Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock?

Objectives: Some centers have recommended including concentrated fibrinogen replacement in massive transfusion protocols (MTPs). Given our center's policy of aggressive early balanced resuscitation (1:1:1), beginning prehospital, we hypothesized that our rates of hypofibrinogenemia may be lower than those previously reported. Methods: In this retrospective cohort study, patients presenting to our trauma center November 2017 to April 2021 were reviewed. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography angle <60. Univariate and multivariable analyses assessed risk factors for HYPOFIB. Inverse probability of treatment weighting analyses assessed the relationship between cryoprecipitate administration and outcomes. Results: Of 29 782 patients, 6618 level 1 activations, and 1948 patients receiving emergency release blood, <1%, 2%, and 7% were HYPOFIB. HYPOFIB patients were younger, had higher head Abbreviated Injury Scale value, and had worse coagulopathy and shock. HYPOFIB had lower survival (48% vs 82%, p<0.001), shorter time to death (median 28 (7, 50) vs 36 (14, 140) hours, p=0.012), and were more likely to die from head injury (72% vs 51%, p<0.001). Risk factors for HYPOFIB included increased age (OR (95% CI) 0.98 (0.96 to 0.99), p=0.03), head injury severity (OR 1.24 (1.06 to 1.46), p=0.009), lower arrival pH (OR 0.01 (0.001 to 0.20), p=0.002), and elevated prehospital red blood cell to platelet ratio (OR 1.20 (1.02 to 1.41), p=0.03). Among HYPOFIB patients, there was no difference in survival for those that received early cryoprecipitate (within 2 hours; 40 vs 47%; p=0.630). On inverse probability of treatment weighted analysis, early cryoprecipitate did not benefit the full cohort (OR 0.52 (0.43 to 0.65), p<0.001), nor the HYPOFIB subgroup (0.28 (0.20 to 0.39), p<0.001). Conclusions: Low rates of hypofibrinogenemia were found in our center which treats hemorrhage with early, balanced resuscitation. Previously reported higher rates may be partially due to unbalanced resuscitation and/or delay in resuscitation initiation. Routine empiric inclusion of concentrated fibrinogen replacement in MTPs is not supported by the currently available data. Level of evidence: Level III.

Exposure to statin therapy decreases the incidence of venous thromboembolism after trauma.

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in trauma patients, despite chemoprophylaxis. Statins have been shown capable of acting upon the endothelium. We hypothesized that statin therapy in the pre- or in-hospital settings leads to a decreased incidence of VTE. METHODS: We conducted a retrospective cohort study of injured patients who received statin therapy pre- or in-hospital. Adult, highest-level trauma activation patients admitted January 2018 - June 2022 were included. Patients on prehospital anticoagulants, history of inherited bleeding disorder, and who died within the first 24 hours were excluded. Statin users were matched to non-users by statin use indications including age, current heart and cardiovascular conditions and history, hyperlipidemia, injury severity, and body mass index. Time to in-hospital statin initiation and occurrence of VTE and other complications within 60 days were collected. Differences between groups were determined by univariate, multivariable logistic regression, and Cox proportional hazard analyses. RESULTS: Of 3,062 eligible patients, 79 were statin users that were matched to 79 non-users. There were no differences in admissions demographics, vital signs, injury pattern, transfusion volumes, lengths of stay, or mortality between groups. The overall VTE incidence was 10.8% (17/158). Incidence of VTE in statin users was significantly lower (3%) than non-users (19%; P = 0.003). Differences between statin users and non-users were observed for rates of DVT (0% vs 9%), PE (3% vs 15%), and sepsis (0% vs 5%). Exposure to statins was associated with an 82% decreased risk of developing VTE (hazard ratio = 0.18, 95% CI 0.04 - 0.86; P = 0.033). CONCLUSIONS: Statin exposure was associated with decline in VTE and lower individual rates of DVT, PE, and sepsis. Our findings indicate that statins should be evaluated further as a possible adjunctive therapy for VTE chemoprophylaxis after traumatic injury. LEVEL OF EVIDENCE AND STUDY TYPE: Level III, Retrospective Cohort Study.

