Convergent evolution in the supercoiling of prokaryotic flagellar filaments.

The supercoiling of bacterial and archaeal flagellar filaments is required for motility. Archaeal flagellar filaments have no homology to their bacterial counterparts and are instead homologs of bacterial type IV pili. How these prokaryotic flagellar filaments, each composed of thousands of copies of identical subunits, can form stable supercoils under torsional stress is a fascinating puzzle for which structural insights have been elusive. Advances in cryoelectron microscopy (cryo-EM) make it now possible to directly visualize the basis for supercoiling, and here, we show the atomic structures of supercoiled bacterial and archaeal flagellar filaments. For the bacterial flagellar filament, we identify 11 distinct protofilament conformations with three broad classes of inter-protomer interface. For the archaeal flagellar filament, 10 protofilaments form a supercoil geometry supported by 10 distinct conformations, with one inter-protomer discontinuity creating a seam inside of the curve. Our results suggest that convergent evolution has yielded stable superhelical geometries that enable microbial locomotion.

DNA triplet repeat expansion and mismatch repair.

DNA mismatch repair is a conserved antimutagenic pathway that maintains genomic stability through rectification of DNA replication errors and attenuation of chromosomal rearrangements. Paradoxically, mutagenic action of mismatch repair has been implicated as a cause of triplet repeat expansions that cause neurological diseases such as Huntington disease and myotonic dystrophy. This mutagenic process requires the mismatch recognition factor MutSß and the MutLα (and/or possibly MutLγ) endonuclease, and is thought to be triggered by the transient formation of unusual DNA structures within the expanded triplet repeat element. This review summarizes the current knowledge of DNA mismatch repair involvement in triplet repeat expansion, which encompasses in vitro biochemical findings, cellular studies, and various in vivo transgenic animal model experiments. We present current mechanistic hypotheses regarding mismatch repair protein function in mediating triplet repeat expansions and discuss potential therapeutic approaches targeting the mismatch repair pathway.

Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.

Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. We present structures of hExo1 in complex with a DNA substrate, followed by mutagenesis studies, and propose a common mechanism by which this nuclease family recognizes and processes diverse DNA structures. hExo1 induces a sharp bend in the DNA at nicks or gaps. Frayed 5' ends of nicked duplexes resemble flap junctions, unifying the mechanisms of endo- and exonucleolytic processing. Conformational control of a mobile region in the catalytic site suggests a mechanism for allosteric regulation by binding to protein partners. The relative arrangement of substrate binding sites in these enzymes provides an elegant solution to a complex geometrical puzzle of substrate recognition and processing.

Tad and toxin-coregulated pilus structures reveal unexpected diversity in bacterial type IV pili.

Type IV pili (T4P) are ubiquitous in both bacteria and archaea. They are polymers of the major pilin protein, which has an extended and protruding N-terminal helix, α1, and a globular C-terminal domain. Cryo-EM structures have revealed key differences between the bacterial and archaeal T4P in their C-terminal domain structure and in the packing and continuity of α1. This segment forms a continuous α-helix in archaeal T4P but is partially melted in all published bacterial T4P structures due to a conserved helix breaking proline at position 22. The tad (tight adhesion) T4P are found in both bacteria and archaea and are thought to have been acquired by bacteria through horizontal transfer from archaea. Tad pilins are unique among the T4 pilins, being only 40 to 60 residues in length and entirely lacking a C-terminal domain. They also lack the Pro22 found in all high-resolution bacterial T4P structures. We show using cryo-EM that the bacterial tad pilus from Caulobacter crescentus is composed of continuous helical subunits that, like the archaeal pilins, lack the melted portion seen in other bacterial T4P and share the packing arrangement of the archaeal T4P. We further show that a bacterial T4P, the Vibrio cholerae toxin coregulated pilus, which lacks Pro22 but is not in the tad family, has a continuous N-terminal α-helix, yet its α1 s are arranged similar to those in other bacterial T4P. Our results highlight the role of Pro22 in helix melting and support an evolutionary relationship between tad and archaeal T4P.

The evolution of archaeal flagellar filaments.

