Preclinical Studies on Mechanisms Underlying the Protective Effects of Propranolol in Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity amongst trauma patients. Its treatment is focused on minimizing progression to secondary injury. Administration of propranolol for TBI maydecrease mortality and improve functional outcomes. However, it is our sense that its use has not been universally adopted due to low certainty evidence. The literature was reviewed to explore the mechanism of propranolol as a therapeutic intervention in TBI to guide future clinical investigations. Medline, Embase, and Scopus were searched for studies that investigated the effect of propranolol on TBI in animal models from inception until June 6, 2023. All routes of administration for propranolol were included and the following outcomes were evaluated: cognitive functions, physiological and immunological responses. Screening and data extraction were done independently and in duplicate. The risk of bias for each individual study was assessed using the SYCLE's risk of bias tool for animal studies. Three hundred twenty-three citations were identified and 14 studies met our eligibility criteria. The data suggests that propranolol may improve post-TBI cognitive and motor function by increasing cerebral perfusion, reducing neural injury, cell death, leukocyte mobilization and p-tau accumulation in animal models. Propranolol may also attenuate TBI-induced immunodeficiency and provide cardioprotective effects by mitigating damage to the myocardium caused by oxidative stress. This systematic review demonstrates that propranolol may be therapeutic in TBI by improving cognitive and motor function while regulating T lymphocyte response and levels of myocardial reactive oxygen species. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies.

Damage-control vascular surgery in Canada: supporting surgeons and teams.

SummaryIn Canada, trauma patients often present initially to non-trauma hospitals without vascular surgeons on site. Local surgeons need skills and support for damage-control vascular surgery. Canadian training programs in general surgery should equip trainees with skills in this area, including resuscitation, identification of vascular injury, hemorrhage control, and temporizing measures (e.g., shunts, ligation). Caring for trauma patients is a multidisciplinary endeavour; understanding local/regional skill sets and from whom to seek help is vital. Opportunities for skills maintenance should also be encouraged for surgeons practising at sites where acutely injured patients present.

Antiplatelets versus anticoagulants in the treatment of blunt cerebrovascular injury (BCVI) - A systematic review and meta-analysis.

INTRODUCTION: Blunt cerebrovascular injury (BCVI) occurs in 1-3% of blunt traumas and is associated with stroke, disability, and mortality if unrecognized and untreated. Early detection and treatment are imperative to reduce the risk of stroke, however, there is significant variation amongst centers and trauma care providers in the specific medical management strategy used. This study compares antiplatelets vs. anticoagulants to determine BCVI-related stroke risk and bleeding complications to better understand the efficacy and safety of various treatment strategies. METHODS: A systematic review of MEDLINE, Embase, and Cochrane CENTRAL databases was conducted with the assistance of a medical librarian. The search was supplemented with manual review of the literature. Included studies reported treatment-stratified risk of stroke following BCVI. All studies were screened independently by two reviewers, and data was extracted in duplicate. Meta-analysis was conducted using pooled estimates of odds ratios (OR) with a random-effects model using Mantel-Haenszel methods. RESULTS: A total of 3315 studies screened yielded 39 studies for inclusion, evaluating 6552 patients (range 8 - 920 per study) with a total of 7643 BCVI. Stroke rates ranged from 0% to 32.8%. Amongst studies included in the meta-analysis, there were a total of 405 strokes, with 144 (35.5%) occurring on therapy, for a total stroke rate of 4.5 %. Meta-analysis showed that stroke rate after BCVI was lower for patients treated with antiplatelets vs. anticoagulants (OR 0.57; 95% CI 0.33-0.96, p = 0.04); when evaluating only the 9 studies specifically comparing ASA to heparin, the stroke rate was similar between groups (OR 0.43; 95% CI 0.15-1.20, p = 0.11). Eleven studies evaluated bleeding complications and demonstrated lower risk of bleeding with antiplatelets vs. anticoagulants (OR 0.29; 95% CI 0.13-0.63, p = 0.002); 5 studies evaluating risk of bleeding complications with ASA vs. heparin showed lower rates of bleeding complications with ASA (OR 0.16; 95% CI 0.04-0.58, p = 0.005). CONCLUSIONS: Treatment of patients with BCVI with antiplatelets is associated with lower risks of stroke and bleeding complications compared to treatment with anticoagulants. Use of ASA vs. heparin specifically was not associated with differences in stroke risk, however, patients treated with ASA had fewer bleeding complications. Based on this evidence, antiplatelets should be the preferred treatment strategy for patients with BCVI.