Addition of aspirin to venous thromboembolism chemoprophylaxis safely decreases venous thromboembolism rates in trauma patients.

Background: Trauma patients exhibit a multifactorial hypercoagulable state and have increased risk of venous thromboembolism (VTE). Despite early and aggressive chemoprophylaxis (CP) with various heparin compounds ("standard" CP; sCP), VTE rates remain high. In high-quality studies, aspirin has been shown to decrease VTE in postoperative elective surgical and orthopedic trauma patients. We hypothesized that inhibiting platelet function with aspirin as an adjunct to sCP would reduce the risk of VTE in trauma patients. Methods: We performed a retrospective observational study of prospectively collected data from all adult patients admitted to an American College of Surgeons Level I Trauma center from January 2012 to June 2015 to evaluate the addition of aspirin (sCP+A) to sCP regimens for VTE mitigation. Cox proportional hazard models were used to assess the potential benefit of adjunctive aspirin for symptomatic VTE incidence. Results: 10,532 patients, median age 44 (IQR 28 to 62), 68% male, 89% blunt mechanism of injury, with a median Injury Severity Score (ISS) of 12 (IQR 9 to 19), were included in the study. 8646 (82%) of patients received only sCP, whereas 1886 (18%) patients received sCP+A. The sCP+A cohort displayed a higher median ISS compared with sCP (13 vs 11; p<0.01). The overall median time of sCP initiation was hospital day 1 (IQR 0.8 to 2) and the median day for aspirin initiation was hospital day 3 (IQR 1 to 6) for the sCP+A cohort. 353 patients (3.4%) developed symptomatic VTE. Aspirin administration was independently associated with a decreased relative hazard of VTE (HR 0.57; 95% CI 0.36 to 0.88; p=0.01). There were no increased bleeding or wound complications associated with sCP+A (point estimate 1.23, 95% CI 0.68 to 2.2, p=0.50). Conclusion: In this large trauma cohort, adjunctive aspirin was independently associated with a significant reduction in VTE and may represent a potential strategy to safely mitigate VTE risk in trauma patients. Further prospective studies evaluating the addition of aspirin to heparinoid-based VTE chemoprophylaxis regimens should be sought. Level of evidence: Level III/therapeutic.

Hypofibrinogenemia following injury in 186 children and adolescents: identification of the phenotype, current outcomes, and potential for intervention.

Objectives: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion. Methods: All patients <18 years of age presenting to our trauma center 11/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography (r-TEG) angle <60 degrees. Our analysis sought to define risk factors for presenting with HYPOFIB, the impact on outcomes, and whether early replacement improved mortality. Results: 4169 patients were entered into the trauma registry, with 926 level 1 trauma activations, of which 186 patients received emergency-release blood products during this time; 1%, 3%, and 10% were HYPOFIB, respectively. Of the 186 patients of interest, 18 were HYPOFIB and 168 were non-HYPOFIB. The HYPOFIB patients were significantly younger, had lower field and arrival Glasgow Coma Scale, had higher head Abbreviated Injury Scale, arrived with worse global coagulopathy, and died from brain injury. Non-HYPOFIB patients were more likely to have (+)focused assessment for the sonography of trauma on arrival, sustained severe abdominal injuries, and die from hemorrhage. 12% of patients who received early cryoprecipitate (0-2 hours) had higher mortality by univariate analysis (55% vs 31%, p=0.045), but no difference on multivariate analysis (OR 0.36, 95% CI 0.07 to 1.81, p=0.221). Those receiving early cryoprecipitate who survived after pediatric intensive care unit (PICU) admission had lower PICU fibrinogen and r-TEG alpha-angle values. Conclusion: In pediatric trauma, patients with hypofibrinogenemia on admission are most likely younger and to have sustained severe brain injury, with an associated mortality of over 80%. Given the absence of bleeding-related deaths in HYPOFIB patients, this study does not provide evidence for the empiric use of cryoprecipitate in the initial administration of a massive transfusion protocol. Level of Evidence: Level III - Therapeutic/Care Management.

TIME-DEPENDENT CHANGES IN PROINFLAMMATORY MEDIATORS ARE ASSOCIATED WITH TRAUMA-RELATED VENOUS THROMBOEMBOLISM.

