Citations

Objective: The identification of reliable biomarkers in trauma patients (pts) remains a clinical challenge. Nucleosomes, which are DNA wrapped around histone protein cores, have been used as reliable markers for quantification in sepsis, acute respiratory distress syndrome, and lymphoma. We hypothesized that: 1) levels of circulating nucleosomes quantified after traumatic injury, specifically histone H3.1 and its citrullinated R8 posttranslation modification (H3R8 Cit), would be increased after trauma and 2) that levels of circulating nucleosomes would be further, increased in pts who went on to develop venous thromboembolism (VTE), as these nucleosomes may be clot-enhancing mediators. Methods: Trauma pts presenting to a Level I trauma center were evaluated for inclusion in a prospective case-cohort study, and citrated blood samples were collected within 12 hours of injury. Pts were followed for up to 90 days and VTE occurrence was confirmed via autopsy or imaging. Pts who developed incident, symptomatic VTE, and those who did not develop VTE were selected at a 1:3 ratio. The effect of trauma was assessed by comparison with healthy volunteer samples. Circulating nucleosomes were quantified using Nu.Q H3.1 and Nu.Q H3R8 Cit assays. Data are presented as median [interquartile range] or n (%), with Wilcoxon Rank-Sum or chi-squared test performed between trauma pts who developed symptomatic VTE versus those who did not, with a P value < 0.05 as statistically significant. Results: A total of 639 trauma pts were analyzed [51 years (33, 65), 71.0% male, 94.1% blunt, injury severity scores 17 (9, 27)]. Both H3.1 [359.7 (58.4, 1769.3) vs. 21.5 (15.3, 26.6) ng/mL, P < 0.001] and H3R8 Cit levels [209.4 (45.4, 665.5) vs. 22.3 (16.2, 28.9) ng/mL, P < 0.001] were greater in trauma pts than in 10 healthy volunteers. The 160 pts with VTE were then compared with 479 without VTE. VTE pts had a median time to VTE of 8.5 days, with 91 developing symptomatic deep venous thrombosis, 48 with pulmonary embolism, and 21 with both deep venous thrombosis and pulmonary embolism. No significant differences were found in age, sex, or mechanism between pts with or without VTE. However, VTE pts had higher injury severity scores [24 (14, 34), 14 (9, 24), P < 0.001] and body mass index [29.1 (24.3, 34.2), 27.6 (24.2, 32.0) kg/m 2 , P = 0.037]. A greater percentage of VTE pts underwent surgery requiring general anesthesia (53.1%, 34.0%, P < 0.001) and received blood transfusions within 24 hours of injury (51.9%, 24.0%, P < 0.001). H3.1 levels were significantly greater in trauma pts who developed VTE compared with those who did not [828.4 (112.0, 3186.5), vs. 276.7 (50.3, 1237.0) ng/mL, P < 0.001], as were H3R8 Cit levels [350.4 (77.4, 729.5), vs. 189.2 (40.8, 632.6) ng/mL, P = 0.005]. No differences in levels of H3.1 and H3R8 Cit were found between early (diagnosed day 0–7 after injury) and late (diagnosed > day 7) VTE. Conclusions: Levels of the H3.1 and H3R8 Cit nucleosomes are elevated early after traumatic injury, especially in those who developed VTE. These findings underscore the importance of understanding the pathophysiology of nucleosomes in inducing VTE and their role as biomarkers

Background: Sinonasal malignancies (SNM) are rare cancers associated with poor prognosis and impaired quality of life (QOL). The 22-question Sino-Nasal Outcome Test (SNOT-22) has been used to assess QOL in patients with SNM. Objective: To determine the minimal clinically important difference (MCID) for the SNOT-22 in patients with SNM. Methods: About 264 patients with SNM were drawn from a prospective, longitudinal, multi-institutional study. SNOT-22 scores were collected at pre-treatment baseline and follow-up through 5 years post-treatment. Cronbach’s alpha was used to assess the internal consistency of the SNOT-22. Distribution-based approaches were used to estimate the MCID. Multivariable regression identified factors associated with SNOT-22 improvement exceeding the determined MCID. Results: Cronbach’s alpha was >.85. The estimated MCIDs were: 1.44 (Cohen’s effect size), 1.32 (standard error of the mean), 10.45 (1/2 of baseline standard deviation), and 3.67 (minimum detectable change). The mean MCID across methods was 4.22. Multivariable regression demonstrated higher odds of clinically meaningful improvement from baseline in patients with early-stage disease (odds ratio (OR) 3.510, P = .035), no neck irradiation (OR 11.050, P = .014), and neoadjuvant therapy (OR 16.667, P = .047). Conclusions: The SNOT-22 MCID was estimated as 4.22 in a large multi-center cohort of patients with SNM, suggesting that relatively small QOL changes are clinically relevant. When applying the MCID to the current cohort, advanced stage, treatment of neck disease, and not requiring neoadjuvant therapy were predictive of worse QOL.

