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Introduction: Hemorrhage remains a leading cause of death in civilian and military trauma. Hemorrhages also extend to military working dogs, who can experience injuries similar to those of the humans they work alongside. Unfortunately, current physiological monitoring is often inadequate for early detection of hemorrhage. Here, we evaluate if features extracted from the arterial waveform can allow for early hemorrhage prediction and improved intervention in canines. Methods: In this effort, we extracted more than 1,900 features from an arterial waveform in canine hemorrhage datasets prior to hemorrhage, during hemorrhage, and during a shock hold period. Different features were used as input to decision tree machine learning (ML) model architectures to track three model predictors-total blood loss volume, estimated percent blood loss, and area under the time versus hemorrhaged blood volume curve. Results: ML models were successfully developed for total and estimated percent blood loss, with the total blood loss having a higher correlation coefficient. The area predictors were unsuccessful at being directly predicted by decision tree ML models but could be calculated indirectly from the ML prediction models for blood loss. Overall, the area under the hemorrhage curve had the highest sensitivity for detecting hemorrhage at approximately 4 min after hemorrhage onset, compared to more than 45 min before detection based on mean arterial pressure. Conclusion: ML methods successfully tracked hemorrhage and provided earlier prediction in canines, potentially improving hemorrhage detection and objectifying triage for veterinary medicine. Further, its use can potentially be extended to human use with proper training datasets.

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Hemorrhagic shock and subsequent resuscitation can cause significant dysregulation of critical systems, including the vascular endothelium. Following hemorrhage, the endothelial lining (glycocalyx) can shed, causing release of glycocalyx components, endothelial activation, and systemic inflammation. A canine model of hemorrhagic shock was used to evaluate five resuscitation fluids, including Lactated Ringers+Hetastarch, Whole Blood (WB), Fresh Frozen Plasma+packed Red Blood Cells (FFP+pRBC), and two hemoglobin-based oxygen carrier (HBOC) fluids, for their impact on glycocalyx shedding. Under anesthesia, purpose-bred adult canines were instrumented and subjected to a controlled hemorrhage with blood being drawn until a mean arterial pressure of <50 mmHg was reached or 40 % of the estimated blood volume was removed. Canines were left in shock for 45 mins before being resuscitated with one of the resuscitation fluids over 30 mins. Following resuscitation, the dogs were monitored up to 2 weeks. Following an additional 3-4 weeks for washout, the canines repeated the protocol, undergoing each resuscitation fluid individually. Blood samples were collected during each round at various timepoints for serum isolation, which was used for detection of glycocalyx biomarker. Comparison of baseline and post-hemorrhage alone showed a significant reduction in serum protein (p<0.0001), heparan sulfate (p<0.001), and syndecan-1 (p<0.0001) concentrations, and a significant increase in hyaluronan (p<0.0001) concentration. Intercomparisons of resuscitation fluids indicated minimal differences in glycocalyx markers over time. Comparisons within each fluid showed dynamic responses in glycocalyx biomarkers over time. Relative to individual baselines, syndecan-1 was significantly reduced after resuscitation in most cases (p<0.0001), excluding WB and FFP+pRBC. In all cases, VE-cadherin was significantly elevated at 24 hr compared to baseline (p<0.001). Hyaluronan was significantly elevated by 3 hr in all cases (p<0.01), except for HBOC fluids. Total glycosaminoglycans were significantly reduced only at 3 hr (p<0.001) for non-HBOC fluids. Similarly, heparan sulfate was significantly reduced with all fluids between resuscitation and 24 hr (p<0.01), except WB. The temporal changes in canine glycocalyx biomarkers were atypical of hemorrhage response in other species. This suggests that the hemorrhage lacked severity and/or typical glycocalyx biomarkers do not reflect the canine endothelium compared to other species. Further research is needed to characterize the canine endothelium and the response to resuscitation fluids.