ABSTRACT: Background: Tissue trauma and hemorrhage result in pronounced activation of the innate immune system. Given known crosstalk between inflammation and coagulation, soluble inflammatory mediators could be associated with venous thromboembolisms (VTEs) after major trauma. Objectives : This study aimed to identify plasma inflammatory mediators that are independent predictors of VTE risk in trauma patients. Methods: We performed a secondary analysis of the Pragmatic Randomized Optimal Platelets and Plasma Ratios (PROPPR) study. Plasma levels of 27 cytokines/chemokines were measured by Bio-Plex at admission and 2, 4, 6, 12, 24, 48, and 72 h later. Patients who died from exsanguination or within 24 h were excluded. Mann-Whitney tests were performed to assess no-VTE and VTE groups at each time point. Multivariable logistic regression was used to determine the adjusted effects of inflammatory mediators on VTE risk. Results: Eighty-six of the 575 patients (15%) included developed VTE. Interleukin (IL)-1ra, IL-6, IL-8, IL-10, eotaxin, granulocyte colony-stimulating factor, interferon-γ-inducible protein, monocyte chemoattractant protein 1 (MCP-1), and chemokine ligand 5 (regulated on activation, normal T cell expressed and secreted) were all significantly increased among VTE patients. Multivariable analyses demonstrated that IL-6, IL-8, interferon-γ-inducible protein, and MCP-1 were independently associated with VTE. Cox proportional hazards modeling identified IL-6, IL-8, and MCP-1 as independent predictors of accelerated VTE development. We identified significant correlations between inflammation and markers of coagulation and endothelial activation. Conclusion: Sustained systemic inflammation is a key driver of VTE risk after major trauma. Therapeutics targeting innate immune activation should be considered for development of future multimodal strategies to augment current VTE prophylaxis.

Injury-induced endotheliopathy: What you need to know.

ABSTRACT: The endotheliopathy of trauma involves a complex interplay between the glycocalyx, von Willebrand factor, and platelets that leads to abnormalities in coagulation, inflammation, and endothelial cell (EC) function. The current review presents a synopsis of EC function under homeostatic conditions, the structure and function of the endothelial glycocalyx; mechanisms of EC injury and activation after trauma; pathological consequences of the EoT at the cellular level; and clinical implications of the EoT. Recent evidence is presented that links the EoT to extracellular vesicles and hyperadhesive ultralarge von Willebrand factor multimers through their roles in coagulopathy. Lastly, potential therapeutics to mitigate the EoT are discussed. Most research to date has focused on blood products, primarily plasma, and its contribution to restoring postinjury EC dysfunction. Additional therapeutic adjuvants that target the glycocalyx, ultralarge von Willebrand factor, low ADAMTS-13, and pathologic extracellular vesicles are reviewed. Much of the pathobiology of EoT is known, but a better mechanistic understanding can help guide therapeutics to further repair the EoT and improve patient outcomes.

Soluble endothelial protein C receptor is an independent predictor of venous thromboembolism after severe injury: Secondary analysis of a prospective cohort study.

BACKGROUND: Venous thromboembolism is a leading cause of morbidity after trauma. Endothelial cells are essential regulators of coagulation. Although endothelial cell dysregulation is widely reported after trauma, the link between endothelial injury and venous thromboembolism has not been reported. METHODS: We conducted a secondary analysis of the Pragmatic Randomized Optimal Platelets and Plasma Ratios study. Deaths from hemorrhage or within 24 hours were excluded. Venous thromboembolism was diagnosed by duplex ultrasound or chest computed tomography. Endothelial markers soluble endothelial protein c receptor, thrombomodulin, and syndecan-1 were measured in plasma by enzyme-linked immunosorbent assay and compared over the first 72 hours from admission using the Mann-Whitney test. Multivariable logistic regression assessed the adjusted effects of endothelial markers on venous thromboembolism risk. RESULTS: Of 575 patients enrolled, 86 developed venous thromboembolism (15%). The median time to venous thromboembolism was 6 days ([Q1, Q3], [4, 13]). No differences were identified in demographics or injury severity. Soluble endothelial protein c receptor, thrombomodulin, and syndecan-1 showed significant increases over time among patients who developed venous thromboembolism compared to those who did not. Using the last available values, patients were stratified into high and low-soluble endothelial protein c receptor, thrombomodulin, and syndecan-1 groups. Multivariable analyses revealed an independent association between elevated soluble endothelial protein c receptor and venous thromboembolism risk (odds ratio 1.63; 95% confidence interval 1.01, 2.63; P = .04). Cox proportional hazards modeling demonstrated a strong yet nonsignificant trend between elevated soluble endothelial protein c receptor and time to venous thromboembolism. CONCLUSION: Plasma markers of endothelial injury, particularly soluble endothelial protein c receptor, are strongly associated with trauma-related venous thromboembolism. Therapeutics targeting endothelial function could mitigate the incidence of venous thromboembolism after trauma.

