Engineering Low Volume Resuscitants for the Prehospital Care of Severe Hemorrhagic Shock.

Globally, traumatic injury is a leading cause of suffering and death. The ability to curtail damage and ensure survival after major injury requires a time-sensitive response balancing organ perfusion, blood loss, and portability, underscoring the need for novel therapies for the prehospital environment. Currently, there are few options available for damage control resuscitation (DCR) of trauma victims. We hypothesize that synthetic polymers, which are tunable, portable, and stable under austere conditions, can be developed as effective injectable therapies for trauma medicine. In this work, we design injectable polymers for use as low volume resuscitants (LVRs). Using RAFT polymerization, we evaluate the effect of polymer size, architecture, and chemical composition upon both blood coagulation and resuscitation in a rat hemorrhagic shock model. Our therapy is evaluated against a clinically used colloid resuscitant, Hextend. We demonstrate that a radiant star poly(glycerol monomethacrylate) polymer did not interfere with coagulation while successfully correcting metabolic deficit and resuscitating animals from hemorrhagic shock to the desired mean arterial pressure range for DCR - correcting a 60% total blood volume (TBV) loss when given at only 10% TBV. This highly portable and non-coagulopathic resuscitant has profound potential for application in trauma medicine.

Effectiveness of an anti-inflammatory diet versus low-fat diet for knee osteoarthritis: the FEAST randomised controlled trial protocol.

INTRODUCTION: Chronic inflammation plays a key role in knee osteoarthritis pathophysiology and increases risk of comorbidities, yet most interventions do not typically target inflammation. Our study will investigate if an anti-inflammatory dietary programme is superior to a standard care low-fat dietary programme for improving knee pain, function and quality-of-life in people with knee osteoarthritis. METHODS AND ANALYSIS: The eFEct of an Anti-inflammatory diet for knee oSTeoarthritis study is a parallel-group, assessor-blinded, superiority randomised controlled trial. Following baseline assessment, 144 participants aged 45-85 years with symptomatic knee osteoarthritis will be randomly allocated to one of two treatment groups (1:1 ratio). Participants randomised to the anti-inflammatory dietary programme will receive six dietary consultations over 12 weeks (two in-person and four phone/videoconference) and additional educational and behaviour change resources. The consultations and resources emphasise nutrient-dense minimally processed anti-inflammatory foods and discourage proinflammatory processed foods. Participants randomised to the standard care low-fat dietary programme will receive three dietary consultations over 12 weeks (two in-person and one phone/videoconference) consisting of healthy eating advice and education based on the Australian Dietary Guidelines, reflecting usual care in Australia. Adherence will be assessed with 3-day food diaries. Outcomes are assessed at 12 weeks and 6 months. The primary outcome will be change from baseline to 12 weeks in the mean score on four Knee injury and Osteoarthritis Outcome Score (KOOS4) subscales: knee pain, symptoms, function in daily activities and knee-related quality of life. Secondary outcomes include change in individual KOOS subscale scores, patient-perceived improvement, health-related quality of life, body mass and composition using dual-energy X-ray absorptiometry, inflammatory (high-sensitivity C reactive protein, interleukins, tumour necrosis factor-α) and metabolic blood biomarkers (glucose, glycated haemoglobin (HbA1c), insulin, liver function, lipids), lower-limb function and physical activity. ETHICS AND DISSEMINATION: The study has received ethics approval from La Trobe University Human Ethics Committee. Results will be presented in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000440729.

CRISPR/Cas9-Based Disease Modeling and Functional Correction of Interleukin 7 Receptor Alpha Severe Combined Immunodeficiency in T-Lymphocytes and Hematopoietic Stem Cells.

