Publications

BACKGROUND: In traumatic hemorrhage, transfusion of donor-derived platelets improve hemostasis and survival, but their availability is often limited by supply constraints and short shelf-life. To address this, we have developed SynthoPlate (SP), a synthetic platelet nanotechnology, that mimics the primary hemostatic functions of natural platelets, and have recently advanced its manufacturing into a shelf-stable, lyophilized powder for rapid aqueous-reconstitution and on-demand use.

OBJECTIVE: We aimed to evaluate the feasibility, safety and efficacy of administering SP intraosseously (IO) in a rat model of traumatic hemorrhage, considering the critical clinical relevance of IO access in prehospital and combat medicine.

METHODS: We first assessed SP's hemostatic cooperativity with rat platelets using a microfluidic assay. Next, SP was administered IO in rats to evaluate safety and biodistribution. Finally, 0.5 mg/kg of SP was administered IO in a rat liver laceration model to assess effects on hemodynamics, blood loss, and survival.

RESULTS: Microfluidic studies confirmed SP's hemostatic capability in platelet-depleted rat plasma. In pilot safety studies, IO-administered SP was well tolerated at doses up to 20 mg/kg, 40 times the proposed effective dose. In efficacy studies, rats treated with SP showed significantly reduced blood loss and improved survival compared to controls. SP-treated rats also exhibited higher mean arterial pressure (MAP) post-injury, shorter durations of hypotension, and faster MAP recovery.

CONCLUSION: This first-in-kind study demonstrates the feasibility of administering SP intraosseously to enhance hemostasis and survival in traumatic hemorrhage, supporting its potential as a rapidly deployable, shelf-stable platelet surrogate for use in emergency and austere settings.

IMPORTANCE: The Air Medical Prehospital Triage (AMPT) score may attenuate disparities observed in recent data that demonstrated significantly lower odds of prehospital air medical transport (AMT) use among injured patients of minoritized race and ethnicity groups compared to non-Hispanic White patients.

OBJECTIVE: To evaluate if using the AMPT score is associated with a reduction in racial and ethnic disparities in prehospital AMT use or a mortality benefit in patients who meet AMPT criteria.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of the Pennsylvania Trauma Outcomes Study database from January 2000 to December 2020. Participants included injured patients aged 16 years and older who underwent ground or helicopter emergency medical service transport from the scene of injury, excluding those with transport distances less than 5 miles from the trauma center. Race and ethnicity were reported as per the dataset, which used patient self-report. Data were analyzed from February to August 2025.

EXPOSURE: AMPT-assigned transport mode.

MAIN OUTCOMES AND MEASURES: Actual prehospital transport mode (air vs ground) and AMPT-assigned transport mode were evaluated; in-hospital mortality was assessed by AMPT triage assignment. Socioenvironmental context was evaluated using the Area Deprivation Index (ADI), Social Deprivation Index (SDI), and Distressed Communities Index (DCI).

RESULTS: The study cohort included 307 831 patients (mean [SD] age, 50.0 [25.3] years; 185 288 [60.2%] male; 2727 [0.9%] non-Hispanic Asian, 30 570 [10.2%] non-Hispanic Black, 8471 [2.8%] Hispanic/Latino, 253 491 [84.5%] non-Hispanic White, 4643, and [1.6%] other [including Alaskan Native, American Indian, and Asian, and Pacific Islander]). Non-Hispanic Asian, Non-Hispanic Black, and Hispanic/Latino patients were significantly less likely to undergo prehospital AMT compared to White patients. When assigning prehospital transport mode based on the AMPT score, no significant associations were observed between race and ethnicity and AMT use. Prehospital air vs ground transport was associated with 24% lower odds of mortality among patients who had an AMPT score of 2 or greater (adjusted odds ratio [aOR], 0.76; 95% CI, 0.58-0.99; P = .40). As ADI, DCI, and SDI scores increased, AMT use varied by race and ethnicity. Causal mediation analyses demonstrated that 38% (mediation effect, 0.38; 95% CI, 0.35-0.42), 40% (mediation effect, 0.40; 95% CI, 0.38-0.43), and 13% (mediation effect, 0.13; 95% CI, 0.11-0.18) of the effect of race and ethnicity on prehospital transport mode were explained by ADI, DCI, and SDI scores, respectively.

CONCLUSIONS AND RELEVANCE: The results of this cohort study indicate that standard use of the AMPT score during air medical triage may improve equity in prehospital AMT use.