Risk Indicators of Sarcoidosis Evolution-Unified Protocol (RISE-UP): protocol for a multi-centre, longitudinal, observational study to identify clinical features that are predictive of sarcoidosis progression.

INTRODUCTION: Sarcoidosis is a pulmonary and systemic granulomatous disease with a wide range of potential outcomes, from spontaneous resolution to end-stage organ damage and death. Currently, clinicians have no easy-to-use risk stratification tools for important clinical outcomes in sarcoidosis, such as progressive lung disease. This study will address two clinical practice needs: (1) development of a risk calculator that provides an estimate of the likelihood of pulmonary progression in sarcoidosis patients during the follow-up period and (2) determine the optimal interval for serial clinical monitoring (eg, 6, 12, 18 months) using these risk prediction tools. METHODS AND ANALYSIS: The Risk Indicators of Sarcoidosis Evolution-Unified Protocol study is a National Institutes of Health-sponsored, longitudinal observational study of adults with pulmonary sarcoidosis who will be enrolled at five US tertiary care centres. Participants will be evaluated at approximately 6-month intervals for up to 60 months with collection of lung function, blood samples and clinical data. The target sample size is 557 and the primary objective is to determine which clinical features measured during a routine clinic visit carry the most prognostic information for predicting clinical progression of pulmonary sarcoidosis over the follow-up period. The primary outcome measure will be quantified by a clinically meaningful change in forced vital capacity, forced expiratory volume in 1 s or diffusing capacity of the lung for carbon monoxide. The secondary objective is to determine if blood biomarkers measured during a routine clinic visit can improve the risk assessment modelling for progression of pulmonary sarcoidosis over the follow-up period. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Review Boards at each centre and the reliance Institutional Review Board overseeing the study (WCG, Protocol #20222400). Participants will provide informed consent prior to enrolment. Results will be disseminated via publication in a relevant peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05567133.

Lactobacillus bloodstream infections genetically related to probiotic use in pediatric hematopoietic cell transplant patients.

We describe a cluster of 6 pediatric hematopoietic cell transplant recipients with Lactobacillus bacteremia attributed to probiotic use. Lactobacillus isolates cultured from probiotics and patients' blood were proven to be related using whole-genome sequencing. Clinical studies are needed to evaluate the safety of probiotic use in immunocompromised patients.

Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.

Factores relacionados con absentismo laboral en una compañía minera colombiana / Factors Related to Absenteeism in a Colombian Mining Company / Fatores relacionados ao absenteísmo em uma empresa de mineração colombiana

El absentismo laboral es una condición que afecta cada día a un gran número de empresas y que repercute en los ámbitos económico, social y cultural. Objetivo: Caracterizar el absentismo laboral por causa médica durante 2021 en trabajadores del área operativa de una compañía de extracción de minerales en Antioquia (Colombia). Materiales y métodos: Estudio con enfoque cuantitativo, de tipo descriptivo, retrospectivo para caracterizar el ab-sentismo laboral de una empresa minera, teniendo en cuenta una base de datos suministrada por dicha empresa, en la cual se presentaron los registros de absentismo de los trabajadores de la mina y sus diferentes áreas durante 2021, correspondiente a un total de 1069 incapacidades. Resultados: Los factores asociados con un aumento de la frecuencia del absentismo fueron la antigüedad del trabajador en la empresa, el cargo desempeñado y el área al cual se está adscrito, teniendo así que las causas más frecuentes de absentismo fueron las enfermedades de origen común de tipo respiratorio y traumatismos. Conclusión: El absentismo laboral se encuentra relacionado con el patrón de enfermedad o accidente laboral, y su prevalencia, en cuanto a áreas y sexo, se encuentra relacionada con las características propias de la compañía.