Management of Rib Fractures in the Combat Environment.

Rib fractures in combat casualties are an under-appreciated injury, and their treatment may become more common as more patients survive because of modern body armor and point-ofinjury care. The combat environment has challenges such as equipment availability and sterility. A simple and thoughtful rib fracture treatment algorithm may be useful to reduce the morbidity and mortality of rib fractures in the combat environment. Intravenous lidocaine infusions for patients with traumatic rib fractures may have important combat applications. We propose an algorithm for the management of combat casualties with traumatic rib fractures.

Combat Vascular Access: A Scoping Review.

Medical leadership must decide how to obtain vascular access in a combat environment. Adequate combat trauma resuscitation requires efficient vascular access. A search of the Medline and EMBASE databases was conducted to find articles on combat vascular access. The primary dataset of interest was the type of vascular access obtained. Other data reviewed included who performed the intervention and the success rate of the intervention. The search strategy produced 1,339 results, of which 24 were included in the final analysis. Intravenous (IV), intraosseous (IO), and central venous access have all been used in the prehospital combat environment. This review summarizes the available combat literature to help commanders make an evidence-based decision about their prehospital vascular access strategy.

Central Centrifugal Cicatricial Alopecia Associated With PDL1 Loss and Increased Expression of Caspase 3: A Case Series.

ABSTRACT: Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia that disproportionately affects patients with skin of color. Genetic studies have revealed that approximately 30% of CCCAs are associated with peptidyl arginine deiminase 3 misfolding mutations. Patients with CCCA usually have a poor prognosis with progressive and permanent hair loss. To further characterize CCCA, we evaluated the inflammatory milieu, PDL1, and caspase 3 expression. The data support the idea of CCCA being a CD4-predominant T-cell process. The loss of PDL1 and increase in caspase 3 expression raises the possibility of involvement of the PD1/PDL1 pathway in CCCA.

Efficacy of high dose tranexamic acid (TXA) for hemorrhage: A systematic review and meta-analysis.

BACKGROUND: Standard dose (≤ 1 g) tranexamic acid (TXA) has established mortality benefit in trauma patients. The role of high dose IV TXA (≥2 g or ≥30 mg/kg as a single bolus) has been evaluated in the surgical setting, however, it has not been studied in trauma. We reviewed the available evidence of high dose IV TXA in any setting with the goal of informing its use in the adult trauma population. METHODS: We searched MEDLINE, EMBASE and unpublished sources from inception until July 27, 2022 for studies that compared standard dose with high dose IV TXA in adults (≥ 16 years of age) with hemorrhage. Screening and data abstraction was done independently and in duplicate. We pooled trial data using a random effects model and considered randomized controlled trials (RCTs) and observational cohort studies separately. We assessed the individual study risk of bias using the Cochrane Risk of Bias for RCTs and the Newcastle-Ottawa Scale for observational cohort studies. The overall certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: We included 20 studies with a combined total of 12,523 patients. Based on pooled RCT data, and as compared to standard dose TXA, high dose IV TXA probably decreases transfusion requirements (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.76 to 0.97, moderate certainty) but with possibly no effect on blood loss (mean difference [MD] 43.31 ml less, 95% CI 135.53 to 48.90 ml less, low certainty), and an uncertain effect on thromboembolic events (OR 1.33, 95% CI 0.86 to 2.04, very low certainty) and mortality (OR 0.70, 95% CI 0.37 to 1.32, very low certainty). CONCLUSION: When compared to standard dose, high dose IV TXA probably reduces transfusion requirements with an uncertain effect on thromboembolic events and mortality. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level IV.

The metabolic and lipidomic profiling of the effects of tracheal occlusion in a rabbit model of congenital diaphragmatic hernia.

PURPOSE: Fetal tracheal occlusion (TO) reverses the pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. 'Omic' readouts capture metabolic and lipid processing function, which aid in understanding CDH and TO metabolic mechanisms. METHODS: CDH was created in fetal rabbits at 23 days, TO at 28 days and lung collection at 31 days (Term ∼32 days). Lung-body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. In a cohort, left and right lungs were collected, weighed, and samples homogenized, and extracts collected for non-targeted metabolomic and lipidomic profiling via LC-MS and LC-MS/MS, respectively. RESULTS: LBWR was significantly lower in CDH while CDH + TO was similar to controls (p = 0.003). MTBD was significantly higher in CDH fetuses and restored to control and sham levels in CDH + TO (p < 0.001). CDH and CDH + TO resulted in significant differences in metabolome and lipidome profiles compared to sham controls. A significant number of altered metabolites and lipids between the controls and CDH groups and the CDH and CDH + TO fetuses were identified. Significant changes in the ubiquinone and other terpenoid-quinone biosynthesis pathway and the tyrosine metabolism pathway were observed in CDH + TO. CONCLUSION: CDH + TO reverses pulmonary hypoplasia in the CDH rabbit, in association with a specific metabolic and lipid signature. A synergistic untargeted 'omics' approach provides a global signature for CDH and CDH + TO, highlighting cellular mechanisms among lipids and other metabolites, enabling comprehensive network analysis to identify critical metabolic drivers in disease pathology and recovery. TYPE OF STUDY: Basic Science, Prospective. LEVEL OF EVIDENCE: II.

