Publications

BACKGROUND: Trauma guidelines have historically recommended intubation prior to transfusion, yet intubation and mechanical ventilation can exacerbate hemodynamic instability. We hypothesized that injured patients resuscitated with a circulation-first approach would require fewer blood transfusions and would have lower mortality than those managed with an airway-first approach.

METHODS: This secondary data analysis of the Linking Investigations in Trauma and Emergency Services (LITES) database compared trauma patients in hemorrhagic shock who received blood products and intubation within 30 minutes of each other. 'ABC' patients were intubated first, whereas 'CAB' patients received blood first. A subgroup analysis compared patients with penetrating injuries only. Outcomes included transfusion volume, whole blood (WB) utilization, mortality, and hospital length of stay (HLOS).

RESULTS: 35 CAB and 49 ABC patients were included. The ABC group suffered more blunt injuries (73.5% vs 42.9%, p=0.02) and were more likely to receive WB in the prehospital setting (75.5% vs 48.6%, p=0.02). Transfusion requirements were significantly higher in the CAB group (7195 mL vs 6090 mL, p=0.01), although this was not the case after removal of outliers. In the penetrating cohort (17 CAB, 11 ABC), CAB patients were less likely to be transferred directly from the scene (70.6% vs 72.7%), yet were more likely to receive WB in the prehospital setting (64.7% vs 27.3%). There were no differences with respect to mortality or HLOS.

CONCLUSION: When comparing a circulation-first to an airway-first approach to triage in a unique, severely injured cohort of trauma patients, there was no difference detected in transfusion requirements or mortality. Centers participating in LITES more frequently used CAB over ABC for patients with penetrating trauma. The sample size and characteristics of this cohort limit its generalizability and highlight the need for prospective multicenter trials to guide the triage and management of hemorrhagic shock.

LEVEL OF EVIDENCE: III, prognostic/epidemiological.

Acute kidney injury (AKI) develops in 20-40% of critically injured patients and contributes to poor outcomes. In sepsis and critical illness, dysregulated coagulation and fibrinolysis are linked to microangiopathic kidney dysfunction, but similar relationships in trauma are not well characterized. We performed a secondary analysis of a single-center randomized controlled trial of severely injured adult trauma patients. Plasma thrombin-antithrombin (TAT), plasmin-2-antiplasmin (PAP), and fibrinogen were measured within 2 hours of injury and 6 hours later. The primary outcome was AKI, defined by the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria. Adjusted logistic regression models evaluated biomarker associations with AKI. Receiver operating characteristic analyses identified discriminatory thresholds. Among 149 patients, 30 (20.1%) developed AKI. Patients with AKI had higher TAT and PAP concentrations and lower fibrinogen levels at both time points. The 6-hour TAT-to-fibrinogen ratio was independently associated with AKI (Adjusted OR 7.17; 95% CI 2.34-21.9, p = 0.001, AUC = 0.88). Supplemental analyses demonstrated consistent associations for TAT and fibrinogen individually, whereas PAP was not independently predictive. A 6-hour TAT level < 99 pg/mL identified patients unlikely to develop AKI (negative predictive value [NPV] 93.9%). Fibrinogen levels > 173 mg/dL showed a low likelihood of AKI (NPV 88.2%). Elevated TAT and reduced fibrinogen measured 6 hours after injury were independently associated with AKI. This suggests that early coagulation imbalance may reflect evolving microvascular kidney dysfunction in injured patients and potentially warrants the evaluation of the TAT-to-fibrinogen ratio as an early marker of trauma-related AKI. (NCT02535949).

Pseudomonas aeruginosa is a ubiquitous, Gram-negative bacterium that forms biofilms and is responsible for antibiotic-resistant hospital-acquired infections in humans. The P. aeruginosa BqsRS two-component system regulates biofilm formation and dispersal by sensing extracytoplasmic Fe2+, but the mechanistic details of this process are poorly understood. In this work, we report the crystal and solution structures of the PaBqsR response regulator receiver domain, comprising a (βα)5 response regulator assembly, and the DNA-binding domain, comprising a helix-turn-helix motif. Consistent with its cognate stimulus being Fe2+, we show that PaBqsR binds directly to the promoter region of the feo operon that encodes the bacterial Fe2+ transport system FeoABC. Corroborating these in vitro results, transcriptional studies show that PaBqsR is a global regulator controlling many important genes in PAO1, including the feo operon. Intriguingly, promoter-based assays reveal that PaBqsR is a dynamic regulator that responds to bioavailable Fe2+, likely through the ability of PaBqsR to bind Fe2+ directly via a His-rich motif, independent of the PaBqsS membrane His kinase. To our knowledge, this mode of regulation has not been reported previously among OmpR-like response regulators but represents an important level of control over Fe2+ acquisition in P. aeruginosa that could be an attractive therapeutic target to treat hospital-acquired infections.