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Ischemia-reperfusion injury (IRI) profoundly impacts organ transplantation, especially in orthotopic liver transplantation (OLT). Disruption of the mitochondrial respiratory chain during ischemia leads to ATP loss and ROS production. Reperfusion exacerbates mitochondrial damage, triggering the release of damage-associated molecular patterns (DAMPs) and inflammatory responses. Mitochondrial dysfunction, a pivotal aspect of IRI, is explored in the context of the regulatory role of ectonucleotidases in purinergic signaling and immune responses. CD39, by hydrolyzing ATP and ADP; and CD73, by converting AMP to adenosine, emerge as key players in mitigating liver IRI, particularly through ischemic preconditioning and adenosine receptor signaling. Despite established roles in vascular health and immunity, the impact of ectonucleotidases on mitochondrial function during hepatic IRI is unclear. This review aims to elucidate the interplay between CD39/73 and mitochondria, emphasizing their potential as therapeutic targets for liver transplantation. This article explores the role of CD39/73 in tissue hypoxia, emphasizing adenosine production during inflammation. CD39 and CD73 upregulation under hypoxic conditions regulate immune responses, demonstrating protective effects in various organ-specific ischemic models. However, prolonged adenosine activation may have dual effects, beneficial in acute settings but detrimental in chronic hypoxia. Herein, we raise questions about ectonucleotidases influencing mitochondrial function during hepatic IRI, drawing parallels with cancer cell responses to chemotherapy. The review underscores the need for comprehensive research into the intricate interplay between ectonucleotidases, mitochondrial dynamics, and their therapeutic implications in hepatic IRI, providing valuable insights for advancing transplantation outcomes.

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BACKGROUND: Early administration of adrenaline is associated with improved survival after out-of-hospital cardiac arrest (OHCA). Delays in vascular access may impact the timely delivery of adrenaline. Novel methods for administering adrenaline before vascular access may enhance survival. The objective of this study was to determine whether an initial intramuscular (IM) adrenaline dose followed by standard IV/IO adrenaline is associated with improved survival after OHCA. METHODS STUDY DESIGN: We conducted a before-and-after study of the implementation of an early, first-dose IM adrenaline EMS protocol for adult OHCAs. The pre-intervention period took place between January 2010 and October 2019. The post-intervention period was between November 2019 and May 2024. SETTING: Single-center urban, two-tiered EMS agency. PARTICIPANTS: Adult, nontraumatic OHCA meeting criteria for adrenaline use. INTERVENTION: Single dose (5 mg) IM adrenaline. All other care, including subsequent IV or IO adrenaline, followed international guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to hospital discharge. Secondary outcomes were time from EMS arrival to the first dose of adrenaline, survival to hospital admission, and favorable neurologic function at discharge. RESULTS: Among 1405 OHCAs, 420 (29.9%) received IM adrenaline and 985 (70.1%) received usual care. Fifty-two patients received the first dose of adrenaline through the IV or IO route within the post-intervention period and were included in the standard care group analysis. Age was younger and bystander CPR was higher in the IM adrenaline group. All other characteristics were similar between IM and standard care cohorts. Time to adrenaline administration was faster for the IM cohort [(median 4.3 min (IQR 3.0-6.0) vs. 7.8 min (IQR 5.8-10.4)]. Compared with standard care, IM adrenaline was associated with improved survival to hospital admission (37.1% vs. 31.6%; aOR 1.37, 95% CI 1.06-1.77), hospital survival (11.0% vs 7.0%; aOR 1.73, 95% CI 1.10-2.71) and favorable neurologic status at hospital discharge (9.8% vs 6.2%; aOR 1.72, 95% CI 1.07-2.76). CONCLUSION: In this single-center before-and-after implementation study, an initial IM dose of adrenaline as an adjunct to standard care was associated with improved survival to hospital admission, survival to hospital discharge, and functional survival. A randomized controlled trial is needed to fully assess the potential benefit of IM adrenaline delivery in OHCA.