Interleukin 7 Receptor alpha Severe Combined Immunodeficiency (IL7R-SCID) is a life-threatening disorder caused by homozygous mutations in the IL7RA gene. Defective IL7R expression in humans hampers T cell precursors' proliferation and differentiation during lymphopoiesis resulting in the absence of T cells in newborns, who succumb to severe infections and death early after birth. Previous attempts to tackle IL7R-SCID by viral gene therapy have shown that unregulated IL7R expression predisposes to leukemia, suggesting the application of targeted gene editing to insert a correct copy of the IL7RA gene in its genomic locus and mediate its physiological expression as a more feasible therapeutic approach. To this aim, we have first developed a CRISPR/Cas9-based IL7R-SCID disease modeling system that recapitulates the disease phenotype in primary human T cells and hematopoietic stem and progenitor cells (HSPCs). Then, we have designed a knockin strategy that targets IL7RA exon 1 and introduces through homology-directed repair a corrective, promoterless IL7RA cDNA followed by a reporter cassette through AAV6 transduction. Targeted integration of the corrective cassette in primary T cells restored IL7R expression and rescued functional downstream IL7R signaling. When applied to HSPCs further induced to differentiate into T cells in an Artificial Thymic Organoid system, our gene editing strategy overcame the T cell developmental block observed in IL7R-SCID patients, while promoting full maturation of T cells with physiological and developmentally regulated IL7R expression. Finally, genotoxicity assessment of the CRISPR/Cas9 platform in HSPCs using biased and unbiased technologies confirmed the safety of the strategy, paving the way for a new, efficient, and safe therapeutic option for IL7R-SCID patients.

How Real-World Data Can Facilitate the Development of Precision Medicine Treatment in Psychiatry.

Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements-well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms-to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.

ASSESSMENT OF ABNORMAL SKELETAL MUSCLE PERFUSION BY CONTRAST-ENHANCED ULTRASOUND WITH PARAMETRIC IMAGING IN RATS AFTER SEVERE INJURY, HEMORRHAGIC SHOCK, AND WHOLE BLOOD RESUSCITATION.

ABSTRACT: Background: After severe injury, optical measures of microvascular blood flow (MBF) decrease and do not normalize with resuscitation to normal blood pressure. These changes are associated with organ dysfunction, coagulopathy, and death. However, the pathophysiology is not well understood. Several possible pathways could also contribute to the development of trauma-induced coagulopathy (TIC). A small-animal model of trauma-related MBF derangement that persists after resuscitation and includes TIC would facilitate further study. Parametric contrast-enhanced ultrasound (CEUS) is particularly advantageous in this setting, because it noninvasively assesses MBF in large, deep vascular beds. We sought to develop such a model, measuring MBF with CEUS. Methods: Sixteen male Sprague-Dawley rats were anesthetized, ventilated, and cannulated. Rats were subjected to either no injury (sham group) or a standardized polytrauma and pressure-targeted arterial catheter hemorrhage with subsequent whole blood resuscitation (trauma group). At prespecified time points, CEUS measurements of uninjured quadriceps muscle, viscoelastic blood clot strength, and complete blood counts were taken. Results: After resuscitation, blood pressure normalized, but MBF decreased and remained low for the rest of the protocol. This was primarily driven by a decrease in blood volume with a relative sparing of blood velocity. Viscoelastic blood clot strength and platelet count also decreased and remained low throughout the protocol. Conclusion: We present a rat model of MBF derangement in uninjured skeletal muscle and coagulopathy after polytrauma that persists after resuscitation with whole blood to normal macrohemodynamics. Parametric CEUS analysis shows that this change is primarily due to microvascular obstruction. This platform can be used to develop a deeper understanding of this important process.

Fibrinogen Fragment X Mediates Endothelial Barrier Disruption via Suppression of VE-Cadherin.

INTRODUCTION: Major traumatic injury is associated with early hemorrhage-related and late-stage deaths due to multiple organ failure (MOF). While improvements to hemostatic resuscitation have significantly reduced hemorrhage-related deaths, the incidence of MOF among trauma patients remains high. Dysregulation of vascular endothelial cell (EC) barrier function is a central mechanism in the development of MOF; however, the mechanistic triggers remain unknown. Accelerated fibrinolysis occurs in a majority of trauma patients, resulting in high circulating levels of fibrin(ogen) degradation products, such as fragment X. To date, the relationship between fragment X and EC dysregulation and barrier disruption is unknown. The goal of this study was to determine the effects of fragment X on EC barrier integrity and expression of paracellular junctional proteins that regulate barrier function. METHODS: Human lung microvascular endothelial cells (HLMVECs) were treated with increasing concentrations of fragment X (1, 10, and 100 µg/mL), and barrier function was monitored using the xCELLigence live-cell monitoring system. Quantitative PCR (qPCR) was performed to measure changes in EC expression of 84 genes. Immunofluorescent (IF) cytostaining was performed to validate qPCR findings. RESULTS: Fragment X treatment significantly increased endothelial permeability over time (P < 0.05). There was also a significant reduction in VE-cadherin mRNA expression in fragment X-treated HLMVECs compared to control (P = 0.01), which was confirmed by IF staining. CONCLUSIONS: Fragment X may induce EC hyperpermeability by reducing VE-cadherin expression. This suggests that a targeted approach to disrupting EC-fragment X interactions could mitigate EC barrier disruption, organ edema, and MOF associated with major trauma.