IMPORTANCE: Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function.

OBJECTIVE: To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass.

DESIGN, SETTING, AND PARTICIPANTS: A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration-ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025.

INTERVENTION: Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage.

MAIN OUTCOMES AND MEASURES: The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output.

RESULTS: Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, -0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, -1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group.

CONCLUSIONS AND RELEVANCE: For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04834414.

BACKGROUND: Deep-learning neural network algorithms for detecting prostate cancer in MRI have proliferated in the literature. However, out of 30+ studies published since the PROSTATEx challenge, no studies tested the performance of their algorithm against using true external image data sets (studies came from an outside institution that did not supply any training data to the algorithm) while validating against MR-US fusion biopsy or whole-mount prostatectomy. Using true external data sets paints a much clearer picture of real-world clinical performance of an algorithm.

PURPOSE: This work will assess the performance of a published deep learning (DL) neural network algorithm to detect prostate cancer using external studies. The main difference from other studies is the combination of using only MR-US fusion biopsy results as a gold standard; using test data from an institution that did not supply any training data for this version of the algorithm (including studies acquired with an endorectal coil, which were not in the original training set); and comparing the performance of algorithm-generated regions-of-interest (ROIs) versus algorithm heat maps.

METHODS: Patients were included in the study if they had a prostate MRI with at least one radiologist-drawn target on MRI and underwent MR-US fusion biopsy where the target was sampled for pathological analysis. Patients were excluded if they had any history of prostate cancer treatment, had previously undergone MR-US fusion biopsy at our institution, were missing MRI acquisitions, had artifacts in image sets, or if the study had been shared for future algorithm development. MR image data was assessed using a DL research prototype (XProstate) from Siemens Healthineers that produced (a) ROIs in suspected cancer areas with a level of suspicion (LoS) score and (b) heat maps with LoS scores across the entire gland. The XProstate prototype had been trained with 2170 studies from eight different academic institutions. Clinical radiologist, XProstate ROI, and XProstate Heat Map scores were assessed with ROC analysis using pathology results from biopsy as a gold standard.

RESULTS: 202 unique patients were included for assessment of the XProstate research prototype. The ROC curve for the XProstate Heat Map LoS score generated the highest AUC (0.76, 95% CI: 0.70, 0.82) followed by clinical radiologist PI-RADS score (0.73, 95% CI: 0.68, 0.79) and by XProstate ROI LoS score (0.71, 95% CI: 0.65, 0.77). Neither the XProstate Heat Map (AUC difference = 0.03, 95% CI: -0.04, 0.10, p = 0.38) nor the XProstate ROI (AUC difference = -0.02, 95% CI: -0.09, 0.04, p = 0.43) was significantly different from the radiologist PI-RADS score.

CONCLUSIONS: The XProstate prototype demonstrated equivalent performance as clinical radiologists when presented with de novo cases that would mirror a real-world clinical deployment. The automatic ROI delineation more closely matched clinical radiologist performance when using a cutoff of PI-RADS 5 for annotating suspicious regions. Overall, the XProstate prototype provided reasonable clinical performance and this study demonstrated the need to assess Deep Learning prototypes with external institutional test data.

Emergency general surgery (EGS) represents a significant portion of admissions to hospitals and overall surgical care delivery, yet comprehensive outcome tracking and quality improvement efforts have lagged behind elective surgery and trauma care. This article outlines the gap in data and provides three practical solutions to registry development: third-party registry software with dedicated registrars, leveraging existing National Surgical Quality Improvement Program (NSQIP) infrastructure through the EGS-NSQIP module, and automated data extraction from electronic medical records. Each approach offers unique advantages in addressing the dual challenges of case identification and risk-adjusted outcome measurement for both local quality improvement and national benchmarking. The aim of this white paper is to provide pragmatic, scalable data solutions for EGS leaders seeking to implement contemporary quality improvement and verification efforts.

BACKGROUND: Public health emergencies require rapid generation, synthesis, and translation of clinical evidence into practice guidelines; yet, systematic synthesis of the challenges and lessons from these processes remains limited.

OBJECTIVES: The purpose of this study was to examine how evidence on anticoagulation in COVID-19 was generated and translated into clinical guidance, using randomized controlled trials (RCTs) as a case study, and to contextualize these processes with an individual participant data meta-analysis (IPDMA).