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BACKGROUND: Treatment of severe hemorrhagic shock typically involves hemostatic resuscitation with blood products. However, logistical constraints often hamper the wide distribution of commonly used blood products like whole blood. Shelf-stable blood products and blood substitutes are poised to be able to effectively resuscitate individuals in hemorrhagic shock when more conventional blood products are not readily available. METHODS: Purpose-bred adult dogs (n = 6) were anesthetized, instrumented, and subjected to hemorrhagic shock (mean arterial pressure <50 mm Hg or 40% blood volume loss). Then each dog was resuscitated with one of five resuscitation products: (1) lactated ringers solution and hetastarch (LRS/Heta), (2) canine chilled whole blood (CWB), (3) fresh frozen plasma (FFP) and packed red blood cells (pRBC), (4) canine freeze-dried plasma (FDP) and hemoglobin-based oxygen carrier (HBOC), or (5) HBOC/FDP and canine lyophilized platelets (LyoPLT). Each dog was allowed to recover after the hemorrhage resuscitation event and was then subjected to another hemorrhage event and resuscitated with a different product until each dog was resuscitated with each product. RESULTS: At the time when animals were determined to be out of shock as defined by a shock index <1, mean arterial pressure (mmHg) values (mean ± standard error) were higher for FFP/pRBC (n = 5, 83.7 ± 4.5) and FDP/HBOC+LyoPLT (n = 4, 87.8 ± 2.1) as compared with WB (n = 4, 66.0 ± 13.1). A transient increase in creatinine was seen in dogs resuscitated with HBOC and FDP. Albumin and base excess increased in dogs resuscitated with HBOC and FDP products compared with LRS/heta and CWB ( p < 0.01). CONCLUSION: Combinations of shelf-stable blood products compared favorably to canine CWB for resolution of shock. Further research is needed to ascertain the reliability and efficacy of these shelf-stable combinations of products in other models of hemorrhage that include a component of tissue damage as well as naturally occurring trauma.

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Trauma is a common cause of morbidity and mortality in humans and companion animals. Recent efforts in procedural development, training, quality systems, data collection, and research have positively impacted patient outcomes; however, significant unmet need still exists. Coordinated efforts by collaborative, translational, multidisciplinary teams to advance trauma care and improve outcomes have the potential to benefit both human and veterinary patient populations. Strategic use of veterinary clinical trials informed by expertise along the research spectrum (i.e., benchtop discovery, applied science and engineering, large laboratory animal models, clinical veterinary studies, and human randomized trials) can lead to increased therapeutic options for animals while accelerating and enhancing translation by providing early data to reduce the cost and the risk of failed human clinical trials. Active topics of collaboration across the translational continuum include advancements in resuscitation (including austere environments), acute traumatic coagulopathy, trauma-induced coagulopathy, traumatic brain injury, systems biology, and trauma immunology. Mechanisms to improve funding and support innovative team science approaches to current problems in trauma care can accelerate needed, sustainable, and impactful progress in the field. This review article summarizes our current understanding of veterinary and human trauma, thereby identifying knowledge gaps and opportunities for collaborative, translational research to improve multispecies outcomes. This translational trauma group of MDs, PhDs, and DVMs posit that a common understanding of injury patterns and resulting cellular dysregulation in humans and companion animals has the potential to accelerate translation of research findings into clinical solutions.