Flagellar motility has independently arisen three times during evolution: in bacteria, archaea, and eukaryotes. In prokaryotes, the supercoiled flagellar filaments are composed largely of a single protein, bacterial or archaeal flagellin, although these two proteins are not homologous, while in eukaryotes, the flagellum contains hundreds of proteins. Archaeal flagellin and archaeal type IV pilin are homologous, but how archaeal flagellar filaments (AFFs) and archaeal type IV pili (AT4Ps) diverged is not understood, in part, due to the paucity of structures for AFFs and AT4Ps. Despite having similar structures, AFFs supercoil, while AT4Ps do not, and supercoiling is essential for the function of AFFs. We used cryo-electron microscopy to determine the atomic structure of two additional AT4Ps and reanalyzed previous structures. We find that all AFFs have a prominent 10-strand packing, while AT4Ps show a striking structural diversity in their subunit packing. A clear distinction between all AFF and all AT4P structures involves the extension of the N-terminal α-helix with polar residues in the AFFs. Additionally, we characterize a flagellar-like AT4P from Pyrobaculum calidifontis with filament and subunit structure similar to that of AFFs which can be viewed as an evolutionary link, showing how the structural diversity of AT4Ps likely allowed for an AT4P to evolve into a supercoiling AFF.

Outcomes After Respiratory Extracorporeal Life Support in Teens and Young Adults: An Extracorporeal Life Support Organization Registry Analysis.

OBJECTIVES: A recent study from Germany found that survival after respiratory extracorporeal life support (ECLS) was lower among patients 10-20 years old than 20-30 years old. The objective of this study was to compare survival between teenage and young adult patients who receive respiratory ECLS. DESIGN: Retrospective cohort study. SETTING: Extracorporeal Life Support Organization registry, an international prospective quality improvement database. PATIENTS: All patients ages 16-30 years cannulated for respiratory indications from 1990 to 2020 were included. Patients were divided into two groups, teens (16-19 yr old) and young adults (20-30 yr old). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was survival to discharge. Variables were considered for the multivariate logistic regression model if there was both a statistically significant difference (p ≤ 0.05) and a clinically meaningful absolute difference between the groups. A total of 5,751 patients were included, of whom 1,653 (29%) were teens and 4,098 (71%) were young adults. Survival to discharge was higher in young adults than teens, 69% versus 63% (p < 0.001). Severity of illness was higher among teens; however, survival within each stratum defined by Pao2/Fio2 ratio was higher in young adults than in teens. Use of venoarterial ECLS was higher in teens than in young adults, 15% versus 7%, respectively. Teens were more likely to receive high-frequency oscillatory ventilation and this therapy was associated with a longer time from admission to ECLS initiation. After adjusting for variables that differ significantly between the groups, the odds ratio for survival in young adults compared with teens was 1.14 (95% CI, 1.004-1.3). CONCLUSIONS: In this large multicenter retrospective study, mortality was higher in teens than in young adults who received respiratory ECLS. This difference persisted after adjusting for multiple variables and the mechanism underlying these findings remains unclear.

Higher Survival With the Use of Extracorporeal Cardiopulmonary Resuscitation Compared With Conventional Cardiopulmonary Resuscitation in Children Following Cardiac Surgery: Results of an Analysis of the Get With The Guidelines-Resuscitation Registry.

OBJECTIVES: Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation (CPR) is increasingly used in children suffering cardiac arrest after cardiac surgery. However, its efficacy in promoting survival has not been evaluated. We compared survival of pediatric cardiac surgery patients suffering in-hospital cardiac arrest who were resuscitated with extracorporeal CPR (E-CPR) to those resuscitated with conventional CPR (C-CPR) using propensity matching. DESIGN: Retrospective study using multicenter data from the American Heart Association Get With The Guidelines-Resuscitation registry (2008-2020). SETTING: Multicenter cardiac arrest database containing cardiac arrest and CPR data from U.S. hospitals. PATIENTS: Cardiac surgical patients younger than 18 years old who suffered in-hospital cardiac arrest and received greater than or equal to 10 minutes of CPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 1223 patients, 741 (60.6%) received C-CPR and 482 (39.4%) received E-CPR. E-CPR utilization increased over the study period ( p < 0.001). Duration of CPR was longer in E-CPR compared with C-CPR recipients (42 vs. 26 min; p < 0.001). In a propensity score matched cohort (382 E-CPR recipients, 382 C-CPR recipients), E-CPR recipients had survival to discharge (odds ratio [OR], 2.22; 95% CI, 1.7-2.9; p < 0.001). E-CPR survival was only higher when CPR duration was greater than 18 minutes. Propensity matched analysis using patients from institutions contributing at least one E-CPR case ( n = 35 centers; 353 E-CPR recipients, 353 C-CPR recipients) similarly demonstrated improved survival in E-CPR recipients compared with those who received C-CPR alone (OR, 2.08; 95% CI, 1.6-2.8; p < 0.001). CONCLUSIONS: E-CPR compared with C-CPR improved survival in children suffering cardiac arrest after cardiac surgery requiring CPR greater than or equal to 10 minutes.