METHODS: Systematic searches identified RCTs comparing therapeutic- vs nontherapeutic-dose anticoagulation in noncritically ill patients hospitalized for COVID-19. Trial characteristics, evidence accumulation, and associated guideline recommendations were summarized over time. An IPDMA was performed to estimate summary treatment effects using mixed-effects logistic regression.

RESULTS: Evidence evolved from an early coordinated platform RCT (preprint May 2021) to subsequent RCTs published between June 2021 and July 2023. In exploratory counterfactual sequential IPDMA, the pooled treatment effect on organ support or death became statistically significant in May 2021, approximately 13 months after first patient enrollment (adjusted OR: 0.73; 95% CI: 0.58-0.91; 6 RCTs, n = 3,944). Guideline recommendations shifted from uniform endorsement of prophylactic-dose anticoagulation in 2020 to recommendations supporting therapeutic-dose anticoagulation in 2022, with variation in certainty across guidelines. Individual participant data were obtained after completion of data transfer in April 2024 and included 7 RCTs comprising 6,362 patients. Therapeutic-dose anticoagulation reduced the odds of organ support or death (12.9% vs 16.2%; adjusted OR: 0.81; 95% CI: 0.67-0.97). Major bleeding was rare (0.8% vs 0.5%).

CONCLUSIONS: The COVID-19 anticoagulation experience highlights how delays in coordination, data sharing, and synthesis can slow the translation of evidence into practice. Therapeutic-dose anticoagulation was associated with reduced odds of organ support or death and, in this context, serves as a case study of how evidence emerges and is acted upon under conditions of uncertainty. Strengthening coordinated research networks, platform trial infrastructures, prioritized funding, and near-real-time cross-trial synthesis may improve the timeliness, reliability, and responsiveness of evidence systems during future health emergencies.

BACKGROUND: The Early Cold Stored Platelet Transfusion Following Severe Trauma Injury Trial evaluated the safety and efficacy of cold stored platelet (CSP) transfusion in injured patients at risk of hemorrhagic shock. It was a phase II, multicenter, randomized clinical trial conducted from June 2022 to September 2023 at five US level 1 trauma centers. A total of 200 adult patients at risk of hemorrhagic shock (102 CSP, 98 standard care (SC)) were included. Median age was 34±13 years, 85% were males, and injury severity was similar between groups. The original frequentist analysis did not demonstrate a statistically significant difference in 24-hour mortality between CSP (5.9%) transfusion and SC (10.2%, p=0.28).

METHODS: To provide further insight into these findings, a Bayesian logistic regression outcome model with an uninformative prior was performed. To validate the findings further, a sensitivity analysis was performed in addition to analysis using a beta-binomial Bayesian model.

RESULTS: The Bayesian logistic regression model yielded an 89.1% posterior probability that CSP transfusion reduced 24-hour mortality (ß1=-0.668, 95% highest posterior density interval: -1.7 to 0.48). This posterior distribution indicates it is 8.1 times more likely that CSP transfusion improves 24-hour mortality than not. Sensitivity analyses across a spectrum of priors consistently produced posterior probabilities >81%. The beta-binomial model demonstrated a similar 86.2% probability that CSP transfusion reduced 24-hour mortality.

CONCLUSION: These findings suggest a high likelihood of mortality benefit with early CSP transfusion in injured patients at risk of hemorrhagic shock and illustrate the added interpretive value of Bayesian analysis in trauma trials with low event rates.

LEVEL OF EVIDENCE: Level II-therapeutic/care management.

Carrier screening identifies individuals/couples at risk for autosomal recessive conditions, and expanded or universal approaches are increasingly being recommended. Implementation poses clinical, ethical, and logistical challenges that remain underexplored. This scoping review synthesized patient/public and health care practitioner experiences and perspectives on expanded carrier screening (ECS) and universal carrier screening. A search of 4 databases identified 1433 records, plus 19 additional studies. After screening and full-text review (112 articles), 45 studies were included in this review. Content analysis was conducted, and findings were mapped to the theoretical domains framework to guide implementation. Six major categories were identified: (1) attitudes and awareness of screening; (2) barriers and concerns regarding ECS decision-making; (3) personal and broader public-health benefits; (4) ethical, psychological, and equity considerations; (5) infrastructure, clinical, and policy considerations; and (6) research gaps and future directions. Key theoretical domains framework domains included beliefs about consequences, environmental context and resources, social/professional role and identity, and emotion. Engagement with ECS/ universal carrier screening is shaped by intersecting emotional, ethical, and systemic factors. The findings support behaviorally informed strategies and identify critical priorities for future research, education, and policy development.