Citations

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Importance Sex-related disparities affect diagnosis, referral, and prognosis of aortic valvular diseases. Contemporary US data on transcatheter aortic valve implantation (TAVI) by sex are limited. Objective To characterize 10-year trends in TAVI use, periprocedural complications, and long-term outcomes among Medicare beneficiaries, stratified by sex. Design, Setting, and Participants This nationwide, retrospective, population-based cohort study used US Medicare claims data from fee-for-service beneficiaries discharged after TAVI from January 1, 2013, to December 31, 2022. The median follow-up time was 2.19 (IQR, 0.94-3.79) years. Exclusions included patients who had concomitant valve surgery, infective endocarditis, valve-in-valve TAVI, transapical TAVI, TAVI for pure aortic insufficiency, or later conversion to Medicare Advantage. Analyses were conducted between October 1, 2024, and April 1, 2025. Exposure TAVI. Main Outcomes and Measures The primary outcome was all-cause mortality. Secondary outcomes included periprocedural mortality, vascular complications, acute kidney injury, major or life-threatening bleeding, stroke, acute myocardial infarction (AMI), permanent pacemaker implantation (PPI), and hospitalization for heart failure (HF). Adjusted odds ratios (AORs) and hazard ratios (AHRs) with 95% CIs were estimated. Results The study included 314 123 patients (141 233 women [45.0%] and 172 890 men [55.0%]). Women were older than men (mean [SD] age, female: 80.3 [7.8] years; male: 79.4 [7.7] years; standardized mean difference, 12%). The proportion of female patients who underwent TAVI declined from 47.6% in 2013 to 43.6% in 2022 ( P < .001). Compared with men, women had higher periprocedural mortality (2.5% vs 2.2%; AOR, 1.20 [95% CI, 1.14-1.26]), vascular complications (5.8% vs 3.6%; AOR, 1.65 [95% CI, 1.60-1.71]), and bleeding (10.4% vs 6.8%; AOR, 1.67 [95% CI, 1.62-1.71]) but less PPI (16.9% vs 20.0%; AOR, 0.81 [95% CI, 0.79-0.82]). Long-term mortality was lower in female patients (AHR, 0.92; 95% CI, 0.91-0.93), although their risks of HF hospitalization, AMI, stroke, and bleeding were higher. Conclusions and Relevance Among Medicare beneficiaries, women constituted a progressively declining proportion of patients treated with TAVI, experienced more periprocedural complications, and demonstrated modestly better long-term survival compared with men. Further work is needed to understand factors influencing these trends and to refine sex-specific strategies for optimal outcomes.

Abstract Aims To compare the prevalence of autism spectrum disorder (ASD) in children with and without epilepsy using clinical diagnoses and chart review with research‐defined criteria and to examine sex ratios, age at ASD onset, and intellectual disability between groups. Method The Olmsted County birth cohort included 30 490 individuals, of whom 257 (0.84%) had epilepsy diagnosed before 19 years of age. The cohort was previously screened for ASD using three case definitions: research‐inclusive (ASD‐R I ), research‐narrow (ASD‐R N ), and clinically diagnosed ASD (ASD‐C). For those with ASD‐R I , we assessed sex, intellectual disability (IQ < 70), and age at ASD onset. Means and proportions are reported when available. Results ASD prevalence was significantly higher in participants with epilepsy across all definitions: ASD‐R I 21.4% versus 3.2%; ASD‐R N 14.0% versus 1.6%; and ASD‐C 7.9% versus 0.7%. Children with both epilepsy and ASD‐R I were more often female (38.2% vs 25.8%), had higher rates of intellectual disability (56.5% vs 15.4%), and met the ASD‐R I criteria at a younger age (mean 7 years 5 months vs 8 years 8 months). Interpretation Co‐occurring ASD and epilepsy are frequently associated with intellectual disability, earlier age at ASD diagnosis, and reduced male predominance.

Abstract Background and aims Interfacility transfers in rural areas are challenging due to limited ambulance and bed availability, image sharing issues, and access disparities. Regional transfers to strategically located primary stroke centers can reduce time to care, decrease helicopter use, support local economies, and conserve comprehensive stroke center (CSC) resources. This study established a primary stroke center as a regional transfer center (rSTC) within a telestroke network. Methods Over one year, stakeholders created regionally appropriate transfer workflows defined as patients without large vessel occlusion, low likelihood for neurosurgical decompression or critical illness within a rSTC and 4 surrounding centers. Continuous education and prospective case logs were maintained by the rSTC stroke coordinator and a retrospective chart review was conducted one year following the intervention period. Results Of 99 patients requiring transfer, 73 (73.7%) went to the rSTC, with an average stay of 2.1 days, no deaths, and no secondary CSC transfers. The remaining 26 (26.3%) were sent to the CSC, with longer stays (10.6 days) and higher mortality (23.1%). Transfers to the rSTC were faster (60 min vs. 188 min). Financial analysis showed significant EMS savings ($455,111) and local health system benefits ($730,000) when compared to the pre-intervention period. Conclusions Establishing an effective regional transfer model is possible with broad stakeholder engagement and regular network maintenance. rSTCs provide the right level of care for the right patient, improving efficient allocation of healthcare resources and avoiding futile transfers with costly admissions far from home while opening beds and reducing transfer times to CSCs. Conflict of interest Nothing to disclose

