Citations

Background: Despite guideline support for plain radiography (XR) in low-risk pediatric blunt trauma, CT remains the predominant imaging modality for cervical spine evaluation, increasing radiation exposure. We evaluated contemporary XR utilization and its diagnostic performance in children meeting consensus criteria for XR-first imaging. Study Design: We performed a prospective, multicenter observational study of 19,995 children enrolled in the Western Pediatric Cervical Spine Study across 72 U.S. trauma centers (2022–2025). Children appropriate for XR screening (Glasgow Coma Scale score >13, asymptomatic, non-obtunded) were identified using consensus criteria. XR utilization, sensitivity, and negative predictive value (NPV) were assessed, and multivariable logistic regression identified predictors of XR use. Results: XR was performed in 39% of patients overall and varied significantly by trauma center type (pediatric 48% vs adult 14% vs mixed 15%; p<0.001), whereas CT was used in 60%. Among XR-appropriate children (n=12,650), an estimated 7,705 CT examinations could potentially have been replaced with XR. In the overall cohort, XR sensitivity for any cervical spine injury was 30.3% (95% CI 26.2–34.6%) with an NPV of 95.2% (95% CI 94.7–95.7%). In XR-appropriate children, only two clinically significant cervical spine injuries were missed, yielding a sensitivity of 75.0% (95% CI 34.9–96.8%) and an NPV of 99.9% (95% CI 99.9%–100.0%). Conclusions: Plain radiography is substantially underutilized in children meeting consensus criteria for XR-first imaging. In appropriately selected patients, XR demonstrated an NPV of 99.9% for clinically significant cervical spine injury, supporting broader implementation of XR-first imaging strategies to reduce CT utilization and pediatric radiation exposure.

Abstract Objective. Proton minibeam radiation therapy (pMBRT) is a novel spatially fractionated radiation therapy technique that offers improved tumor control and reduced normal tissue toxicity. However, its clinical translation has been hindered in part by limited field sizes, low dose rates, and complex manufacturing. This work describes the design, manufacturing, and commissioning of a novel divergent pMBRT collimator along with accessory components to maximize its versatility and facilitate clinical implementation. Approach. The dosimetric outcomes for pMBRT collimator geometry, including slit width, center-to-center (CTC) spacing, thickness, divergence, and field size, were evaluated using TOPAS Monte Carlo (MC) to maximize surface peak-to-valley dose ratio (PVDR) while maintaining uniform target coverage. The collimator was constructed using brass plates held by aluminum side holders. Commissioning measurements with a PTW Bragg peak chamber and EBT4 radiochromic film were compared to TOPAS and an in-house fast GPU-based MC simulation. Ancillary equipment consisting of lead foils, range shifters, custom apertures, and secondary pMBRT collimators were characterized in tandem. Main results. An optimized divergent pMBRT collimator with 0.5 mm slit width, 2.0 mm CTC distance, and 40 mm thickness produced a surface PVDR of 4.8 while preserving quasi-homogeneous dose in the 6–14 cm depth region. Measured dose profiles demonstrated valley dose agreement within 3% for both TOPAS and GPU-based MC predictions after the simulated collimator geometry was refined to match Bragg-peak chamber average dose measurements. The onset of the quasi-homogeneous dose region was shifted toward shallower depths by using thin lead foils, without significantly impacting entrance PVDR. Apertures sharpened penumbra and enhanced peripheral PVDR. A dual collimator approach produced 2D pinhole dose arrays that resulted in valley doses from MC simulations and film measurements agreeing within ∼5%. Significance. We demonstrated a practical low-cost, large-area divergent physical pMBRT collimation system with validated MC modeling. In addition, we introduce complementary accessories that substantially expand system versatility to facilitate clinical implementation.

Fibrous dysplasia (FD) is a benign bone neoplasm often considered a disease of childhood, with existing literature suggesting lesions typically become quiescent by young adulthood. Consequently, the presentations and surgical outcomes of adult patients remain poorly characterized. This retrospective review analyzed 50 adult patients treated surgically for craniofacial FD at a single institution between 1988 and 2024 to evaluate patterns of presentation, operative indications, and long-term outcomes. The cohort (54.0% male) had a mean follow-up of 15.8 years. Polyostotic involvement was present in 60.0% of patients, and the frontal bone was most affected (51.2%). The median age at presentation was 31 years, and the median age at initial surgery was 34.5 years. The most common surgical indications were visible growth (30.5%) and pain or headache (27.1%). Of the 59 surgeries performed to directly treat FD, bone contouring only was the most common initial operative approach (n=42), followed by en bloc resection and reconstruction (n=7). However, 12% of patients undergoing initial contouring required additional operations for continued growth. All secondary deformities requiring corrective surgery were ocular. In addition, several patients demonstrated delayed recurrence or progression decades after primary surgical intervention. These findings suggest that craniofacial FD may remain symptomatic or continue to progress into adulthood, challenging the traditional paradigm that these lesions necessarily become quiescent after skeletal maturity and highlighting the importance of long-term surveillance in the adult population.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Background Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored. Methods Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers. Results Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions. Conclusions This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

Abstract Rationale To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Methods PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), MassGeneral Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012). Results PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764; ECLIPSE: NCT00292552. This abstract is funded by: NIH and the COPD Foundation

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