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Acute kidney injury is a common complication of trauma and hemorrhagic shock. In a porcine model of hemorrhagic shock, resuscitative endovascular balloon aortic occlusion (REBOA) and hemodilution, we hypothesized that invasive kidney oxygen concentration measurements would correlate more strongly with noninvasive near infra-red spectroscopy (NIRS) oxygen saturation measurements when cutaneous sensors were placed over the kidney under ultrasound guidance compared to placement over the thigh muscle and subcutaneous tissue. Eight anesthetized swine underwent hemorrhagic shock 4 of which were resuscitated with intravenous fluids prior to the return of shed blood (Hemodilution protocol) and 4 of which underwent REBOA prior to resuscitation and return of shed blood (REBOA protocol). There was a moderate correlation between the NIRS and kidney tissue oxygen measurements (r = 0.61 p < 0.001; r = 0.67 p < 0.001; r = 0.66 p < 0.001for left kidney, right kidney, and thigh NIRS respectively). When the animals were separated by protocol, the Hemodilution group showed a weak or nonsignificant correlation between NIRS and kidney tissue oxygen measurements (r = 0.10 p < 0.001; r = 0.01 p = 0.1007; r = 0.28 p < 0.001 for left kidney, right kidney, and thigh NIRS respectively). This contrasts with the REBOA group, where left and right kidney as well as thigh NIRS were moderately correlated with kidney tissue oxygen (r = 0.71 p < 0.001; r = 0.74 p < 0.001; r = 0.70 p < 0.001; for left kidney, right kidney, and thigh NIRS respectively). There was a strong correlation between both kidney NIRS signals and thigh NIRS measurements (r = 0.85 p < 0.001; r = 0.88 p < 0.001;for left kidney vs thigh and right kidney vs thigh respectively). There was also a strong correlation between left and right kidney NIRS (r = 0.90 p < 0.001). These relationships were maintained regardless of the resuscitation protocol. These results suggest that kidney NIRS measurements were more closely related to thigh NIRS measurements than invasive kidney tissue oxygen concentration.

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OBJECTIVE: To describe the use of a synthetic hemostatic dressing, QuikClot Combat Gauze (QCG), in dogs with bleeding wounds. CASE SERIES SUMMARY: Two dogs presented with bleeding traumatic wounds, and QCG was used to achieve hemostasis during stabilization of these dogs. In the other 2 dogs, QCG was used to help attenuate bleeding associated with a surgical procedure. NEW OR UNIQUE INFORMATION PROVIDED: While hemostatic dressings have been widely studied and used in human medicine, there is minimal information on the use and efficacy of these hemostatic dressings in veterinary medicine. This case series describes the use of QCG in dogs with hemorrhaging wounds. QCG could be a valuable resource in veterinary emergency and critical care settings.

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Background: Evolving research on resuscitative endovascular balloon occlusion of the aorta (REBOA) as an adjunct treatment for out-of-hospital cardiac arrest mandates uniform recording and reporting of data. A consensus on which variables need to be collected may enable comparing and merging data from different studies. We aimed to establish a standard set of variables to be collected and reported in future REBOA studies in out-of-hospital cardiac arrest. Methods: A four-round stepwise Delphi consensus process first asked experts to propose without restraint variables for future REBOA research in out-of-hospital cardiac arrest. The experts then reviewed the variables on a 5-point Likert scale and ≥75% agreement was defined as consensus. First authors of published papers on REBOA in out-of-hospital cardiac arrest over the last five years were invited to join the expert panel. Results: The data were collected between May 2022 and December 2022. A total of 28 experts out of 34 primarily invited completed the Delphi process, which developed a set of 31 variables that might be considered as a supplement to the Utstein style reporting of research in out-of-hospital cardiac arrest. Conclusions: This Delphi consensus process suggested 31 variables that enable future uniform reporting of REBOA in out-of-hospital cardiac arrest.