Ruggedized Self-Propelling Hemostatic Gauze Delivers Low Dose of Thrombin and Systemic Tranexamic Acid and Achieves High Survival in Swine With Junctional Hemorrhage.

INTRODUCTION: Hemorrhage is responsible for 91% of preventable prehospital deaths in combat. Bleeding from anatomic junctions such as the groin, neck, and axillae make up 19% of these deaths, and reports estimate that effective control of junctional hemorrhage could have prevented 5% of fatalities in Afghanistan. Hemostatic dressings are effective but are time-consuming to apply and are limited when proper packing and manual pressure are not feasible, such as during care under fire. CounterFlow-Gauze is a hemostatic dressing that is effective without compression and delivers thrombin and tranexamic acid into wounds. Here, an advanced prototype of CounterFlow-Gauze, containing a range of low thrombin doses, was tested in a lethal swine model of junctional hemorrhage. Outcomes were compared with those of Combat Gauze, the current dressing recommended by Tactical Combat Casualty Care. MATERIALS AND METHODS: CounterFlow-Gauze containing thrombin doses of 0, 20, 200, and 500 IU was prepared. Swine received femoral arteriotomies, and CounterFlow-Gauze was packed into wounds without additional manual compression. In a separate study using a similar model of junctional hemorrhage without additional compression, CounterFlow-Gauze containing 500 IU thrombin was tested and compared with Combat Gauze. In both studies, the primary outcomes were survival to 3 h and volume of blood loss. RESULTS: CounterFlow-Gauze with 200 and 500 IU had the highest 3-h survival, achieving 70 and 75% survival, respectively. CounterFlow-Gauze resulted in mean peak plasma tranexamic acid concentrations of 9.6 ± 1.0 µg/mL (mean ± SEM) within 3 h. In a separate study with smaller injury, CounterFlow-Gauze with 500 IU achieved 100% survival to 3 h compared with 92% in Combat Gauze animals. CONCLUSIONS: An advanced preclinical prototype of CounterFlow-Gauze formulated with a minimized thrombin dose is highly effective at managing junctional hemorrhage without compression. These results demonstrate that CounterFlow-Gauze could be developed into a feasible alternative to Combat Gauze for hemorrhage control on the battlefield.

Managing Hemostasis in Space.

Human space travel requires exposure to weightlessness, ionizing radiation, isolation, and austerity. A recent report of internal jugular vein thrombosis in astronauts in low Earth orbit confirms that these exposures also affect vascular biology to influence diseases of thrombosis and hemostasis. This brief review summarizes the known influences of space travel on inflammation, blood coagulation, and the cardiovascular system and conceptualizes how they might combine to affect thrombosis and hemostasis. In the event of a major thrombotic or bleeding emergency, it is anticipated that the unique physiological influences of the space environment and logistical limitations of providing medical care in space would require a response that is unique from our current experience. We also look towards the future to discuss lessons learned from our current experiences on Earth and in space.

Severity of hip dysplasia as the major factor affecting outcome of closed reduction in children with hip dysplasia.

The objective of this study was to analyze a multicenter cohort of children with developmental dysplasia of the hip (DDH) who underwent treatment with closed reduction. We sought to report the effects that severity of hip dysplasia and age have on the development of femoral head avascular necrosis (AVN) and the need for additional procedures. All patients with DDH and minimum 2 years of follow-up who underwent closed reduction were identified. The following variables were recorded: sex, laterality of hip involvement, age, acetabular index (AI), and International Hip Dysplasia Institute (IHDI) grade. The effects of patient age and pre-procedure IHDI grade on the rate of AVN and need for additional procedures after the closed reduction were analyzed using an alpha of 0.05. Seventy-eight total hips were included in the final analysis. The average patient age was 12 months. AVN of the femoral head was reported in 24 hips (30.8%) and 32 hips (41.0%) required additional surgery. Higher pre-op IHDI grade was associated with higher risk of developing Bucholz-Ogden grades II-IV AVN of the femoral head (P = 0.025) and requiring additional surgery (P= 0.033) regardless of patient age. There were no statistically significant differences for the effect of age on the measured outcomes (P > 0.05). These findings suggest that severity of dislocation (IHDI grade) is a significant risk factor for the development of AVN and need for additional procedure.