Work absenteeism is a condition that affects a large number of companies every day, generating an economic, social and cultural impact. Objective: To characterize absenteeism due to medical reasons during the year 2021 in workers of the operative area of a mineral extraction company in Antioquia, Colombia. Material and Methods: A quantitative, descriptive, retrospective study was conducted to characterize absenteeism in the operational area of a mining extraction company in Colombia, taking into account a database provided by the company, which presents the records of absenteeism of workers in the mine and its different areas during the period of 2021, corresponding to a total of 1,069 incapacities. Results: The factors associated with an increase in the frequency of absenteeism were the worker's seniority in the company, the position held and the area to which he/she is assigned, thus having that the most frequent causes of absenteeism were common respiratory diseases and traumatisms. Conclusion: It can be concluded that absenteeism is related to the pattern of occupational illness or accident, and that the prevalence of absenteeism in terms of areas and sex is related to the company's own characteristics.

O absenteísmo é uma condição que afeta muitas empresas todos os dias e tem repercussões nas esferas econômica, social e cultural. Objetivo: Caracterizar o absenteísmo por motivos médicos durante 2021 em trabalhadores da área operacional de uma empresa de extração mineral em Antioquia (Colômbia). Materiais e métodos: Estudo quantitativo, descritivo e retrospectivo para caracterizar o absenteísmo em uma empresa de mineração, levando em conta um banco de dados fornecido pela empresa, no qual foram apresentados os registros de absenteísmo dos trabalhadores da mina e de suas diferentes áreas durante 2021, correspondendo a um total de 1069 incapacidades. Resultados: Os fatores associados a um aumento na frequência de absenteísmo foram a antiguidade do trabalhador na empresa, o cargo ocupado e a área para a qual ele foi designado, sendo que as causas mais frequentes de absenteísmo foram doenças respiratórias de origem comum e traumatismos. Conclusão: O absenteísmo está relacionado ao padrão de doença ou acidente de trabalho, e sua pre-valência, em termos de áreas e sexo, está relacionada às características próprias da empresa

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.

The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx's role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.

Treatment-refractory heart failure as a manifestation of aortic arch atresia.

BACKGROUND: Distal segment atresia (isthmus) is an extremely rare anatomical variant of obstructive aortic arch anomalies. CASE REPORT: We present the case of a newborn who, at 48 hours of life, presented a clinical picture of heart failure. The initial echocardiogram showed a congenital interrupted aortic arch type A, patent ductus arteriosus, and ventricular septal defect. Prostaglandins were initially indicated. Subsequently, a second echocardiogram showed the absence of ductus arteriosus; the CT angiography study confirmed this finding and revealed blood flow to the descending aorta through small intercostal blood vessels. The possibility of atresia of the distal segment (isthmus) of the aortic arch was considered and confirmed at the time of surgery. CONCLUSIONS: Aortic atresia should be considered a diagnostic possibility in the presence of type A interrupted aortic arch since the hemodynamic behavior between them is similar. Surgical medical treatment should be individualized since this condition is frequently an emergency in the neonatal period. However, this is not always the case, as other cases have been reported in schoolchildren and adults.