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BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is frequent. While two network meta-analyses assessed the impact of pharmacological interventions to prevent CSA-AKI, none focused on non-pharmacological interventions. We aim to assess the effectiveness of non-pharmacological interventions to reduce the incidence of CSA-AKI. METHODS: We searched PubMed, Embase, Central and clinical trial registries from January 1, 2004 (first consensus definition of AKI) to July 1, 2023. Additionally, we conducted manual screening of abstracts of major anesthesia and intensive care conferences over the last 5 years and reference lists of relevant studies. We selected all randomized controlled trials (RCTs) assessing a non-pharmacological intervention to reduce the incidence of CSA-AKI, without language restriction. We excluded RCTs of heart transplantation or involving a pediatric population. The primary outcome variable was CSA-AKI. Two reviewers independently identified trials, extracted data and assessed risk of bias. Random-effects meta-analyses were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence. RESULTS: We included 86 trials (25,855 patients) evaluating 10 non-pharmacological interventions to reduce the incidence of CSA-AKI. No intervention had high-quality evidence to reduce CSA-AKI. Two interventions were associated with a significant reduction in CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion (RR, 0.55 [95% CI 0.40-0.76], I2 = 0%; Phet = 0.44) and remote ischemic preconditioning (RR, 0.86 [0.78-0.95]; I2 = 23%; Phet = 0.07). Pulsatile flow during cardiopulmonary bypass was associated with a significant reduction in CSA-AKI incidence but with very low quality of evidence (RR = 0.69 [0.48; 0.99]; I2 = 53%; Phet < 0.01). We found high quality of evidence for lack of effect of restrictive transfusion strategy (RR, 1.02 [95% CI 0.92; 1.12; Phet = 0.67; I2 = 3%) and tight glycemic control (RR, 0.86 [95% CI 0.55; 1.35]; Phet = 0.25; I2 = 26%). CONCLUSIONS: Two non-pharmacological interventions are likely to reduce CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion and remote ischemic preconditioning.

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Aims: The aim of this study was to evaluate the association between chondral injury and interval from anterior cruciate ligament (ACL) tear to surgical reconstruction (ACLr). Methods: Between January 2012 and January 2022, 1,840 consecutive ACLrs were performed and included in a single-centre retrospective cohort. Exclusion criteria were partial tears, multiligament knee injuries, prior ipsilateral knee surgery, concomitant unicompartmental knee arthroplasty or high tibial osteotomy, ACL agenesis, and unknown date of tear. A total of 1,317 patients were included in the final analysis, with a median age of 29 years (interquartile range (IQR) 23 to 38). The median preoperative Tegner Activity Score (TAS) was 6 (IQR 6 to 7). Patients were categorized into four groups according to the delay to ACLr: < three months (427; 32%), three to six months (388; 29%), > six to 12 months (248; 19%), and > 12 months (254; 19%). Chondral injury was assessed during arthroscopy using the International Cartilage Regeneration and Joint Preservation Society classification, and its association with delay to ACLr was analyzed using multivariable analysis. Results: In the medial compartment, delaying ACLr for more than 12 months was associated with an increased rate (odds ratio (OR) 1.93 (95% confidence interval (CI) 1.27 to 2.95); p = 0.002) and severity (OR 1.23 (95% CI 1.08 to 1.40); p = 0.002) of chondral injuries, compared with < three months, with no association in patients aged > 50 years old. No association was found for shorter delays, but the overall dose-effect analysis was significant for the rate (p = 0.015) and severity (p = 0.026) of medial chondral injuries. Increased TAS was associated with a significantly reduced rate (OR 0.88 (95% CI 0.78 to 0.99); p = 0.036) and severity (OR 0.96 (95% CI 0.92 to 0.99); p = 0.017) of medial chondral injuries. In the lateral compartment, no association was found between delay and chondral injuries. Conclusion: Delay was associated with an increased rate and severity of medial chondral injuries in a dose-effect fashion, in particular for delays > 12 months. Younger patients seem to be at higher risk of chondral injury when delaying surgery. The timing of ACLr should be optimally reduced in this population.