ENGINEERED INTRAVENOUS THERAPIES FOR TRAUMA.

Trauma leading to severe hemorrhage and shock on average kills patients within 3 to 6 hours after injury. With average prehospital transport times reaching 1-6 hours in low- to middle-income countries, stopping the bleeding and reversing hemorrhagic shock is vital. First-generation intravenous hemostats rely on traditional drug delivery platforms, such as self-assembling systems, fabricated nanoparticles, and soluble polymers due to their active targeting, biodistribution, and safety. We discuss some challenges translating these therapies to patients, as very few have successfully made it through preclinical evaluation in large-animals, and none have translated to the clinic. Finally, we discuss the physiology of hemorrhagic shock, highlight a new low volume resuscitant (LVR) PEG-20k, and end with considerations for the rational design of LVRs.

A novel melanocortin fusion protein inhibits fibrinogen oxidation and degradation during trauma-induced coagulopathy.

Immune cell inflammation is implicated in the pathophysiology of acute trauma-induced coagulopathy (TIC). We hypothesized that leukocyte inflammation contributes to TIC through the oxidation and proteolysis of fibrinogen. To test this hypothesis, antioxidants and a novel anti-inflammatory melanocortin fusion protein (AQB-565) were used to study the effects of interleukin-6 (IL-6)-stimulated human leukocytes on fibrinogen using single-cell imaging flow cytometry and multiplex fluorescent western blotting. We also studied the effects of AQB-565 on fibrinogen using an in vivo rat trauma model of native TIC. IL-6 induced cellular inflammation and mitochondrial superoxide production in human monocytes, causing fibrinogen oxidation and degradation in vitro. Antioxidants suppressing mitochondrial superoxide reduced oxidative stress and inflammation and protected fibrinogen. AQB-565 decreased inflammation, inhibited mitochondrial superoxide, and protected fibrinogen in vitro. Trauma with hemorrhagic shock increased IL-6 and other proinflammatory cytokines and chemokines, selectively oxidized and degraded fibrinogen, and induced TIC in rats in vivo. AQB-565, given at the onset of hemorrhage, blocked inflammation, protected fibrinogen from oxidation and degradation, and prevented TIC. Leukocyte activation contributes to TIC through the oxidation and degradation of fibrinogen, which involves mitochondrial superoxide and cellular inflammation. Suppression of inflammation by activation of melanocortin pathways may be a novel approach for the prevention and treatment of TIC.

Slow Intravenous Infusion of a Novel Damage Control Cocktail Decreases Blood Loss in a Pig Polytrauma Model.

BACKGROUND: Our objective was to optimize a novel damage control resuscitation (DCR) cocktail composed of hydroxyethyl starch, vasopressin, and fibrinogen concentrate for the polytraumatized casualty. We hypothesized that slow intravenous infusion of the DCR cocktail in a pig polytrauma model would decrease internal hemorrhage and improve survival compared with bolus administration. METHODS: We induced polytrauma, including traumatic brain injury (TBI), femoral fracture, hemorrhagic shock, and free bleeding from aortic tear injury, in 18 farm pigs. The DCR cocktail consisted of 6% hydroxyethyl starch in Ringer's lactate solution (14mL/kg), vasopressin (0.8U/kg), and fibrinogen concentrate (100mg/kg) in a total fluid volume of 20mL/kg that was either divided in half and given as two boluses separated by 30 minutes as control or given as a continuous slow infusion over 60 minutes. Nine animals were studied per group and monitored for up to 3 hours. Outcomes included internal blood loss, survival, hemodynamics, lactate concentration, and organ blood flow obtained by colored microsphere injection. RESULTS: Mean internal blood loss was significantly decreased by 11.1mL/kg with infusion compared with the bolus group (p = .038). Survival to 3 hours was 80% with infusion and 40% with bolus, which was not statistically different (Kaplan Meier log-rank test, p = .17). Overall blood pressure was increased (p < .001), and blood lactate concentration was decreased (p < .001) with infusion compared with bolus. There were no differences in organ blood flow (p > .09). CONCLUSION: Controlled infusion of a novel DCR cocktail decreased hemorrhage and improved resuscitation in this polytrauma model compared with bolus. The rate of infusion of intravenous fluids should be considered as an important aspect of DCR.

