The synthesis of proinflammatory leukotrienes implicated in asthma, allergic rhinitis, and atherosclerosis is initiated by the enzyme 5-lipoxygenase (5-LOX). The crystal structure of human Stable-5-LOX revealed a conformation where the catalytic iron was inaccessible to bulk solvent as two aromatic residues on a conserved helix-α2 (Hα2) plugged the substrate access portal. Whether 5-LOX can also adopt a more open conformation has not been resolved. Here, we present a new conformation of 5-LOX where Hα2 adopts an elongated conformation equivalent to that described in other animal lipoxygenase structures. Our observation of the sigmoidal kinetic behavior of 5-LOX, which is indicative of positive cooperativity, is consistent with a substrate-induced conformational change that shifts the ensemble of enzyme populations to favor the catalytically competent state. Strategic point mutations along Hα2 designed to unlock the closed conformation and elongate Hα2 resulted in improved kinetic parameters, altered limited proteolysis data, and a drastic reduction in the length of the lag phase yielding the most active Stable-5-LOX to date. Structural predictions by AlphaFold2 of these variants statistically favor an elongated Hα2 and reinforce a model in which improved kinetic parameters correlate with a more readily adopted open conformation. Taken together, these data provide valuable insights into the synthesis of leukotrienes.

Background: Tracheobronchial disease, including tracheomalacia (TM) and tracheobronchomalacia (TBM), is a spectrum of congenital and acquired airway disorders characterized by the collapse of the tracheal or mainstem bronchial walls during expiration, particularly when there are increased intrathoracic pressures. Traditional surgical approaches to treat severe medically refractory TM include anterior approaches, such as aortopexy or anterior tracheopexy. Recently, posterior tracheopexy has emerged to address the widened and mobile posterior tracheal membrane which can cause transient airway obstruction. Method: The National Institute of Health, National Library of Medicine, PubMed, and MEDLINE databases were queried for manuscripts related to posterior tracheopexy in the pediatric population. Preoperative diagnostics, anesthetic considerations, operative technique, clinical outcomes, and operative complications were analyzed in each manuscript. Results: Patients with severe medically refractory cases of TM who are being considered for posterior tracheopexy should undergo thorough preoperative workup by a multidisciplinary team. Cross-sectional, dynamic thoracic imaging and a “quadruple endoscopy”, incorporating laryngoscopy, dynamic bronchoscopy, distal bronchoscopy, and esophagogastroduodenoscopy (EGD) should be obtained as part of a standardized preoperative assessment. Posterior tracheopexy for pre-existing TM significantly improves respiratory symptoms, respiratory infection rates, brief resolved unexplained events, and ventilatory dependence. Recently, posterior tracheopexy during TEF/EA repair has been described and aims to reduce the risk of patients developing TM, the risk of TEF recurrence, and respiratory morbidity following TEF/EA repair. An ongoing randomized controlled trial may help to elucidate the efficacy of primary posterior tracheopexy in select neonates with TEF/EA. Conclusions: Posterior tracheopexy is a valuable surgical technique for the treatment of TM or the reduction in respiratory morbidity following TEF/EA repair in select neonates.

Background/Objectives: While standardized guidelines have been established for the evaluation and management of blunt cerebrovascular injuries (BCVIs) in adults, there remains a paucity of standardized guidelines for BCVIs in pediatric populations. Shortcomings in treatment algorithms also persist as uncertainty remains about the optimal approach to manage these cases. A review of the literature was performed to compile the current evidence and provide recommendations based on current overarching trends. Methods: PubMed was queried for studies related to the diagnosis and management of BCVIs in the pediatric population. Prevalence, mechanism of injury (MOI), screening criteria, diagnostic modality, vascular injuries identified, associated injuries, treatment, and patient risk factors were analyzed. Results: The Utah and McGovern criteria were the first tools developed for screening BCVIs in pediatric patients. Among all screening tools, the high sensitivity and specificity of the McGovern criteria support its use as the optimal screening strategy to date for pediatric patients. Given the high prevalence of high-energy MOI, observation is the most common approach chosen due to contraindications to medical therapy. Antiplatelet agents showed no significant differences in stroke prevention or hemorrhagic complications compared to anticoagulation. Strokes represent the primary source of morbidity among pediatric patients with BCVIs. Conclusions: Pediatric BCVIs represent an uncommon but clinically significant consequence of blunt trauma, with a significant risk for ischemic stroke and neurologic morbidity. Early recognition through appropriate screening with pediatric-specific screening criteria, CTA imaging, and timely initiation of grade-based treatment can help mitigate injury progression and complications.