INTRODUCCIÓN: La atresia de segmento distal (istmo) de arco aórtico es una variante anatómica extremadamente rara de las anomalías obstructivas del arco aórtico. CASO CLÍNICO: Se presenta el caso de un recién nacido que a las 48 horas de vida presentó un cuadro clínico de insuficiencia cardiaca. El estudio de ecocardiograma inicial mostró una anomalía congénita de interrupción de arco aórtico tipo A, conducto arterioso y comunicación interventricular. De inicio se indicaron prostaglandinas. Posteriormente, el segundo ecocardiograma mostró la ausencia del conducto arterioso; el estudio de angiotomografía confirmó este hallazgo y también reveló flujo sanguíneo hacia aorta descendente a través de pequeños vasos sanguíneos intercostales. Se consideró la posibilidad de atresia del segmento distal (istmo) de arco aórtico y se confirmó al momento del acto quirúrgico. CONCLUSIONES: La atresia aórtica debe ser considerada como posibilidad diagnóstica en presencia de interrupción de arco aórtico tipo A, ya que el comportamiento hemodinámico entre ellos es similar. El tratamiento médico quirúrgico debe individualizarse, ya que es frecuente que sea una urgencia en el periodo neonatal. Sin embargo, no sucede así siempre, ya que se han reportado casos en escolares y adultos.

Treatment-refractory heart failure as a manifestation of aortic arch atresia / Falla cardiaca refractaria a tratamiento como manifestación de atresia de arco aórtico

Abstract Background: Distal segment atresia (isthmus) is an extremely rare anatomical variant of obstructive aortic arch anomalies. Case report: We present the case of a newborn who, at 48 hours of life, presented a clinical picture of heart failure. The initial echocardiogram showed a congenital interrupted aortic arch type A, patent ductus arteriosus, and ventricular septal defect. Prostaglandins were initially indicated. Subsequently, a second echocardiogram showed the absence of ductus arteriosus; the CT angiography study confirmed this finding and revealed blood flow to the descending aorta through small intercostal blood vessels. The possibility of atresia of the distal segment (isthmus) of the aortic arch was considered and confirmed at the time of surgery. Conclusions: Aortic atresia should be considered a diagnostic possibility in the presence of type A interrupted aortic arch since the hemodynamic behavior between them is similar. Surgical medical treatment should be individualized since this condition is frequently an emergency in the neonatal period. However, this is not always the case, as other cases have been reported in schoolchildren and adults.

Resumen Introducción: La atresia de segmento distal (istmo) de arco aórtico es una variante anatómica extremadamente rara de las anomalías obstructivas del arco aórtico. Caso clínico: Se presenta el caso de un recién nacido que a las 48 horas de vida presentó un cuadro clínico de insuficiencia cardiaca. El estudio de ecocardiograma inicial mostró una anomalía congénita de interrupción de arco aórtico tipo A, conducto arterioso y comunicación interventricular. De inicio se indicaron prostaglandinas. Posteriormente, el segundo ecocardiograma mostró la ausencia del conducto arterioso; el estudio de angiotomografía confirmó este hallazgo y también reveló flujo sanguíneo hacia aorta descendente a través de pequeños vasos sanguíneos intercostales. Se consideró la posibilidad de atresia del segmento distal (istmo) de arco aórtico y se confirmó al momento del acto quirúrgico. Conclusiones: La atresia aórtica debe ser considerada como posibilidad diagnóstica en presencia de interrupción de arco aórtico tipo A, ya que el comportamiento hemodinámico entre ellos es similar. El tratamiento médico quirúrgico debe individualizarse, ya que es frecuente que sea una urgencia en el periodo neonatal. Sin embargo, no sucede así siempre, ya que se han reportado casos en escolares y adultos.

Association of Changes in Antithrombin Activity Over Time With Responsiveness to Enoxaparin Prophylaxis and Risk of Trauma-Related Venous Thromboembolism.