Outcomes of Open Reduction in Children With Developmental Hip Dislocation: A Multicenter Experience Over a Decade.

BACKGROUND: Open reduction of the hip is commonly performed in children with severe developmental dysplasia of the hip, or in cases that are refractory to nonoperative forms of treatment. The open reduction has been associated with numerous complications including avascular necrosis (AVN) of the femoral head, the need for reoperation, and residual radiographic dysplasia. This study seeks to determine the effects of preoperative severity of dysplasia, associated procedures (femoral and acetabular osteotomies), age on AVN, and the need for reoperation. METHODS: Children with developmental dysplasia of the hip and a minimum of 2 years of follow-up who underwent open reduction were identified. The following data points were recorded: sex, laterality of hip involvement, simultaneous procedures, surgical approach used, age, acetabular index, and International Hip Dysplasia Institute grade. We analyzed the effects of preoperative International Hip Dysplasia Institute, age, surgical approach (anterior/medial), bilateral reduction, and simultaneous femoral shortening or pelvic osteotomy on the outcomes of AVN and reoperation. RESULTS: One hundred eighty-five hips in 149 patients were included in this study with an average follow-up of 4 years (range: 2 to 5 y). The average age at index surgery was 23 months (range: 1 to 121 mo). Overall, 60 hips (32.4%) required secondary surgical procedures at an average age of 58.5 months. High-grade AVN was noted in 24 hips (13.0%) and was found to be associated with the severity of the hip dislocation ( P = 0.02). A higher rate of reoperation was found in children over 18 months at the time of open reduction who did not receive an acetabular osteotomy ( P = 0.012). CONCLUSION: Approximately 1/3 of patients require another operative intervention within the first 4 years after open reduction of the hip. We found the severity of hip dislocation to be associated with a higher risk of AVN development. These findings support performing an acetabular osteotomy in children over 18 months of age at the time of open reduction to decrease the likelihood of requiring future reoperation during the first 4 years after the index procedure. LEVEL OF EVIDENCE: Level III.

Can Military Role 1 Practitioners Maintain Their Skills Working at Civilian Level 1 Trauma Centers: A Retrospective, Cross-Sectional Study.

BACKGROUND: Introduction: Military Role 1 practitioners have difficulty maintaining skill competency by working solely in military medical treatment facilities. Recognizing this, the Army Medical Department has renewed focus on physician specialty-specific Individual Critical Task Lists (ICTL) and is increasing the number of military-civilian partnerships, wherein small military treatment teams work full-time in civilian trauma centers. Yet, data to validate this approach is lacking. We hypothesize military Role 1 practitioners working full-time at a civilian Level 1 trauma center would attain similar resuscitation-specific procedural frequency to providers deployed to an active combat zone, and use the emergency medicine (EM) ICTL to compare select procedural frequency between a cohort of trauma patients from a civilian Level 1 trauma center and a cohort of combat casualties from the Department of Defense Trauma Registry (DODTR). METHODS: We compared a selected subset of critically-injured, military-aged (18-35 years) trauma patients who were seen in a Level I Trauma Center emergency department (ED) between January 1, 2016 and December 31, 2017 and dispositioned directly either to the operating room, intensive care unit, or morgue to a selected cohort from the Department of Defense Trauma Registry (DODTR) who were seen in EDs in Iraq and Afghanistan between January 2007 and August 2016 using descriptive statistics. The primary outcome was the frequency of ICTL procedures performed, and the secondary outcome was injury severity. RESULTS: We identified 843 civilian patients meeting inclusion criteria, of 1,719 military-aged patients captured by the trauma registry during the study. The selected cohort from the DODTR included 27,359 patients. Demographics were similar between the 2 groups, except the DODTR cohort included significantly more patients with blast trauma (55% versus 0.4%). We found similar ICTL procedural frequency (1 procedure for every 1.84 patients in the civilian cohort compared to one procedure/1.52 patients in the military cohort). CONCLUSION: Role-1 ICTL trauma procedures were performed at similar frequencies between civilian patients seen at a Level 1 trauma center and combat casualties. With proper practice implementation, the opportunity exists for Role 1 practitioners to maintain their trauma resuscitation skills at civilian trauma centers.

A Multicompartmental Diffusion Model for Improved Assessment of Whole-Body Diffusion-weighted Imaging Data and Evaluation of Prostate Cancer Bone Metastases.