Study Design. Subanalysis of a prospective, multicenter, observational study at 72 US adult, pediatric, and mixed trauma centers. Objective. We investigated trauma-related risk factors and patient-level factors associated with multiregional spinal column injury, defined as cervical spine injury (CSI) requiring treatment and thoracolumbar injury (TLI). Summary of Background Data. Traumatic spinal injury causes morbidity and mortality in pediatric patients. Injuries to multiple spinal column regions require early identification and thoughtful management. Methods. All children <18 years undergoing cervical spine evaluation after blunt multisystem trauma were prospectively identified and enrolled. Clinically significant CSI was defined by cervical spine surgery or halo placement. TLI incidence and management was recorded. The primary outcome was multiregional spinal column injury (CSI+TLI). Results. Of 19,651 enrolled patients, 1484 children (7.5%) experienced a TLI, 159 (0.81%) had CSI requiring treatment, and 30 (0.15%) had CSI+TLI. Multivariate analysis revealed that the trauma-related factors mechanism of injury ( P <0.001), rib fractures (odds ratio (OR) 2.8 [2.3-3.4]), hemothorax/pneumothorax (OR 2.0 [1.7-2.4]), bowel injury (OR 4.0 [2.9-5.4]), pelvic fracture (OR 1.5 [1.2-1.9]), and clinically significant CSI (OR 1.9 [1.2-2.9]) were independently associated with TLI. Of the 159 children with clinically significant CSI, 30 also experienced TLI (19%). Multivariate analysis identified prehospitalization intubation (OR 3.1 [1.1-8.4]) and rib fractures (OR 3.9 [1.2-12.8]) as independent associations with CSI+TLI. Conclusions. Of children with CSI requiring treatment, 19% experienced TLI. MOI and various trauma-related injuries were independently associated with TLI, whereas prehospitalization intubation and rib fractures were independent risk factors for CSI+TLI. These factors should trigger screening for multiregional spinal column injury in pediatric trauma patients. Furthermore, if there is known TLI, the cervical spine should be evaluated, and if there is significant CSI, then dedicated imaging of the thoracic and lumbar spine is indicated. Level of Evidence. III

Compared with two-dimensional MR elastography (MRE), three-dimensional MRE demonstrated better test-retest repeatability, between–field-strength reproducibility, and between-day reproducibility at 3 T for measurement of liver stiffness in adults with severe obesity but failed more frequently.

Abstract INTRODUCTION : Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early‐onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well‐characterized sample with sporadic EOAD. METHODS : Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early‐onset non‐AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS : After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p‐tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non‐amnestic cognitive impairment across the sample. DISCUSSION : These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD‐specific and non‐specific plasma markers may play across the course of AD care.

ABSTRACT Pharmacy preceptors are central to experiential learning, yet there is a lack of guidance on how to integrate generative artificial intelligence (GenAI) into precepting. This paper serves as a practical “how‐to” resource, offering actionable strategies and examples to help preceptors implement GenAI into clinical education. Based on examples from multiple institutions and the best available literature in pharmacy practice and education, we outline step‐by‐step approaches for designing learning activities, adapting assessment methods, and modeling effective artificial intelligence (AI) use, with a focus on optimizing learner engagement, personalizing instruction, cultivating critical thinking, and building AI literacy. Implementation guidance includes creating transparent AI use policies, safeguarding confidentiality, preventing deskilling, and embedding GenAI into feedback and evaluation processes. By incorporating these recommendations, preceptors can augment experiential education into a setting where learners can explore GenAI applications and build the judgment required to use AI responsibly in pharmacy practice.

The persistent shortage of allogenic donor organs has driven the exploration of xenotransplantation as a viable alternative for patients with end-stage liver disease. This review investigates the progress and challenges in liver xenotransplantation, focusing on the use of genetically engineered animals, particularly pigs, as potential organ donors. This narrative review discusses various sources of xenografts, highlighting their advantages and limitations, and provides a historical overview of liver xenotransplantation, encompassing both clinical and experimental experiences. Key obstacles, such as immunological rejection, coagulation dysfunction, and the risk of zoonotic infections, are analyzed, with emphasis on how these challenges have been addressed through genetic modifications and adjunctive therapies. Recent clinical trials are also reviewed, offering insights into the outcomes and lessons learned from these pioneering efforts. We also explored the regulatory, legal, and ethical considerations critical to advancing liver xenotransplantation into clinical practice, along with future perspectives on the field’s evolution. This comprehensive overview aims to provide a clear understanding of the current state of liver xenotransplantation and the strategies being developed to overcome existing barriers, paving the way for future clinical applications.