Based on mRNA Expression Profiles of 57 Patient-Derived Colorectal Cancer Stem-Like Cell (CRC-SC) Lines Compared With Normal Colonic Epithelial Stem-Like Cells (NCE-SCs), we Identified Five CRC Subtypes. The First Subtype of CRC-SCs Showed Markedly Increased Expression of MUC12, PIGR, PLA2G2A, SLC4A4, and ZG16, Which Were Barely Detectable in the Other Subtypes. Importantly, Their Expression Correlated With Favorable Outcomes in Both the Discovery Cohort and Independent Two Test Cohorts From Public Databases. The Remaining Four Subtypes Showed High Expression of DEFA6, BST2, MAGEA6, or IGF2 Compared With NCE-SCs. Although the Expression of Each Gene Individually Influenced Patient Outcomes, Additional Co-Expressed Genes Within Each Subtype Were Also Associated With Prognosis. Furthermore, Integrating the Five Subtype-Specific Signatures Produced a Practical Prognostic Indicator, Designated as the General Colorectal Cancer Signature (GCS), and Provided Individualized Predictive Signatures for Each Patient. The Clinical Significance of GCS Was Further Validated in a Novel Orthotopic Xenograft Mouse Model, Which Recapitulated Patient Outcomes: CRC-SCs With Low GCS Scores Developed Distinct Liver and Lung Metastases, Whereas Those With High Scores Did Not. Apparent Associations Were Observed Between Activating RAS/RAF Mutations and BST2 Expression, and Between the Absence of SMAD4 Mutation and IGF2 Expression, but These Had no Significant Impact on Patient Survival, Suggesting That Driver Gene Mutations May Not Directly Influence GCS. Collectively, Our Findings Provide a Comprehensive Overview of Clinically Relevant Molecular Subtypes of CRC-SCs, Representing the Current Landscape of CRC Molecular Expression Subtypes. They Also Enable Rapid, Low-Cost Outcome Prediction and Suggest Potential Targets for Therapeutics Development.

BACKGROUND: During shock, neutrophil-mediated glycocalyx degradation can lead to exposure of the procoagulant endothelial surface and consequent organ injury. Resuscitation using crystalloid fluids may augment this endothelial damage, while resuscitation using plasma may preserve glycocalyx health. We hypothesised that resuscitation with plasma would preserve glycocalyx integrity by reducing inflammation, glycocalyx shedding, and dyscoagulation in a controlled model of systemic inflammation in human volunteers.

METHODS: Twelve healthy male volunteers were injected with 2 ng kg-1 lipopolysaccharide (LPS) to induce systemic inflammation. Thirty minutes after LPS administration, participants were randomised to receive 10 ml kg-1 of either balanced salt solution or solvent detergent plasma (SDP). Plasma syndecan-1, a marker of glycocalyx degradation, was the primary outcome. Additionally, plasma biomarkers of inflammation, neutrophil extracellular trap formation, glycocalyx degradation, endothelial injury, and coagulation were measured serially, by bead-based or enzyme-linked immunoassays.

RESULTS: LPS induced a systemic inflammatory response, accompanied by endothelial injury as indicated by increased levels of syndecan-1 (median increase: 2920-4430 pg ml-1, P<0.05). Participants receiving SDP had lower levels of neutrophils and plasma matrix metalloproteinase-9, compared with those receiving balanced salt solution. Neutrophil extracellular trap formation, inflammation, and glycocalyx degradation were not affected by fluid therapy. SDP reduced LPS-induced prolonged prothrombin time, but had no impact on other biomarkers of coagulation.

CONCLUSIONS: In human endotoxaemia, plasma resuscitation reduced leucocyte and neutrophil levels but did not reduce glycocalyx degradation, when compared with equal volume resuscitation with a balanced crystalloid solution.