Purpose To develop a multicompartmental signal model for whole-body diffusion-weighted imaging (DWI) and apply it to study the diffusion properties of normal tissue and metastatic prostate cancer bone lesions in vivo. Materials and Methods This prospective study (ClinicalTrials.gov: NCT03440554) included 139 men with prostate cancer (mean age, 70 years ± 9 [SD]). Multicompartmental models with two to four tissue compartments were fit to DWI data from whole-body scans to determine optimal compartmental diffusion coefficients. Bayesian information criterion (BIC) and model-fitting residuals were calculated to quantify model complexity and goodness of fit. Diffusion coefficients for the optimal model (having lowest BIC) were used to compute compartmental signal-contribution maps. The signal intensity ratio (SIR) of bone lesions to normal-appearing bone was measured on these signal-contribution maps and on conventional DWI scans and compared using paired t tests (α = .05). Two-sample t tests (α = .05) were used to compare compartmental signal fractions between lesions and normal-appearing bone. Results Lowest BIC was observed from the four-compartment model, with optimal compartmental diffusion coefficients of 0, 1.1 × 10-3, 2.8 × 10-3, and >3.0 ×10-2 mm2/sec. Fitting residuals from this model were significantly lower than from conventional apparent diffusion coefficient mapping (P < .001). Bone lesion SIR was significantly higher on signal-contribution maps of model compartments 1 and 2 than on conventional DWI scans (P < .008). The fraction of signal from compartments 2, 3, and 4 was also significantly different between metastatic bone lesions and normal-appearing bone tissue (P ≤ .02). Conclusion The four-compartment model best described whole-body diffusion properties. Compartmental signal contributions from this model can be used to examine prostate cancer bone involvement. Keywords: Whole-Body MRI, Diffusion-weighted Imaging, Restriction Spectrum Imaging, Diffusion Signal Model, Bone Metastases, Prostate Cancer Clinical trial registration no. NCT03440554 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Margolis in this issue.

Involuntary refreshing of mental representations.

Laboratory tasks have revealed that mental representations (e.g., mental imagery) can enter consciousness in a manner that is involuntary, reliable, and insuppressible. These effects illuminate the capacities of involuntary processes as well as the function of voluntary, conscious processing. The Reflexive Imagery Task was developed a decade ago to investigate these involuntary effects systematically. Can refreshing yield such involuntary effects? Refreshing is the reactivating in mind of a mental representation that was activated moments ago. It is associated with mental rehearsal and executive function. We investigated whether a mental representation (subvocalization of an object name) can arise in consciousness involuntarily after a delayed interval, when the relevant stimulus is no longer present, and in response to a cue. In Experiment 1, participants were instructed not to refresh a previously presented (6 s before) stimulus in response to a cue. Involuntary refreshing occurred on a substantive proportion (0.56) of the trials. Experiment 2 replicated and extended this finding (proportion of the trials = 0.53) with a refreshing task that was more challenging than that of Experiment 1. Our findings suggest that mental representations arising from processes such as refreshing can occur involuntarily. We discuss the theoretical implications of this conclusion.

Rates and Levels of Elite Sport Participation at 5 Years After Revision ACL Reconstruction.

BACKGROUND: There is a paucity of data regarding return to play (RTP), level of competition, and longevity of play after revision of anterior cruciate ligament (ACL) reconstruction (ACLR) in elite athletes. PURPOSE: To report RTP rates and competition levels in elite athletes at the point of RTP, as well as at 2 and 5 years after revision ACLR, and the effect of meniscal and chondral pathology at revision surgery on these outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective review of a consecutive series of all revision ACLRs undertaken by the senior author between 2009 and 2019, with a minimum 2-year follow-up, was carried out. Outcome measures were RTP rates and competition level. RESULTS: A total of 49 knees in 48 elite athletes met the inclusion criteria. After revision ACLR, 43 (87.8%) elite athletes achieved RTP, of whom 75.5% were at the same level. At 2 years after surgery, 39 (79.6%) were still playing, 25 (51%) at the same level; at 5 years after surgery, 20 (44.4%) were still playing, 9 (20%) at the same level. Elite athletes with <50% thickness or no articular cartilage lesions were more likely to RTP (94.6% vs 66.7%; P = .026), as well as return to the same competition level (83.8% vs 50%; P = .047), compared with those with ≥50% thickness chondral lesions. Those without medial meniscal pathology were more likely to RTP at the same level after revision surgery (94.4% vs 64.5%; P = .036). The median time elite athletes continued to play after revision ACLR was 73 months (95% CI, 43.4-102.6); 23 months at the same level (95% CI, 13.6-32.4). The probability of still playing at 5 years after surgery was 55.9%, with a 22.5% chance of maintaining preinjury competition level. CONCLUSION: In elite athletes, RTP rates and competition level decreased over time after revision ACLR. The presence of >50% thickness chondral pathology was associated with lower RTP rates and competition level at RTP time, while medial meniscal pathology was associated with lower competition level at RTP.