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BACKGROUND: The study of chronic pain and its treatments requires a robust animal model with objective and quantifiable metrics. Porcine neuropathic pain models have been assessed with peripheral pain recordings and behavioral responses, but thus far central nervous system electrophysiology has not been investigated. This work aimed to record non-invasive, somatosensory-evoked potentials (SEPs) via electroencephalography in order to quantitatively assess chronic neuropathic pain induced in a porcine model. NEW METHOD: Peripheral neuritis trauma (PNT) was induced unilaterally in the common peroneal nerve of domestic farm pigs, with the contralateral leg serving as the control for each animal. SEPs were generated by stimulation of the peripheral nerves distal to the PNT and were recorded non-invasively using transcranial electroencephalography (EEG). The P30 wave of the SEP was analyzed for latency changes. RESULTS: P30 SEPs were successfully recorded with non-invasive EEG. PNT resulted in significantly longer P30 SEP latencies (p < 0.01 [n = 8]) with a median latency increase of 14.3 [IQR 5.0 - 17.5] ms. Histological results confirmed perineural inflammatory response and nerve damage around the PNT nerves. COMPARISON WITH EXISTING METHOD(S): Control P30 SEPs were similar in latency and amplitude to those previously recorded invasively in healthy pigs. Non-invasive recordings have numerous advantages over invasive measures. CONCLUSIONS: P30 SEP latency can serve as a quantifiable neurological measure that reflects central nervous system processing in a porcine model of chronic pain. Advancing the development of a porcine chronic pain model will facilitate the translation of experimental therapies into human clinical trials.

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PURPOSE: To evaluate the heterogeneity in the definition of delirium in randomized controlled trials (RCTs) included in meta-analyses of delirium in intensive care units (ICUs) and to explore whether intervention effect depends on the definition used. METHODS: We searched PubMed for meta-analyses including RCTs evaluating prevention or treatment strategies of delirium in ICU. The definition of delirium was collected from RCTs and classified as validated (DSM criteria, CAM-ICU, ICDSC, NEECHAM, DRS-R98) or non-validated (non-validated scales, set of symptoms, physician appreciation or not reported). We conducted a meta-epidemiological analysis to compare intervention effects between trials using or not a validated definition by a two-step method as primary analysis and a multilevel model as secondary analysis. A ratio of odds ratios (ROR) < 1 indicated larger intervention effects in trials using a non-validated definition. RESULTS: Of 149 RCTs (41 meta-analyses), 109 (73.1%) used a validated definition and 40 (26.8%) did not (including 31 [20.8%] not reporting the definition). The primary analysis of 7 meta-analyses (30 RCTs) found no significant difference in intervention effects between trials using a validated definition and the others (ROR = 0.54, 95% CI 0.27-1.08), whereas the secondary multilevel analysis including 12 meta-analyses (67 RCTs) found significantly larger effects for trials using a non-validated versus a validated definition (ROR = 0.36, 95% CI 0.21-0.62). CONCLUSION: The definition of delirium was heterogeneous across RCTs, with one-fifth not reporting how they evaluated delirium. We did not find a significant association with intervention effect in the primary analysis. The secondary analysis including more studies revealed significantly larger intervention effects in trials using a non-validated versus a validated definition.

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Preclinical large animal models of chronic heart failure (HF) are crucial to both understanding pathological remodeling and translating fundamental discoveries into novel therapeutics for HF. Canine models of ischemic cardiomyopathy are historically limited by either high early mortality or failure to develop chronic heart failure. Twenty-nine healthy adult dogs (30 ± 4 kg, 15/29 male) underwent thoracotomy followed by one of three types of left anterior descending (LAD) coronary artery ligation procedures: group 1 (n = 4) (simple LAD: proximal and distal LAD ligation); group 2 (n = 14) (simple LAD plus lateral wall including ligation of the distal first diagonal and proximal first obtuse marginal); and group 3 (n = 11) (total LAD devascularization or TLD: simple LAD plus ligation of proximal LAD branches to both the right and left ventricles). Dogs were followed until chronic severe HF developed defined as left ventricular ejection fraction (LVEF) < 40% and NH2-terminal-prohormone B-type natriuretic peptide (NT-proBNP) > 900 pmol/L. Overall early survival (48-h postligation) in 29 dogs was 83% and the survival rate at postligation 5 wk was 69%. Groups 1 and 2 had 100% and 71% early survival, respectively, yet only a 50% success rate of developing chronic HF. Group 3 had excellent survival at postligation 48 h (91%) and a 100% success in the development of chronic ischemic HF. The TLD approach, which limits full LAD and collateral flow to its perfusion bed, provides excellent early survival and reliable development of chronic ischemic HF in canine hearts.NEW & NOTEWORTHY The novel total left anterior descending devascularization (TLD) approach in a canine ischemic heart failure model limits collateral flow in the ischemic zone and provides excellent early survival and repeatable development of chronic ischemic heart failure in the canine heart. This work provides a consistent large animal model for investigating heart failure mechanisms and testing novel therapeutics.