Child Opportunity Index and Pediatric Extracorporeal Membrane Oxygenation Outcomes; the Role of Diagnostic Category.

OBJECTIVES: To study the impact of social determinants of health (SDoH) on pediatric extracorporeal membrane oxygenation (ECMO) outcomes. DESIGN, SETTING, AND PATIENTS: Retrospective study of children (< 18 yr) supported on ECMO (October 1, 2015 to March 1, 2021) using Pediatric Health Information System (44 U.S. children's hospitals). Patients were divided into five diagnostic categories: neonatal cardiac, pediatric cardiac, neonatal respiratory, pediatric respiratory, and sepsis. SDoH included the Child Opportunity Index (COI; higher indicates social advantage), race, ethnicity, payer, and U.S. region. Children without COI were excluded. Diagnostic category-specific clinical variables related to baseline health and illness severity were collected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children supported on ECMO experienced a 33% in-hospital mortality (2863/8710). Overall, children with lower COI, "other" race, Hispanic ethnicity, public insurance and from South or West regions had greater mortality. Associations between SDoH and ECMO outcomes differed between diagnostic cohorts. Bivariate analyses found that only pediatric cardiac patients had an association between COI or race and mortality. Multivariable logistic regression analyses examined relationships between SDoH, clinical variables and mortality within diagnostic categories. Pediatric cardiac patients had 5% increased odds of death (95% CI, 1.01-1.09) for every 10-point decrement in COI, while Hispanic ethnicity was associated with higher survival (adjusted odds ratio [aOR] 0.72 [0.57-0.89]). Children with heart disease from the highest COI quintile had less cardiac-surgical complexity and earlier cannulation. Independent associations with mortality were observed in sepsis for Black race (aOR 1.62 [1.06-2.47]) and other payer in pediatric respiratory patients (aOR 1.94 [1.23-3.06]). CONCLUSIONS: SDoH are statistically associated with pediatric ECMO outcomes; however, associations differ between diagnostic categories. Influence of COI was observed only in cardiac patients while payer, race, and ethnicity results varied. Further research should investigate differences between diagnostic cohorts and age groups to understand drivers of inequitable outcomes.

Early survival benefit of a low-profile endograft in blunt traumatic aortic injury.

OBJECTIVE: The aim of this study was to demonstrate the safety and effectiveness of a low-profile thoracic endograft (19-23 French) in subjects with blunt traumatic aortic injury. METHODS: A prospective, multicenter study assessed the RelayPro thoracic endograft for the treatment of traumatic aortic injury. Fifty patients were enrolled at 16 centers in the United States between 2017 and 2021. The primary endpoint was 30-day all-cause mortality. RESULTS: The cohort was mostly male (74%), with a mean age of 42.4 ± 17.2 years, and treated for traumatic injuries (4% Grade 1, 8% Grade 2, 76% Grade 3, and 12% Grade 4) due to motor vehicle collision (80%). The proximal landing zone was proximal to the left subclavian artery in 42%, and access was primarily percutaneous (80%). Most (71%) were treated with a non-bare stent endograft. Technical success was 98% (one early type Ia endoleak). All-cause 30-day mortality was 2% (compared with an expected rate of 8%), with an exact two-sided 95% confidence interval [CI] of 0.1%, 10.6% below the performance goal upper limit of 25%. Kaplan-Meier analysis estimated freedom from all-cause mortality to be 98% at 30 days through 4 years (95% CI, 86.6%-99.7%). Kaplan-Meier estimated freedom from major adverse events, all-cause mortality, paralysis, and stroke, was 98.0% at 30 days and 95.8% from 6 months to 4 years (95% CI, 84.3%-98.9%). There were no strokes and one case of paraplegia (2%) during follow-up. CONCLUSIONS: RelayPro was safe and effective and may provide an early survival benefit in the treatment of blunt traumatic aortic injury.

The neurobiology of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Is there a role for extracorporeal membrane oxygenation in children with acute liver failure? A retrospective analysis of the Extracorporeal Life Support Organization Registry.