A Systematic Review of Prehospital Combat Airway Management.

Medical leadership must decide how prehospital airways will be managed in a combat environment, and airway skills can be complicated and difficult to learn. Evidence informed airway strategies are essential. A search was conducted in Medline and EMBASE databases for prehospital combat airway use. The primary data of interest was what type of airway was used. Other data reviewed included: who performed the intervention and the success rate of the intervention. The search strategy produced 2,624 results, of which 18 were included in the final analysis. Endotracheal intubation, cricothyroidotomy, supraglottic airways, and nasopharyngeal airways have all been used in the prehospital combat environment. This review summarizes the entirety of the available combat literature such that commanders may make an evidence-based informed decision with respect to their airway management policies.

Systematic and scoping reviews: A comparison and overview.

In this article, we compare and contrast methods of reviewing, summarizing, and synthesizing the literature, including systematic reviews, scoping reviews, and narrative reviews. Review articles are essential to help investigators wade through the plethora of exponentially growing medical literature. In the era of evidence-based medicine, a systematic approach is required. A systematic review is a formalized method to address a specific clinical question by analyzing the breadth of published literature while minimizing bias. Systematic reviews are designed to answer narrow clinical questions in the PICO (population, intervention, comparison, and outcome) format. Alternatively, scoping reviews use a similar systematic approach to a literature search in order to determine the breadth and depth of knowledge on a topic; to clarify definitions, concepts, and themes; or sometimes as a precursor to a systematic review or hypothesis generator to guide future research. However, scoping reviews are less constrained by a priori decisions about which interventions, controls, and outcomes may be of interest. Traditional narrative reviews still have a role in informing practice and guiding research, particularly when there is a paucity of high-quality evidence on a topic.

Neurothekeoma With PI3K w552*, ALK P1469S, SMO G461S, and ERBB3 L77M Genetic Alterations.

ABSTRACT: Neurothekeoma, a lesion of possible fibrohistiocytic origin, is a rare, benign, superficial soft tissue tumor, histologically subclassified in 3 types: myxoid, cellular, or mixed. It clinically presents as a solitary, pink to brown nodule, ranging from 0.3 to 2.0 cm. Four point mutations (PI3K w552*, ALK P1469S, SMO G461S, and ERBB3 L77M) were identified by next-generation sequencing of a neurothekeoma presenting in the left inner thigh of a 53-year-old man. We highlight novel genetic alterations (SMO G461S and ERBB3 L77M) and previously known mutations (PI3KCA w552* and ALK P1469S) that play a role in other pathogenic pathways, but to the best of our knowledge, these have not yet been reported in neurothekeoma.

Histopathology of Hidradenitis Suppurativa: A Systematic Review.

Hidradenitis suppurativa (HS) is a chronic inflammatory scarring disease felt to be related to occlusion of the hair follicle unit in intertriginous areas. We perform a systematic review on HS histopathology to evaluate current knowledge and discuss future directions. PubMed and Scopus databases were searched for relevant articles published from January 1985 to January 2021 that discussed the pathology of HS. Additional articles were identified by hand-searching, which entailed manually scanning selected journals. A total of 355 citations were identified in the primary search within the main databases. Two hundred and seventy-nine articles were excluded after a review of titles, abstracts, and duplicates. Sixty-one studies did not meet the inclusion criteria or were found to be duplicates, resulting in a total of 15 articles for analysis. Three articles were hand-searched. This comprehensive systematic review of the histopathology of HS confirms a high prevalence of follicular occlusion, follicular hyperkeratosis, and hyperplasia of the follicular epithelium. These findings support the central role of follicular occlusion in the development and progression of HS while providing a potential path to directing therapeutics against follicular occlusion.

The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

A Reproducible and Effective Technique for Coronary Sinus Injury Repair.