Case: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification. Scoliosis may develop and progress rapidly, especially during adolescence. We report 4 patients with FOP and scoliosis during early adolescence: A 12-year-old girl underwent T4-S2 posterior spinal fusion (PSF); another 12-year-old girl underwent T4-S2 PSF; a 13-year-old boy underwent T3-L4 PSF; and a 14-year-old girl was managed nonoperatively because the complex deformity and ankylosed shoulders could not be adequately balanced with surgery. Conclusion: In patients with FOP, surgical intervention can reduce thoracic deformity and improve pulmonary function but carries substantial risks, including heterotopic ossification.

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 Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Background Flow‐related ghost artifact from a 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence results from unsaturated magnetization of incoming arterial flow. This is especially common on MR scanners equipped with smaller radiofrequency (RF) transmit coils. A high‐performance compact 3T (C3T) scanner features a smaller RF‐transmit coil (inner diameter 37 cm, length 40 cm), leading to a rapid fall‐off of the B1 field below the neck. This configuration results in more intense flow‐related ghost artifacts, especially in younger patients. Purpose The C3T scanner's smaller RF‐transmit coil provides RF field coverage over the brain region, causing bright in‐flow arterial signals and flow‐related artifacts in the conventional 3D‐MPRAGE scans. The purpose of this study is to suppress these artifacts by adding a RF saturation band (RFSB) pulses to the 3D‐MPRAGE sequence. Methods The RFSB was added to the 3D‐MPRAGE sequence as a preparation pulse option. To test the effectiveness, 37 subjects were scanned on the C3T under an IRB‐approved protocol using 3D‐MPRAGE with and without RFSB. Ten of those subjects underwent repeated scans with and without RFSB to evaluate test‐retest reliability. A consensus evaluation by two neuroradiologists was performed on all data to compare signal to noise ratio, image contrast, presence of artifacts, and diagnostic confidence. Quantitative analysis included calculating test‐retest differences by image subtraction and evaluating the variance in flow‐artifact‐induced image intensity between the scans with and without RFSB. Additionally, one subject was scanned on a whole‐body 3T scanner using a transmit/receive (T/R) head coil to demonstrate the method's applicability across different MRI platforms as a proof of concept. Results The Wilcoxon signed‐rank test of the neuroradiologist evaluations showed a significant reduction in artifacts and an improvement in diagnostic confidence in the posterior fossa region with and without RFSB ( p < 0.0001). Test–retest analysis showed that adding RFSB significantly reduced image intensity variability in the cerebellum, even among subjects without visible flow artifacts. The normalized difference decreased from 8.71% to 6.41% ( p = 0.0059), suggesting improved image reliability in regions prone to flow‐related artifacts. Additionally, similar findings were observed in scans on a whole‐body 3T with a T/R head coil, demonstrating the broader applicability of this method. Conclusion Incorporating RFSB into 3D‐MPRAGE scans effectively reduces flow‐related ghost artifact on the C3T scanner, improving image quality and diagnostic confidence. These findings suggest that the proposed method could be widely implemented across MRI systems utilizing a smaller RF‐transmit coil.

