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Importance Trimodal therapy (TMT) is included as an alternative to radical cystectomy (RC) for definitive management of muscle-invasive bladder cancer (MIBC) in current clinical guidelines. Moreover, a 2023 retrospective analysis reported similar oncologic outcomes between these treatments among patients deemed fit for RC. Data regarding the comparative value of these treatments are lacking. Objective To evaluate the comparative cost-effectiveness of TMT and RC for treatment of MIBC. Design, Setting, and Participants This economic evaluation compared cost-effectiveness of treatments using a health transition state microsimulation model of patients with bladder cancer treated between 2005 and 2017 with 5- and 10-year horizons from a Medicare perspective. Model probabilities were informed by multicenter retrospective analyses published in 2023 comparing TMT with RC. The index patient was aged 71 years, with clinical stage T2-4aN0M0 MIBC, solitary tumor smaller than 7 cm, no or unilateral hydronephrosis, adequate bladder function, and lack of multifocal or extensive carcinoma in situ. Patients unfit for RC, radiation, or cisplatin-based chemotherapy were excluded. Exposures TMT and RC. Main Outcome and Measures Primary outcomes included effectiveness measured in quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) using a willingness-to-pay threshold of $100 000 per QALY. Sensitivity analyses were performed to assess the robustness of the model. Results For the index patient, at 5 years, the average cost was $30 525 higher for TMT than RC. Average QALYs were 3.87 and 3.94 for RC and TMT, respectively. As such, TMT was not cost-effective at 5-year (ICER, $464 291 per QALY) or 10-year (ICER, $308 638 per QALY) time horizons. On 1-way sensitivity analyses, TMT would become cost-effective if (1) TMT costs were less than $17 605; or (2) TMT resulted in an 11.6% improvement in metastasis-free survival relative to RC. Conclusions and Relevance In this economic evaluation study of TMT and RC for treatment of MIBC, TMT was associated with improved quality of life but was not cost-effective relative to RC at 5 and 10 years given higher treatment costs. These findings highlight the importance of developing policy initiatives that help reduce TMT costs and of providing patients with accurate expectations of long-term toxic effects to help guide preference-sensitive care.

Importance The APOE ε4 variant is causally linked to cerebral amyloid angiopathy and is a risk factor for intracranial hemorrhage (ICH) among warfarin-treated patients with atrial fibrillation. Nevertheless, its impact on those treated with apixaban remains unknown. Objective To test the hypothesis that APOE ε4 allele carriership is associated with an increased risk of ICH in patients with atrial fibrillation taking apixaban. Design, Setting, and Participants This cohort study involved data from the All of Us Research Program, a longitudinal, population-based study in the United States. Inclusion criteria were age older than 50 years, history of atrial fibrillation, and anticoagulation with apixaban. Participants with a history of ischemic stroke or ICH were excluded. Up to 3 years of follow-up data were available. Data were collected from 2017 to 2022 and analyzed from November 2023 to December 2024. Exposure APOE ε2, ε3, and ε4 were ascertained using variants rs429358 and rs7412. APOE ε4 was modeled dichotomously (noncarriers [no alleles] vs carriers [1 or 2 alleles]). Main Outcomes and Measures Incident ICH, including any new intraparenchymal, subdural, or subarachnoid hemorrhage after initiation of apixaban therapy. Results Of 413 477 All of Us participants, 2038 were eligible. Their mean (SD) age was 71 (9) years; 918 (45%) were female, 1120 (55%) were male, and 1710 (83%) had European ancestry. Among these participants, 483 (23.7%) were carriers of at least 1 APOE ε4 allele. After a median follow-up of 2.9 years, 26 participants sustained an ICH (cumulative incidence, 1.5%; 95% CI, 1.0%-2.2%), of whom 12 (cumulative incidence, 3.1%; 95% CI, 1.7%-5.3%) were carriers and 14 (cumulative incidence, 1%; 95% CI, 0.6%-1.7%) were noncarriers ( P = .007). Multivariable Cox proportional hazard models confirmed this association: compared with noncarriership, APOE ε4 carriership was associated with a 3-fold increase in the risk of ICH (hazard ratio, 3.07; 95% CI, 1.42-6.65). APOE information improved the discrimination of risk prediction scores (C statistic of 0.74 and 0.68 for models with and without APOE , respectively; P = .03). Conclusions and Relevance Further research is needed to evaluate whether cerebral amyloid angiopathy mediates the observed association and whether APOE e4 information improves clinical decision-making about anticoagulation therapy in patients with atrial fibrillation. The latter is important now that APOE information is used in clinical settings to guide antiamyloid treatment for Alzheimer disease and has been returned to millions of persons by direct-to-consumer genotyping companies.