Data describing the use of extracorporeal membrane oxygenation (ECMO) in pediatric acute liver failure (PALF) are scarce. Thus, we aimed to describe the use of ECMO in patients with PALF using the data from the Extracorporeal Life Support Organization (ELSO) Registry between January 1, 2010, to December 31, 2022. We described patients' characteristics at ECMO initiation, outcome, and factors associated with mortality. A total of 335 children underwent ECMO support in the context of PALF. Veno-arterial (VA) ECMO was the most prevalent mode (66.6%), followed by veno-venous (VV) ECMO (33.4%). Extracorporeal cardiopulmonary resuscitation (ECPR) was used in 21.5% of the cardiac arrest. In-hospital mortality was 66.6%. Both higher lactate (OR 1.128, CI 1.06-1.209, p < 0.001) and PaCO2 (OR 1.022, CI 1.001-1.047, p 0.05) levels before ECMO reported greater odds of mortality. Low body weight, persistence of hyperlactatemia (OR 0.985, CI 0.973-0.997, p 0.013), and hyperbilirubinemia (OR 2.477, CI 1.042-6.100, p 0.045) after 24 h from ECMO deployment were associated to greater odds of mortality. CONCLUSIONS: Our results suggest that the use of ECMO for the management of respiratory and cardiac failure in patients with PALF should be considered with caution and that further research is needed to understand its role in this specific high-risk population. WHAT IS KNOWN: • Pediatric acute liver failure (PALF) is a clinical syndrome associated with significant morbidity and mortality. • Data on the use of extracorporeal membrane oxygenation (ECMO) in the context of PALF are scarce and controversial. WHAT IS NEW: • ECMO to manage acute respiratory and/or cardiac failure in the context of PALF should be considered with caution. • Bleeding and thrombotic complications in children with acute liver failure receiving ECMO are similar to the ones reported in the general pediatric population.

Death by Neurologic Criteria in Children Undergoing Extracorporeal Cardiopulmonary Resuscitation: Retrospective Extracorporeal Life Support Organization Registry Study, 2017-2021.

OBJECTIVES: To determine factors associated with brain death in children treated with extracorporeal cardiopulmonary resuscitation (E-cardiopulmonary resuscitation). DESIGN: Retrospective database study. SETTINGS: Data reported to the Extracorporeal Life Support Organization (ELSO), 2017-2021. PATIENTS: Children supported with venoarterial extracorporeal membrane oxygenation (ECMO) for E-cardiopulmonary resuscitation. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Data from the ELSO Registry included patient characteristics, blood gas values, support therapies, and complications. The primary outcome was brain death (i.e., death by neurologic criteria [DNC]). There were 2,209 children (≥ 29 d to < 18 yr of age) included. The reason for ECMO discontinuation was DNC in 138 patients (6%), and other criteria for death occurred in 886 patients (40%). Recovery occurred in 1,109 patients (50%), and the remaining 76 patients (4%) underwent transplantation. Fine and Gray proportional subdistribution hazards' regression analyses were used to examine the association between variables of interest and DNC. Age greater than 1 year ( p < 0.001), arterial blood carbon dioxide tension (Pa co2 ) greater than 82 mm Hg ( p = 0.022), baseline lactate greater than 15 mmol/L ( p = 0.034), and lactate 24 hours after cannulation greater than 3.8 mmol/L ( p < 0.001) were independently associated with greater hazard of subsequent DNC. In contrast, the presence of cardiac disease was associated with a lower hazard of subsequent DNC (subdistribution hazard ratio 0.57 [95% CI, 0.39-0.83] p = 0.004). CONCLUSIONS: In children undergoing E-cardiopulmonary resuscitation, older age, pre-event hypercarbia, higher before and during ECMO lactate levels are associated with DNC. Given the association of DNC with hypercarbia following cardiac arrest, the role of Pa co2 management in E-cardiopulmonary resuscitation warrants further studies.

Extracorporeal Cardiopulmonary Resuscitation Use Among Children With Cardiac Disease in the ICU: A Meta-Analysis and Meta-Regression of Data Through March 2024.