Severe polytrauma and hemorrhage is a common and life-threatening condition often leading to intensive care unit admission for those who survive their initial injury. The injury itself, hypoperfusion from hemorrhagic shock, and resuscitative efforts introduce a complex set of hemostatic derangements collectively referred to as trauma-induced coagulopathy (TIC). Although the trauma population is notoriously heterogenous, TIC can generally be divided into an "early" hypocoagulable phase and then a "late" hypercoagulable, prothrombotic phase. Existing literature on TIC focuses heavily on reversing and preventing hypocoagulation in the early, acute phase. However, intensivists commonly manage patients throughout the later post-acute resuscitation phase of TIC, during which thrombotic complications are common and may lead to major morbidity and mortality. Derangements in platelet activation, endothelial dysfunction, suppression of fibrinolysis, and crosstalk between the innate immune and coagulation systems all contribute to the prothrombotic late TIC phenotype. Deep venous thrombosis and other macrovascular thrombotic complications also commonly occur after trauma. Thrombosis prophylaxis and treatment present a challenge for patients still at high risk for bleeding. An in-depth understanding of risk factors specific to trauma patients, including iatrogenic contributions from resuscitation and hemostatic efforts in the pre-intensive care phase, can help stratify thromboembolic risk and optimize prophylaxis and surveillance efforts. We stress the importance of an individualized approach to assessment of hemorrhagic and thrombotic risks for each patient. Here, we summarize the underlying contributors to the prothrombotic phenotype in late TIC, including a description of emerging roles for HMGB1, extracellular vesicles, and endogenous inhibitors. Additionally, a general approach to thromboprophylaxis, monitoring, and anticoagulation in this patient population are discussed. Finally, we summarize relevant risk stratification systems and guidelines for clinical management of thromboembolic risk among trauma patients, and highlight limitations in these systems and guidelines as areas for future research.

Climate change and the global energy crisis have led to an increasing need for greenhouse gas remediation and clean energy sources. The electrochemical CO2 reduction reaction (CO2RR) is a promising solution for both issues as it harvests waste CO2 and chemically reduces it to more useful forms. However, the high overpotential required for the reaction makes it electrochemically unfavorable. Here, we fabricate a novel electrode composed of TiO2 nanoparticles grown in situ on MXene charge acceptor 2D sheets with excellent CO2RR characteristics. A straightforward solvothermal method was used to grow the nanoparticles on the Ti3C2Tx MXene flakes. The electrochemical performance of the TiO2/MXene electrodes was analyzed. The Faradaic efficiencies of the TiO2/MXene electrodes were determined, with a value of 99.41% at -1.9 V (vs. Ag/AgCl). Density functional theory mechanistic analysis was used to reveal the most likely mechanism resulting in the production of one CO molecule along with a carbonate anion through ∗CO, ∗O, and activated CO22- intermediates. Bader charge analysis corroborated this pathway, showing that CO2 gains a greater negative charge when TiO2/MXene serves as a catalyst compared to MXene or TiO2 alone. These results show that TiO2/MXene nanocomposite electrodes may be very useful in the conversion of CO2 while still being efficient in both time and cost.

BACKGROUND: Existing clinical coagulation assays are inadequate to evaluate posttraumatic platelet dysfunction in children.

OBJECTIVES: To elucidate changes in flow-dependent platelet function after injury in children using a microfluidic assay.

METHODS: We enrolled 18 children who presented with highest-acuity trauma activation and 10 healthy children at an academic pediatric center. For the control cohort, outpatient blood samples were collected, and for the trauma cohort, blood was collected in the trauma bay for conventional coagulation tests, thromboelastography, von Willebrand factor A1 domain activity, and a microfluidic assay using a stenotic channel (shear rate = 3500 s-1).

RESULTS: The trauma cohort characteristics were 67% male, median (IQR) age 6 years (4-12), median (IQR) injury severity score 17 (9-26), and 78% blunt mechanism. In total, 50% required blood transfusion and 11% (2/18) died. While thromboelastography maximum amplitude (59.9 ± 6.1 mm) and platelet counts (306.3 ± 111.1 × 103 cells/μL) were within normal limits, the microfluidic assay revealed significantly lower platelet deposition in the trauma cohort versus the control cohort (1.18 ± 0.25 vs 3.06 ± 0.82 mean fluorescence intensity fold change; P < .0001). Lower levels of platelet deposition correlated with receipt of blood transfusion within 6 hours of arrival (r = -0.44, P = .048). von Willebrand factor A1 domain activity was not different between groups and was not correlated with platelet deposition based on mean fluorescence intensity fold change (R 2 < 0.0001).

CONCLUSION: Posttraumatic platelet dysfunction was observed by utilizing a microfluidic assay in a pediatric trauma cohort. Further study is needed to understand the underlying mechanisms and significance of posttraumatic platelet dysfunction in children.

INTRODUCTION: Following the COVID-19 pandemic, the role of virtual family medicine care is evolving. It can be tempting to consider only the technological aspects of virtual care; we argue we must attend to compassion's essential role in virtual family medicine care. This research aimed to understand the components contributing to compassionate family medicine virtual care and how these were demonstrated.

METHODS: We conducted a qualitative Constructivist Grounded Theory study with 2 components; individual interviews with patients and family physicians (FP), and Collaborative Discussions, informed by the interviews, that brought patients and FPs together. Data collection and analysis were iterative using a constant comparative analysis.