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BACKGROUND: Beyond the question of short-term survival, days spent at home could be considered a patient-centered outcome in critical care trials. RESEARCH QUESTION: What are the days spent at home and health care trajectories during the year after surviving critical illness? STUDY DESIGN AND METHODS: Data were extracted on adult survivors spending at least 2 nights in a French ICU during 2018 who were treated with invasive mechanical ventilation or vasopressors or inotropes. Trauma, burn, organ transplant, stroke, and neurosurgical patients were excluded. Stays at home, death, and hospitalizations were reported before and after ICU stay, using state sequence analysis. An unsupervised clustering method was performed to identify cohorts based on post-ICU trajectories. RESULTS: Of 77,132 ICU survivors, 89% returned home. In the year after discharge, these patients spent a median of 330 (interquartile range [IQR], 283-349) days at home. At 1 year, 77% of patients were still at home and 17% had died. Fifty-one percent had been re-hospitalized, and 10% required a further ICU admission. Forty-eight percent used rehabilitation facilities, and 5.7%, hospital at home. Three clusters of patients with distinct post-ICU trajectories were identified. Patients in cluster 1 (68% of total) survived and spent most of the year at home (338 [323-354] days). Patients in cluster 2 (18%) had more complex trajectories, but most could return home (91%), spending 242 (174-277) days at home. Patients in cluster 3 (14%) died, with only 37% returning home for 45 (15-90) days. INTERPRETATION: Many patients had complex health care trajectories after surviving critical illness. Wide variations in the ability to return home after ICU discharge were observed between clusters, which represents an important patient-centered outcome.

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Up to 50% of patients with trauma develop acute kidney injury (AKI), in part due to poor renal perfusion after severe blood loss. AKI is currently diagnosed based on a change in serum creatinine concentration from baseline or prolonged periods of decreased urine output. Unfortunately, baseline serum creatinine concentration data is unavailable in most patients with trauma, and current estimation methods are inaccurate. In addition, serum creatinine concentration may not change until 24-48 h after the injury. Lastly, oliguria must persist for a minimum of 6 h to diagnose AKI, making it impractical for early diagnosis. AKI diagnostic approaches available today are not useful for predicting risk during the resuscitation of patients with trauma. Studies suggest that urinary partial pressure of oxygen (PuO2) may be useful for assessing renal hypoxia. A monitor that connects the urinary catheter and the urine collection bag was developed to measure PuO2 noninvasively. The device incorporates an optical oxygen sensor that estimates PuO2 based on luminescence quenching principles. In addition, the device measures urinary flow and temperature, the latter to adjust for confounding effects of temperature changes. Urinary flow is measured to compensate for the effects of oxygen ingress during periods of low urine flow. This article describes a porcine model of hemorrhagic shock to study the relationship between noninvasive PuO2, renal hypoxia, and AKI development. A key element of the model is the ultrasound-guided surgical placement in the renal medulla of an oxygen probe, which is based on an unsheathed optical microfiber. PuO2 will also be measured in the bladder and compared to the kidney and noninvasive PuO2 measurements. This model can be used to test PuO2 as an early marker of AKI and assess PuO2 as a resuscitative endpoint after hemorrhage that is indicative of end-organ rather than systemic oxygenation.