OBJECTIVE: Epidemiologic data on extracorporeal cardiopulmonary resuscitation (ECPR) use in children with cardiac disease after in-hospital cardiac arrest (IHCA) are lacking. We aimed to investigate trends in ECPR use over time in critically ill children with cardiac disease. DATA SOURCES: We performed a secondary analysis of a recent systematic review (PROSPERO CRD42020156247) to investigate trends in ECPR use in children with cardiac disease. PubMed, Web of Science, Embase, and Cumulative Index to Nursing and Allied Health Literature were screened (inception to September 2021). For completeness of this secondary analysis, PubMed was also rescreened (September 2021 to March 2024). STUDY SELECTION: Observational studies including epidemiologic data on ECPR use in children with cardiac disease admitted to an ICU. DATA EXTRACTION: Data were extracted by two independent investigators. The risk of bias was assessed using the National Heart Lung and Blood Institutes Quality Assessment Tools. Random-effects meta-analysis was used to compute a pooled proportion of subjects undergoing ECPR; meta-regression was used to assess trends in ECPR use over time. DATA SYNTHESIS: Of the 2664 studies identified, 9 (17,669 patients) included data on ECPR use in children with cardiac disease. Eight were cohort studies, 1 was a case-control, 8 were retrospective, 1 was prospective, 6 were single-center, and 3 were multicenter. Seven studies were included in the meta-analysis; all were judged of good quality. By meta-analysis, we found that a pooled proportion of 21% (95% CI, 15-29%) of pediatric patients with cardiac disease experiencing IHCA were supported with ECPR. By meta-regression adjusted for category of patients (surgical vs. general cardiac), we found that the use of ECPR in critically ill children with cardiac disease significantly increased over time ( p = 0 .026). CONCLUSIONS: About one-fifth of critically ill pediatric cardiac patients experiencing IHCA were supported with ECPR, and its use significantly increased over time. This may partially explain the increased trends in survival demonstrated for this population.

Anticoagulation Monitoring and Targets: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding anticoagulation monitoring assays and target levels in pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Anticoagulation monitoring of pediatric patients on ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool or the revised Cochrane risk of bias for randomized trials, as appropriate and the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for clinical recommendations focused on anticoagulation monitoring and targets, using a web-based modified Delphi process to build consensus (defined as > 80% agreement). One weak recommendation, two consensus statements, and three good practice statements were developed and, in all, agreement greater than 80% was reached. We also derived some resources for anticoagulation monitoring for ECMO clinician use at the bedside. CONCLUSIONS: There is insufficient evidence to formulate optimal anticoagulation monitoring during pediatric ECMO, but we propose one recommendation, two consensus and three good practice statements. Overall, the available pediatric evidence is poor and significant gaps exist in the literature.

Priorities for Clinical Research in Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From the Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus. DATA SOURCES: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill neonates and children. DATA EXTRACTION: Within each of the eight subgroups, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: Following the systematic review of MEDLINE, EMBASE, and Cochrane Library databases from January 1988 to May 2021, and the consensus process for clinical recommendations and consensus statements, PEACE panel experts constructed research priorities using the Child Health and Nutrition Research Initiative methodology. Twenty research topics were prioritized, falling within five domains (definitions and outcomes, therapeutics, anticoagulant monitoring, protocolized management, and impact of the ECMO circuit and its components on hemostasis). CONCLUSIONS: We present the research priorities identified by the PEACE expert panel after a systematic review of existing evidence informing clinical care of neonates and children managed with ECMO. More research is required within the five identified domains to ultimately inform and improve the care of this vulnerable population.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Outcomes of Endovascular and Open Surgical Therapy for Popliteal Artery Injury.

BACKGROUND: Popliteal arterial injury carries an appreciable risk of limb loss and, despite advances in stent and stent-graft technology, endovascular therapy for popliteal arterial trauma is infrequently used when compared with traditional open repair. Thus, this study aims to assess outcomes of endovascular management (EM) with open surgery (OS) as a historical reference. METHODS: An electronic search was performed (from January 2010 until June 2023) using multiple databases. Initial records were screened against eligibility criteria. Next, the full-text manuscript of articles that passed the title and abstract assessment was reviewed for relevancy of data points. Data from articles passing the inclusion criteria were extracted and tabulated. Comparative analysis was completed by performing chi-square tests and 2-sampled t-tests (Welch's). RESULTS: The 24 selected studies described 864 patients (96 EM; 768 OS). In the endovascular group, patients underwent procedures primarily for blunt trauma using covered, self-expanding stents, resulting in universal technical success and patency. Patients had an average length of stay of 7.99 ± 7.5 days and follow-up time of 33.0 ± 7.0 months, with 21% undergoing fasciotomies, 6% undergoing amputation, and 4% having pseudoaneurysms. Patients in the OS group were evenly divided between blunt and penetrating trauma, chiefly undergoing vein graft interposition and exhibiting fasciotomy and amputation rates of 66% and 24%, respectively. Patients had an average length of stay of 5.66 ± 4.6 days and a 96% survival rate at discharge. CONCLUSIONS: The current evidence sheds light on the nature of treatment offered by EM and OS treatment and suggests EM is associated with several important positive outcomes. Although it is difficult to directly compare endovascular and open surgical techniques, the data with respect to open surgical management of popliteal artery trauma can still provide a powerful frame of reference for the outcomes of EM to date. However, this claim is weak due to the little published data for EM of popliteal trauma, publication bias accompanying the published studies, and general, selection bias. Additional prospective data are necessary to define patients who specifically benefit from endovascular repair.