RESULTS: We recruited nineteen patient and fourteen FP participants for the first component and 6 patient and 4 FP participants for the second. We identified 4 themes: Conveying virtual compassion through actions; External factors affecting virtual compassion; Virtual visits extending compassionate care; and Role of the patient-FP relationship. These themes can be characterized as a stance that FPs assume in their practice of virtual care.

DISCUSSION: We highlight 4 themes important to the delivery of compassionate virtual care. We provide specific actions FPs may consider in delivering virtual care. Offering virtual visits was viewed as a compassionate bridge between in-person visits.

CONCLUSION: Our findings support that it is possible to convey compassion in virtual visits including telephone interactions. As virtual care evolves, our findings can support patients and family physicians to safeguard compassion so that it remains a hallmark of care for all modes of delivery.

BACKGROUND: The use of tranexamic acid in trauma patients at risk for hemorrhage remains controversial. This guideline evaluates the use of tranexamic acid in two clinical settings, the prehospital environment and the inpatient setting. In addition, this PMG evaluates the use TXA in specific populations and at different dosages and evaluates the potential risks associated with its use.

METHODS: Using the Grading of Recommendations Assessment, Development and Evaluation methodology, an EAST working group conducted a systematic review using MEDLINE, EMBASE, and COCHRANE CENTRAL. Articles in English from 2000 through 2023 were considered in evaluating four PICO questions relevant to the use of TXA in injured trauma patients at risk of hemorrhage (defined as patients with a systolic blood pressure (SBP) ≤90 mm Hg or a heart rate ≥110/min or suspicion for active hemorrhage).

RESULTS: Thirty studies were identified for qualitative analysis, of which 24 met criteria for meta-analysis. TXA was associated with a significant reduction in 24-hour mortality in both prehospital (log risk ratio, -0.29; 95% confidence interval, -0.53 to -0.05; p = 0.02) and in-hospital settings (-0.38[-0.69, -0.06]; p = 0.02). A similar benefit was observed at 30-days across both settings (prehospital: -0.18[-0.35, -0.00]; p = 0.05, in-hospital: -0.24[-0.40, -0.07]; p = 0.01). In patients with SBP ≤75 mm Hg, TXA reduced mortality, but this was not found to be significant (-0.18 [-0.46, 0.09]; p = 0.20). The incidence of vaso-occlusive events did not differ between groups in either setting. Moreover, a large heterogeneity regarding TXA dosing regimens and comparison groups across studies was observed.

CONCLUSION: Based on current available evidence, we conditionally recommend for the routine use of TXA in the prehospital and in-hospital settings. We cannot recommend for or against the use of an initial higher dose of bolus TXA. Finally, we conditionally recommend for the routine use of TXA in patients with severe hypotension.

LEVEL OF EVIDENCE: Level 1: Meta-analysis.

BACKGROUND: The volume-outcome relationship in trauma centers is well established, including geriatric volume. With an increasing geriatric population, it remains unclear whether a tipping point exists for these complex patients who overwhelm centers. Our objective was to evaluate whether the proportion of geriatric patients relative to total volume impacts outcomes.

METHODS: This retrospective cohort study analyzed patients aged >15 years from the Trauma Quality Program Patient Use File dataset between the years 2017 and 2021. We calculated the center-level annual geriatric proportion of total adult patient volume. Generalized additive mixed models evaluated nonlinear effects between geriatric proportion and mortality for geriatric and nongeriatric patients adjusted for demographics, vitals, injury characteristics, center characteristics, frailty, and comorbidities.

RESULTS: We included 3,989,267 patients from 605 centers. Increasing geriatric proportion was associated with improving mortality for geriatric patients until reaching thresholds of 65% of total volume, where mortality plateaued. Importantly, at a geriatric proportion of 61%, mortality for nongeriatric adults began to increase (adjusted odds ratio per 5% increase: 1.04; 95% confidence interval: 1.01-1.08). Geriatric Charlson Comorbidity Index was related to nongeriatric mortality in the highest quartile of geriatric proportion (adjusted odds ratio: 1.18, 95% confidence interval: 1.11-1.25).

CONCLUSION: Center-level geriatric proportion is an important predictor of both geriatric and nongeriatric trauma outcomes. At higher proportions of geriatric patients, the loss of the volume-outcome benefit and even increase in mortality suggests the medically complex geriatric population may overwhelm centers, leading to worse outcomes among all patients. These findings may inform trauma system planning to optimize care of our geriatric and nongeriatric patients.