ABSTRACT Background and Aims Out‐of‐hospital cardiac arrest stands as the primary cause of worldwide mortality. Therefore, all healthcare workers must comprehensively understand and practically apply cardiopulmonary resuscitation (CPR). To address the paucity of literature on this subject, we conducted a nationwide survey among healthcare professionals in Pakistan. Methods This nationwide cross‐sectional study was based on an online questionnaire. The sample pool comprised healthcare professionals and medical students from all over Pakistan. The survey comprised 18 questions aimed to assess the comprehension of CPR, determine the source of their basic life support (BLS) training, and evaluate their competence in performing CPR in real‐life situations. Results The sample size consisted of 951 participants from Pakistan. A total of 712 responders (75%) reported having received CPR or CPR with an Automated External Defibrillator (AED) course, and the same percentage reported that their respective universities had organized the course. The responders reported that the BLS course was made mandatory in only 60% of cases. Most of the respondents were first‐year medical students (21%) and postgraduates (21%). Most of the respondents (78%) professed that the courses had been theoretical as well as practical, and 66% felt confident enacting CPR in out‐of‐hospital settings. Overall, no province was able to achieve a score of greater than 50% when assessed about their knowledge regarding cardiac arrest and CPR. Conclusion This study provides a detailed insight into Pakistan healthcare workers' CPR knowledge and perceptions belonging to different provinces, institutes, designations, and specialties. The participants reported being confident in performing CPR but demonstrated gaps when assessed regarding the revised guidelines and their performance in different scenarios. There is room for further research in overcoming the language barriers and other discrepancies faced by this study.

ABSTRACT Cardiogenic shock (CS) remains a high morbidity and mortality condition worldwide frequently complicating acute myocardial infarction (AMI) and decompensated heart failure (HF). Within the management of CS, mechanical circulatory support (MCS) devices play a critical role in maintaining hemodynamic stability, preserving end‐organ perfusion and bridging patients through to recovery, implantation of durable support or transplantation. Despite their use, optimal timing of initiation, as well as patient and device selection remain unclear. This review explores the current landscape of MCS devices, surrounding evidence and key distinctions between devices. With increasing acknowledgment for the heterogeneity of CS, understanding the strengths and limitations of each device remains crucial to improving outcomes in this high‐risk population.

AbstractPurposeWhile standard MR elastography (MRE) uses harmonic mechanical waves, there are some applications in which imaging and analysis of transient mechanical motion are of interest. Wavelet MRE has been developed for detecting broadband motion from transient excitation. The goal of this study was to evaluate the accuracy and efficiency of wavelet MRE for transient displacement detection in brain MRE applications.MethodsTransient motion was induced in a gel phantom, while MRE images were acquired using bipolar motion‐encoding gradient (MEG) at multiple frequencies (20–200 Hz). Displacements were estimated using (1) combinations of multiple MEGs forming the wavelet MRE and (2) deconvolution from a single MEG. These estimated displacements were used to calculate the MRE phase for each MEG. Correlation (r2) between the calculated and acquired phases was evaluated.Three healthy volunteers were scanned twice in a clinical scanner using wavelet MRE with an occipital impact. Time‐resolved brain translation, rotation, and maximal principal strain were calculated. Repeatability was assessed both qualitatively and through Pearson correlation.ResultsWavelet MRE outperformed standard MRE in displacement estimation, showing higher correlations between calculated and acquired phase, even with fewer phase offsets. In the volunteer study, consistent temporal motion dynamics and spatial maximal principal strain distributions across repeated scans demonstrated the repeatability of wavelet MRE.ConclusionThis study validated the accuracy and efficiency of wavelet MRE for broadband motion detection and demonstrated its feasibility and repeatability in vivo. This technique shows promise for advancing our understanding of the injury risks and mechanisms associated with sports‐related head trauma.