Identifying Risk Factors for Poor Outcomes Following Popliteal Vascular Injuries.

BACKGROUND: Popliteal artery injuries (PAIs) may have amputation rates as high as 20%. This study focuses on identifying risk factors associated with major amputations following PAIs in a large single-center cohort. Additionally, we assess the impact of repairing or ligating concomitant popliteal vein injuries. METHODS: A retrospective chart review encompassing 2011 to 2023 was conducted at a large urban level 1 trauma center. Patients with PAIs were included. Demographics and clinical data were analyzed, and univariate and multivariate evaluations identified significant risk factors for amputation. In patients with concomitant popliteal vein injuries, we compared outcomes between those who underwent popliteal vein repair and ligation. RESULTS: One hundred eighty eight patients with PAIs were identified; 10 underwent index amputation and were excluded. Univariate analysis followed by multivariate analysis revealed that obesity (P = 0.0132) and neurologic deficits on arrival (P = 0.0096) were associated with amputation. In the subgroup with popliteal vein injuries (N = 93), there was no significant difference in amputation rates between those who had vein repair (P = 0.21) and those who underwent ligation (P = 0.84) on logistic regression analysis. Likewise, popliteal vein ligation did not impact duration of fasciotomy closure (P = 0.20) or skin graft area (P = 0.48) based on linear regression analysis. CONCLUSIONS: Our study suggests that major amputations following PAIs are more likely in obese patients with neurologic deficits. It also suggests that venous ligation in cases of concomitant popliteal vein injuries does not significantly impact early limb salvage rate. Further research is needed to determine the optimal approach for managing concomitant popliteal vein injuries.

Lower Extremity Vascular Injury in the Pediatric Trauma Patient: Management and Outcomes at an Adult Level I Trauma Center.

BACKGROUND: Traumatic vascular injuries of the lower extremity in the pediatric population are uncommon but can result in significant morbidity. The objective of this study is to demonstrate our experience with these injuries by describing patterns of traumatic vascular injury, the initial management, and data regarding early outcomes. METHODS: In total, 506 patients presented with lower extremity vascular injury between January 1, 2009 and January 1, 2021 to Grady Memorial Hospital, an urban, adult Level I trauma center in Atlanta, Georgia. Thirty-two of the 506 patients were aged less than 18 years and were evaluated for a total of 47 lower extremity vascular injuries. To fully elucidate the injury patterns and clinical course in this population, we examined patient demographics, mechanism of injury, type of vessel injured, surgical repair performed, and early outcomes and complications. RESULTS: The median (interquartile range) age was 16 (2) years (range, 3-17 years), and the majority were male (n = 29, 90.6%). Of the vascular injuries identified, 28 were arterial and 19 were venous. Of these injuries, 14 patients had combined arterial-venous injuries. The majority of injuries were the result of a penetrating injury (n = 28, 87.5%), and of these, all but 2 were attributed to gunshot wounds. Twenty-seven vascular interventions were performed by nonpediatric surgeons: 11 by trauma surgeons, 13 by vascular surgeons, 2 by orthopedic surgeons, and 1 by an interventional radiologist. Two patients required amputation: 1 during the index admission and 1 delayed at 3 months. Overall survival was 96.9%. CONCLUSIONS: Vascular injuries as the result of trauma at any age often require early intervention, and we believe that these injuries in the pediatric population can be safely managed in adult trauma centers with a multidisciplinary team composed of trauma, vascular, and orthopedic surgeons with the potential to decrease associated morbidity and mortality from these injuries.