Background/objectives: Falls are a leading cause of traumatic injury and hospitalization for adults over the age of 65. While common, bed-related falls are relatively understudied when compared to ambulatory falls. The aim of this study is to characterize the risk factors for the hospitalization of older adults presenting to U.S. emergency departments (EDs) after a fall from bed. Methods: This was a cross-sectional study using publicly available data from the U.S. Consumer Product Safety Commission’s National Electronic Injury Surveillance System (NEISS) from 2014 to 2023, including all adults over the age of 65 presenting to the NEISS’s participating EDs with bed-related fall injuries. We identified fall injuries using a keyword search of the NEISS narratives and determined how the fall occurred by manually reviewing a randomized 3% sample of the narratives. We summarized demographics and injury patterns with descriptive statistics. We constructed a multivariable logistic regression model to identify risk factors for hospitalization and used Poisson regression to assess temporal trends in fall incidence and hospital admissions. Results: An estimated average of 320,751 bed-related fall injuries presented to EDs annually from 2014 to 2023. ED visits increased by 2.85% per year, while hospital admissions rose by 5.67% per year (p < 0.001). The most common injury patterns were superficial injuries (contusions, abrasions, lacerations, avulsions, and punctures) (28.6%), fractures (21.7%), and internal injuries (including concussions) (21.6%). Most of the falls occurred while transitioning into or out of bed (34.4%) or falling out of bed (56.8%). Hospitalization was required in 34.1% of cases and was associated with male sex, medication use at time of injury, and fracture injuries. Conclusions: Bed-related falls and associated hospitalizations are increasing among older adults. ED providers should understand risk factors for hospitalization in these common injuries such as male sex, medication use at time of injury, and high-risk injury patterns. Additionally, prevention efforts should focus on helping older adults remain safely in bed and then assisting with transitions into or out of bed.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

8513 Background: The MET pathway is a known mediator of EGFR-TKI resistance and represents a therapeutic vulnerability to select MET-TKIs. Savo is an oral, highly selective MET-TKI that, when combined with osi, has the potential to overcome MET-driven resistance after progressive disease (PD) on osi. The Phase 2 SAVANNAH study has demonstrated clinically meaningful activity with the combination of savo + osi in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC and MET overexpression/amplification (NCT03778229). Isolating the efficacy of savo in the use of savo + osi is a key question for this combination. Methods: A subset of SAVANNAH included eligible pts who had EGFRm advanced NSCLC with MET overexpression (IHC 3+ intensity in ≥90% of tumor cells [IHC3+/≥90%]) and/or amplification (≥10 MET gene copies by FISH [FISH10+]) after PD on first-line (1L) osi; asymptomatic stable brain metastases (treated/untreated) were allowed. Pts were randomized 2:1 (double-blind) to savo 300 mg BID + osi 80 mg QD, or savo 300 mg BID + PBO (stratified by investigator [INV] assessed baseline [BL] brain metastases [yes/no]), until INV-assessed PD per RECIST 1.1. Brain imaging occurred at BL and PD; pts with brain metastases were re-imaged at each tumor assessment to PD. Endpoints included objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) by BICR and INV; CNS PFS, and presence/absence of CNS lesions at PD by BICR. Results: Overall, 73 pts were randomized (savo + osi n=48; savo + PBO n=25). At BL, median age: 67 vs 65 years, female: 73% vs 64%, White: 73% vs 52% in the savo + osi and savo + PBO arms, respectively. Efficacy outcomes (ORR, DoR, and PFS) were higher with savo + osi than savo + PBO (Table). CNS PFS events by CNS BICR occurred in 5/14 (36% savo + osi) and 2/4 pts (50% savo + PBO). In pts without BL brain metastases, none of the 13 pts (savo + osi) with RECIST PD by BICR had a new CNS lesion; 6/11 pts in the savo + PBO arm developed a new CNS lesion. Conclusions: In EGFRm advanced NSCLC with MET IHC3+/≥90% and/or FISH10+ status after PD on 1L osi, efficacy of savo 300 mg BID + osi was numerically greater than savo + PBO and showed promising CNS activity. To date, this is one of the largest randomized data sets presented evaluating an oral MET-TKI in EGFRm NSCLC. Efficacy findings from SAVANNAH suggest that targeting both EGFR and MET is key and support further investigation of savo + osi and CNS activity in the Phase 3 SAFFRON study. Clinical trial information: NCT03778229 . Assessment Savo + osi (n=48) Savo + placebo (n=25) ORR, % (95% CI) BICR 58 (43, 72) 16 (5, 36) INV 54 (39, 69) 24 (9, 45) DoR, mo, median (95% CI) BICR 11.8 (6.0, NC) 4.5 (2.6, NC) INV 8.0 (4.9, 11.7) 4.2 (2.6, NC) PFS, mo, median (95% CI) BICR 8.3 (5.8, 15.1) 3.6 (1.4, 5.7) INV 7.6 (5.6, 11.0) 2.7 (1.4, 4.1) BICR, blinded independent central review; CI, confidence interval; mo, months; NC, not calculable.