Hyperfibrinolysis drives mechanical instabilities in a simulated model of trauma induced coagulopathy.

INTRODUCTION: Trauma induced coagulopathy (TIC) is common after severe trauma, increasing transfusion requirements and mortality among patients. TIC has several phenotypes, with primary hyperfibrinolysis being among the most lethal. We aimed to investigate the contribution of hypercoagulation, hemodilution, and fibrinolytic activation to the hyperfibrinolytic phenotype of TIC, by examining fibrin formation in a plasma-based model of TIC. We hypothesized that instabilities arising from TIC will be due primarily to increased fibrinolytic activation rather than hemodilution or tissue factor (TF) induced hypercoagulation. METHODS: The influence of TF, hemodilution, fibrinogen consumption, tissue plasminogen activator (tPA), and the antifibrinolytic tranexamic acid (TXA) on plasma clot formation and structure were examined using rheometry, optical properties, and confocal microscopy. These were then compared to plasma samples from trauma patients at risk of developing TIC. RESULTS: Combining TF-induced clot formation, 15 % hemodilution, fibrinogen consumption, and tPA-induced fibrinolysis, the clot characteristics and hyperfibrinolysis were consistent with primary hyperfibrinolysis. TF primarily increased fibrin polymerization rates and reduced fiber length. Hemodilution decreased clot optical density but had no significant effect on mechanical clot stiffness. TPA addition induced primary clot lysis as observed mechanically and optically. TXA restored mechanical clot formation but did not restore clot structure to control levels. Patients at risk of TIC showed increased clot formation, and lysis like that of our simulated model. CONCLUSIONS: This simulated TIC plasma model demonstrated that fibrinolytic activation is a primary driver of instability during TIC and that clot mechanics can be restored, but clot structure remains altered with TXA treatment.

Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia.

BACKGROUND: Noncompressible truncal hemorrhage (NCTH) remains a leading cause of preventable death on the battlefield. Definitively managing severe NCTH requires surgery within the first hour after injury, which is difficult when evacuating casualties from remote and austere environments. During delays to surgery, hemostatic interventions that are performed prehospital can prevent coagulopathy and hemorrhagic shock and increase the likelihood that casualties survive to receive definitive care. We previously reported that a self-propelling thrombin-containing powder (SPTP) can be delivered percutaneously into the abdomen as a minimally invasive intervention and can self-disperse through pooled blood to deliver the hemostatic agents thrombin and tranexamic acid locally to noncompressible intracavitary wounds. We hypothesized that, in swine with massive NCTH, dilutional coagulopathy, and hypothermia, delivering SPTP could extend survival times. METHODS: Ten swine (n = 5 per group) underwent NCTH from a Grade V liver injury following a midline laparotomy. The laparotomy was closed with sutures afterwards, creating a hemoperitoneum, and animals were managed with crystalloid fluid resuscitation, or crystalloid resuscitation and SPTP. Self-propelling thrombin-containing powder was delivered into the closed abdomen using a CO 2 -powered spray device and a catheter placed into the hemoperitoneum, entering through the upper right quadrant using the Seldinger technique. Survival to 1 and 3 hours was recorded. In an additional animal, hemorrhage was created laparoscopically, and SPTP was imaged in situ within the abdomen to visually track dispersion of the particles. RESULTS: Self-propelling thrombin-containing powder dispersed as far as 35 ± 5.0 cm within the abdomen. It increased survival to 1 and 3 hours (Kaplan-Meier p = 0.007 for both). The median survival time was 61 minutes with SPTP and 31 minutes without ( p = 0.016). CONCLUSION: Self-propelling thrombin-containing powder effectively disperses medications throughout a hemoperitoneum and increases survival in a model of NCTH. It is a promising strategy for nonsurgical management of NCTH, warranting further testing of its safety and efficacy.