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INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) causes a severe ischemia-reperfusion injury. Endovascular Perfusion Augmentation for Critical Care (EPACC) has emerged as a hemodynamic/mechanical adjunct to vasopressors and crystalloid for the treatment of post-REBOA ischemia-reperfusion injury. The objective of the study is to examine the impact of EPACC as a tool for a wean from complete REBOA compared to standard resuscitation techniques. METHODS: Nine swine underwent anesthesia and then a controlled 30% blood volume hemorrhage with 30 min of supraceliac total aortic occlusion to create an ischemia-reperfusion injury. Animals were randomized to standardized critical care (SCC) or 90 min of EPACC followed by SCC. The critical care phase lasted 270 min after injury. Hemodynamic markers and laboratory values of ischemia were recorded. RESULTS: During the first 90 min the intervention phase SCC spent 60% (54%-73%) and EPACC spent 91% (88%-92%) of the time avoiding proximal hypotension (<60 mm Hg), P = 0.03. There was also a statistically significant decrease in cumulative norepinephrine dose at the end of the experiment between SCC (80.89 mcg/kg) versus EPACC (22.03 mcg/kg), P = 0.03. Renal artery flow during EPACC was similar compared to SCC during EPACC, P = 0.19. But during the last hour of the experiment (after removal of aortic balloon) the renal artery flow in EPACC (2.9 mL/kg/min) was statistically significantly increased compared to SCC (1.57 mL/min/kg), P = 0.03. There was a statistically significant decrease in terminal creatinine in the EPACC (1.7 mg/dL) compared to SCC (2.1 mg/dL), P = 0.03. CONCLUSIONS: The 90 min of EPACC as a weaning adjunct in the setting of a severe ischemia-reperfusion injury after complete supraceliac REBOA provides improved renal flow with improvement in terminal creatinine compared to SCC with stabilized proximal hemodynamics and decreased vasopressor dose.

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BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.

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INTRODUCTION: Adverse drug reaction reports are usually manually assessed by pharmacovigilance experts to detect safety signals associated with drugs. With the recent extension of reporting to patients and the emergence of mass media-related sanitary crises, adverse drug reaction reports currently frequently overwhelm pharmacovigilance networks. Artificial intelligence could help support the work of pharmacovigilance experts during such crises, by automatically coding reports, allowing them to prioritise or accelerate their manual assessment. After a previous study showing first results, we developed and compared state-of-the-art machine learning models using a larger nationwide dataset, aiming to automatically pre-code patients' adverse drug reaction reports. OBJECTIVES: We aimed to determine the best artificial intelligence model identifying adverse drug reactions and assessing seriousness in patients reports from the French national pharmacovigilance web portal. METHODS: Reports coded by 27 Pharmacovigilance Centres between March 2017 and December 2020 were selected (n = 11,633). For each report, the Portable Document Format form containing free-text information filled by the patient, and the corresponding encodings of adverse event symptoms (in Medical Dictionary for Regulatory Activities Preferred Terms) and seriousness were obtained. This encoding by experts was used as the reference to train and evaluate models, which contained input data processing and machine-learning natural language processing to learn and predict encodings. We developed and compared different approaches for data processing and classifiers. Performance was evaluated using receiver operating characteristic area under the curve (AUC), F-measure, sensitivity, specificity and positive predictive value. We used data from 26 Pharmacovigilance Centres for training and internal validation. External validation was performed using data from the remaining Pharmacovigilance Centres during the same period. RESULTS: Internal validation: for adverse drug reaction identification, Term Frequency-Inverse Document Frequency (TF-IDF) + Light Gradient Boosted Machine (LGBM) achieved an AUC of 0.97 and an F-measure of 0.80. The Cross-lingual Language Model (XLM) [transformer] obtained an AUC of 0.97 and an F-measure of 0.78. For seriousness assessment, FastText + LGBM achieved an AUC of 0.85 and an F-measure of 0.63. CamemBERT (transformer) + Light Gradient Boosted Machine obtained an AUC of 0.84 and an F-measure of 0.63. External validation for both adverse drug reaction identification and seriousness assessment tasks yielded consistent and robust results. CONCLUSIONS: Our artificial intelligence models showed promising performance to automatically code patient adverse drug reaction reports, with very similar results across approaches. Our system has been deployed by national health authorities in France since January 2021 to facilitate pharmacovigilance of COVID-19 vaccines. Further studies will be needed to validate the performance of the tool in real-life settings.

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