Objective Motor neuron disease (MND) is a progressive neurological disorder with no known cure that damages motor neurons. The purpose of this analysis is to examine the place of death for MND patients in the United States during the coronavirus disease 2019 (COVID-19) pandemic and to investigate the extent of specific comorbidities. Methods We obtained death certificate and associated comorbidities data for all U.S. MND deaths from 2018 to 2021 and conducted a population-based cross-sectional analysis of the deaths pre-COVID-19 (2018-2019) and during COVID-19 (2020-2021). We hypothesized that place of death and comorbidities associated with place of death for MND patients in the United States were altered during the COVID-19 pandemic in comparison to the 2 years period before the pandemic. Results We analyzed 30 066 MND deaths (14 562 pre-COVID-19 and 15 504 during COVID-19) aged 20 years and older. During COVID-19, MND deaths at home increased (54.4% vs 45.5% pre-COVID). Hispanic individuals had an increased likelihood of dying at home compared to a nursing home or hospice (OR = 1.57, 95%CI: 1.22-2.02), but a decreased likelihood compared to a hospital (OR = 0.61, 95% CI: 0.51-0.72). Among the top comorbidities listed, there was a 27.8% increase in diabetes mellitus and a 20.2% increase in essential hypertension during COVID-19. During COVID-19, diabetes mellitus was more commonly reported as a comorbidity for deaths occurring in hospitals (OR = 1.40, 95%CI: 1.03-1.89) or at home (OR = 1.26, 95%CI: 1.03-1.55), while essential hypertension was more commonly reported with deaths at home (OR = 1.17, 95%CI: 1.01-1.36). Conclusion Our analysis showed an increase in at-home MND deaths as well as certain comorbidities during the COVID-19 pandemic, suggesting MND patients had a higher likelihood of death from non-COVID-19 comorbidities.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

ABSTRACTVarious cutaneous adnexal neoplasms have been associated with gene fusions as the main driver of their histogenesis, most of which showed poroid or hidradenomatous differentiation or represented other tumors of sweat glands. Recently, we encountered two cases of primitive basaloid neoplasms of predominantly folliculogenic/pilosebaceous origin, both surprisingly harboring recurrent EWSR1 rearrangements. Both tumors presented in young patients of either sex (1 F; 17 years; 1 M; 37 years) and involved the dermis and subcutaneous tissue of the abdominal wall (case 1) and the buttock (case 2). Histologically, the tumors were composed of primitive, basaloid cells with areas of keratinization (case 1) or foci of sebaceous differentiation (case 2) and stained strongly with keratins, p40 (case 1) or p63 (case 2), while lacking significant CD99 expression in both cases. Case 1 harbored an EWSR1::FLI1 fusion while case 2 harbored an EWSR1::PBX3 fusion. Clinical follow‐up was available for case 2 and showed no evidence of disease at 15 months of follow‐up. Methylation profiling showed case 1 to cluster with cutaneous squamous cell carcinoma, while case 2 was independent but positioned close to salivary gland epithelial‐myoepithelial carcinoma. These findings expand on the histopathologic and molecular genetic features of basaloid tumors with apparent adnexal differentiation and raise awareness to carefully interpret and correlate molecular findings with morphology and immunophenotype to avoid misinterpretation as a mesenchymal neoplasm.