Importance: Venous thromboembolism (VTE) affects 2% to 20% of recovering trauma patients, despite aggressive prophylaxis with enoxaparin. Antithrombin is a primary circulating anticoagulant and crucial component of enoxaparin thromboprophylaxis. Approximately 20% of trauma patients present with antithrombin deficiency (antithrombin activity <80%). Objective: To examine time-dependent changes in antithrombin activity, responsiveness to enoxaparin, as measured by anti-factor Xa (anti-FXa) levels, and incidence of VTE after severe trauma and to assess the association of ex vivo antithrombin supplementation with patients' sensitivity to enoxaparin prophylaxis. Design, Setting, and Participants: This single-center, prospective cohort study was performed at a level 1 trauma center between January 7, 2019, and February 28, 2020. Adult trauma patients admitted to the trauma service at high risk for VTE, based on injury pattern and severity, were screened and enrolled. Patients who were older than 70 years, were pregnant, had a known immunologic or coagulation disorder, or were receiving prehospital anticoagulants were excluded. Exposures: Blood samples were collected on emergency department arrival and daily for the first 8 days of hospitalization. Main Outcomes and Measures: Patients' antithrombin activity and anti-FXa levels were measured by a coagulation analyzer, and thrombin generation was measured by calibrated automated thrombography. Responsiveness to enoxaparin was assessed by measuring anti-FXa levels 4 to 6 hours after the first daily enoxaparin dose and compared between patients who developed VTE and who did not. In addition, the associations of ex vivo supplementation of antithrombin with plasma anti-FXa levels were assessed. Results: Among 150 patients enrolled (median [IQR] age, 35 [27-53] years; 37 [24.7%] female and 113 [75.3%] male; 5 [3.3%] Asian, 32 [21.3%] Black, and 113 [75.3%] White; and 51 [34.0%] of Hispanic ethnicity), 28 (18.7%) developed VTE. Patients with VTE had significantly lower antithrombin activity on admission compared with patients without VTE (median [IQR], 91% [79%-104%] vs 100% [88%-112%]; P = .04), as well as lower antithrombin activity on hospital days 5 (median (IQR), 90% [83%-99%] vs 114% [99%-130%]; P = .011), 6 (median [IQR], 97% [81%-109%] vs 123% [104%-134%]; P = .003), 7 (median [IQR], 82% [74%-89%] vs 123% [110%-140%]; P < .001), and 8 (median [IQR], 99% [85%-100%] vs 123% [109%-146%]; P = .011). Anti-FXa levels were significantly lower in patients with VTE vs those without VTE at hospital day 4 (median [IQR], 0.10 [0.05-0.14] IU/mL vs 0.18 [0.13-0.23] IU/mL; P = .006), day 6 (median [IQR], 0.12 [0.08-0.14] IU/mL vs 0.22 [0.13-0.28] IU/mL; P = .02), and day 7 (median [IQR], 0.11 [0.08-0.12] IU/mL vs 0.21 [0.13, 0.28] IU/mL; P = .002). Multivariable analyses found that for every 10% decrease in antithrombin activity during the first 3 days, the risk of VTE increased 1.5-fold. Conclusions and Relevance: The results of this cohort study suggest that after severe trauma, antithrombin deficiency is common and contributes to enoxaparin resistance and VTE. Interventional studies are necessary to determine the efficacy of antithrombin supplementation in the reduction of VTE incidence.

Endotheliopathy is Associated with a 24-hour Fibrinolysis Phenotype Described by Low TEG Lysis and High D-Dimer after Trauma: a Secondary Analysis of the PROPPR Study.

Objectives: Determine associations between biomarkers of endotheliopathy, 24-hour fibrinolysis phenotypes and clinical outcomes after trauma. Background: The vascular endothelium is a critical regulator of hemostasis and organ function. The relationship between markers of endotheliopathy and fibrinolysis following trauma has not been evaluated. Methods: We performed a secondary analysis of prospectively collected biomarker data in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial. We stratified subjects by 24-hour thromboelastography (TEG) percent clot lysis (LY30) and plasma D-dimer (DD) levels and evaluated differences in endotheliopathy biomarkers and clinical outcomes between subjects with one of four 24-hour fibrinolysis phenotypes: LY30 0.9-2.9% (LY30norm), LY30 >2.9% (LY30high), LY30 <0.9% and low DD (LY30low+DDlow), and LY30 <0.9% and high DD (LY30low+DDhigh). Results: The analysis included 168 subjects with LY30norm, 32 with LY30high, 147 with LY30low+DDlow and 124 with LY30low+DDhigh. LY30low+DDhigh subjects had greater injury severity and a higher incidence of severe head injury, multiorgan failure (MOF), and mortality than the other phenotypes. All endotheliopathy biomarkers were significantly higher in the LY30low+DDhigh phenotype. Adjusting for injury severity, mechanism and head trauma, 24-hour angiopoietin-2 and soluble thrombomodulin were independently associated with the LY30low+DDhigh phenotype. Both endothelial biomarkers were discriminating for MOF. Subjects with thrombomodulin level >9.5 ng/mL and angiopoietin-2 level >3.6 ng/mL accounted for 64% of subjects who developed MOF. Conclusions: In a multicenter trauma cohort, subjects with a fibrinolysis phenotype characterized by low TEG lysis and elevated DD 24 hours after injury have significantly worse endotheliopathy and clinical outcomes. Our findings support mechanistic evaluations of the role of the endothelium in fibrinolysis dysregulation that may drive late-stage organ injury.

