stage 1), moderate or greater mitral regurgitation or left atrial enlargement or atrial fibrillation (stage 2), pulmonary hypertension or moderate or greater tricuspid regurgitation (stage 3), and significant right ventricular dysfunction (stage 4). The primary outcome was the association between cardiac damage stages and all-cause mortality under medical surveillance. RESULTS: Of 4026 patients (median age, 72 [61–80] years), 78% had moderate AR, 11% had moderate-severe, and 11% had severe AR. Cardiac damage was present in 87% of patients: 14% in stage 1, 53% in stage 2, 18% in stage 3, and 2% in stage 4. In a multivariable model, including age, sex, AR severity, and Charlson Comorbidity Index, cardiac damage stages were associated with mortality. Adjusted hazard ratios were 1.42 (95% CI, 1.04–1.96) for stage 1, 1.58 (95% CI, 1.21–2.06) for stage 2, 2.78 (95% CI, 2.10–3.67) for stage 3, and 5.34 (95% CI, 3.67–7.76) for stage 4. Adding cardiac damage staging to multivariable models improved predictive accuracy for mortality, increasing the concordance statistics from 0.73 (95% CI, 0.71–0.75) to 0.76 (95% CI, 0.74–0.77). CONCLUSIONS: Cardiac damage is present in nearly 90% of patients with moderate or greater AR and is associated with increased mortality, highlighting the need for a more comprehensive evaluation of cardiac structure and function beyond the aortic valve and left ventricle.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of “Don’t eat me”–signaling genes, upregulation of many RNA genes, decreased frequency of “inflammatory” lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

ABSTRACT Enzalutamide and abiraterone are hormonal treatments that improve survival in metastatic castration‐resistant prostate cancer. Identifying genetic variants associated with the clearance of these drugs may aid in improved dosing and outcomes. We performed genetic association studies of enzalutamide and abiraterone oral clearance in the Alliance A031201 clinical trial. Genome‐wide genotyping was performed with the primary analysis limited to European‐descent participants. Pharmacogene metabolic phenotypes were estimated using PyPGx and Stargazer. Associations of metabolic activity groups for CYP3A4 , CYP3A5 , CYP2C19 and SLCO1B1 with enzalutamide clearance ( N = 706) and CYP3A4 , SLCO2B1 and UGT1A4 with abiraterone clearance ( N = 323) were tested by linear regression. Targeted SNP associations were assessed for abiraterone clearance at loci proximal to major metabolizing genes. Full genome‐wide association studies were performed for both sets of clearance values. No significant associations were identified between metabolic phenotypes and enzalutamide or abiraterone oral clearance SNPs in the SULT2A1 5′ flanking region were significantly associated with lower abiraterone clearance, (rs296373, minor allele frequency = 0.15, β = −0.457, p = 3.2E‐06). Liver protein and liver and adrenal gland gene expression QTL databases indicated significantly lower SULT2A1 expression patterns for individuals carrying associated alleles, likely explaining the lower abiraterone oral clearance. CYP2C8*3 was associated with higher enzalutamide clearance ( p = 0.012), but this was not significant after correction for multiple testing. This study is the first to identify the genetic association of SULT2A1, known to be involved in the metabolism of steroids in the liver and adrenal glands, with abiraterone clearance. Genetic variation in SULT2A1 may be useful to inform personalized dosing of abiraterone. ClinicalTrials.gov Identifier: NCT01949337