Objective: Coronary sinus injury related to the use of a retrograde cardioplegia catheter is a rare but potentially life-threatening complication with mortality reported as high as 20%. We present a series of iatrogenic coronary sinus injuries as well as an effective method of repair without any ensuing mortality. Methods: There were 3,004 cases that utilized retrograde cardioplegia at our institution from 2007 to 2018. Of these, 15 patients suffered a coronary sinus injury, an incidence of 0.49%. A pericardial roof repair was performed in 14 cases in which autologous pericardium was sutured circumferentially to normal epicardium around the injury with purified bovine serum albumin and glutaraldehyde injected into the newly created space as a sealant. Incidence of perioperative morbidity and mortality, operative time, and length of stay were collected. Results: In our series, there were no intraoperative or perioperative mortalities. Procedure types included coronary artery bypass grafting (CABG), valve replacement and repair, or combined CABG and valve procedures. Median (interquartile range) cross-clamp time was 100 (88 to 131) minutes, cardiopulmonary bypass duration was 133 (114 to 176) minutes, and length of stay was 6 (4 to 8) days. None of the patients returned to the operating room for hemorrhage, and there were no complications associated with the repair of a coronary sinus injury when using the pericardial roof technique. Conclusions: Coronary sinus injuries can result in difficult to manage perioperative bleeding and potentially lethal consequences from cardiac manipulation. Our series supports the pericardial roof technique as an effective solution to a challenging intraoperative complication.

Management of vascular trauma across Canada: A cohort study with implications for practice.

BACKGROUND: The aim of this study was to provide a description of vascular trauma and its management at trauma centers across Canada. METHODS: This retrospective cohort study evaluated patients from 8 Canadian level 1 trauma centers (2011-2015). Medical records were queried to identify adult patients who survived to hospital with major vascular injury. Major vascular injury was defined as injury to named arterial or venous vessels in the legs, arms torso, and neck. Data collected included patient demographics, injury mechanism, injury details, management and clinical outcomes. RESULTS: A total of 1330 patients were included. Patients were 76% male with a mean age of 43 (SD 18.8). Reported injuries were 63% blunt, 36% penetrating, and the remainder mixed. The most common specific mechanisms of injury were motor vehicle collision (36%), stabbing (26%), and falls (16%), with gunshot injuries accounting for <5%. Pre-hospital tourniquets were applied in 27 patients (2%). The mean Injury Severity Score (ISS) was 24 (SD 14.5). We identified injuries to named vessels of the neck (32%), thorax (23%), abdomen and pelvis (27%), upper extremity (14%) and lower extremity (10%). Specific vascular injuries included transection (50%), complete occlusion (11%), partial occlusion (39%), and pseudoaneurysm formation (11%). Injuries were managed non-operatively in 32%, with definitive open surgical management (24%), endovascular management (9%) and with damage control techniques in the operating room (3%). Amputation occurred in 10% of lower extremity and 5% of upper extremity injuries. Responsibility for vascular injury management was undertaken by a wide variety of specialists (n = 17). Overall, in-hospital mortality was 13%, and 2% of patients underwent amputation. CONCLUSION: This study describes the nature and management of vascular injuries across Canada. The variability in injury mechanisms, management strategies, specialty responsible for management, and outcomes have important implications for practice change and knowledge translation.

Preliminary Characterization of NP339, a Novel Polyarginine Peptide with Broad Antifungal Activity.

Fungi cause disease in nearly one billion individuals worldwide. Only three classes of antifungal agents are currently available in mainstream clinical use. Emerging and drug-resistant fungi, toxicity, and drug-drug interactions compromise their efficacy and applicability. Consequently, new and improved antifungal therapies are urgently needed. In response to that need, we have developed NP339, a 2-kDa polyarginine peptide that is active against pathogenic fungi from the genera Candida, Aspergillus, and Cryptococcus, as well as others. NP339 was designed based on endogenous cationic human defense peptides, which are constituents of the cornerstone of immune defense against pathogenic microbes. NP339 specifically targets the fungal cell membrane through a charge-charge-initiated membrane interaction and therefore possesses a differentiated safety and toxicity profile to existing antifungal classes. NP339 is rapidly fungicidal and does not elicit resistance in target fungi upon extensive passaging in vitro. Preliminary analyses in murine models indicate scope for therapeutic application of NP339 against a range of systemic and mucocutaneous fungal infections. Collectively, these data indicate that NP339 can be developed into a highly differentiated, first-in-class antifungal candidate for poorly served invasive and other serious fungal diseases.