Proteomic characterization of isolated Arabidopsis clathrin-coated vesicles reveals evolutionarily conserved and plant-specific components.

In eukaryotes, clathrin-coated vesicles (CCVs) facilitate the internalization of material from the cell surface as well as the movement of cargo in post-Golgi trafficking pathways. This diversity of functions is partially provided by multiple monomeric and multimeric clathrin adaptor complexes that provide compartment and cargo selectivity. The adaptor-protein assembly polypeptide-1 (AP-1) complex operates as part of the secretory pathway at the trans-Golgi network (TGN), while the AP-2 complex and the TPLATE complex jointly operate at the plasma membrane to execute clathrin-mediated endocytosis. Key to our further understanding of clathrin-mediated trafficking in plants will be the comprehensive identification and characterization of the network of evolutionarily conserved and plant-specific core and accessory machinery involved in the formation and targeting of CCVs. To facilitate these studies, we have analyzed the proteome of enriched TGN/early endosome-derived and endocytic CCVs isolated from dividing and expanding suspension-cultured Arabidopsis (Arabidopsis thaliana) cells. Tandem mass spectrometry analysis results were validated by differential chemical labeling experiments to identify proteins co-enriching with CCVs. Proteins enriched in CCVs included previously characterized CCV components and cargos such as the vacuolar sorting receptors in addition to conserved and plant-specific components whose function in clathrin-mediated trafficking has not been previously defined. Notably, in addition to AP-1 and AP-2, all subunits of the AP-4 complex, but not AP-3 or AP-5, were found to be in high abundance in the CCV proteome. The association of AP-4 with suspension-cultured Arabidopsis CCVs is further supported via additional biochemical data.

Defining CD4 T helper and T regulatory cell endotypes of progressive and remitting pulmonary sarcoidosis (BRITE): protocol for a US-based, multicentre, longitudinal observational bronchoscopy study.

INTRODUCTION: Sarcoidosis is a multiorgan granulomatous disorder thought to be triggered and influenced by gene-environment interactions. Sarcoidosis affects 45-300/100 000 individuals in the USA and has an increasing mortality rate. The greatest gap in knowledge about sarcoidosis pathobiology is a lack of understanding about the underlying immunological mechanisms driving progressive pulmonary disease. The objective of this study is to define the lung-specific and blood-specific longitudinal changes in the adaptive immune response and their relationship to progressive and non-progressive pulmonary outcomes in patients with recently diagnosed sarcoidosis. METHODS AND ANALYSIS: The BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints study is a US-based, NIH-sponsored longitudinal blood and bronchoscopy study. Enrolment will occur over four centres with a target sample size of 80 eligible participants within 18 months of tissue diagnosis. Participants will undergo six study visits over 18 months. In addition to serial measurement of lung function, symptom surveys and chest X-rays, participants will undergo collection of blood and two bronchoscopies with bronchoalveolar lavage separated by 6 months. Freshly processed samples will be stained and flow-sorted for isolation of CD4 +T helper (Th1, Th17.0 and Th17.1) and T regulatory cell immune populations, followed by next-generation RNA sequencing. We will construct bioinformatic tools using this gene expression to define sarcoidosis endotypes that associate with progressive and non-progressive pulmonary disease outcomes and validate the tools using an independent cohort. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Review Boards at National Jewish Hospital (IRB# HS-3118), University of Iowa (IRB# 201801750), Johns Hopkins University (IRB# 00149513) and University of California, San Francisco (IRB# 17-23432). All participants will be required to provide written informed consent. Findings will be disseminated via journal publications, scientific conferences, patient advocacy group online content and social media platforms.