Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection.

Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. The uptake of both Leishmania promastigotes (insect-stage parasites) and amastigotes (proliferative-stage parasites in humans and mice) by phagocytes is thought to be mainly host cell driven, not parasite driven. Our previous work indicates that host Src- and Abl-family kinases facilitate Leishmania entry into macrophages and pathogenesis in murine cutaneous leishmaniasis. Here, we demonstrate that host spleen tyrosine kinase (SYK) is required for efficient uptake of Leishmania promastigotes and amastigotes. A Src-family kinase-Abl-family kinase-SYK signaling cascade induces Leishmania amastigote internalization. Finally, lesion size and parasite burden during Leishmania infection is significantly decreased in mice lacking SYK in monocytes or by treatment with the SYK inhibitor entospletinib. In summary, SYK is required for maximal Leishmania uptake by macrophages and disease in mice. Our results suggest potential for treating leishmaniasis using host cell-directed agents.

Trends in prehospital cervical collar utilization in trauma patients: Closer, but not there yet.

OBJECTIVE: This study aims to assess the change in cervical spine (C-spine) immobilization frequency in trauma patients over time. We hypothesize that the frequency of unnecessary C-spine immobilization has decreased. METHODS: A retrospective chart review of adult trauma patients transported to our American College of Surgeons-verified Level I trauma center from January 1, 2014, to December 31, 2021, was performed. Emergency medical services documentation was manually reviewed to record prehospital physiology and the application of a prehospital cervical collar (c-collar). C-spine injuries were defined as cervical vertebral fractures and/or spinal cord injuries. Univariate and year-by-year trend analyses were used to assess changes in C-spine injury and immobilization frequency. RESULTS: Among 2906 patients meeting inclusion criteria, 12% sustained C-spine injuries, while 88% did not. Patients with C-spine injuries were more likely to experience blunt trauma (95% vs. 68%, p < 0.001), were older (46 years vs. 41 years, p < 0.001), and had higher Injury Severity Scores (31 vs. 18, p < 0.001). They also exhibited lower initial systolic blood pressures (108 mm Hg vs. 119 mm Hg, p < 0.001), lower heart rates (92 beats/min vs. 97 beats/min, p < 0.05), and lower Glasgow Coma Scale scores (9 vs. 11, p < 0.001). In blunt trauma, c-collars were applied to 83% of patients with C-spine injuries and 75% without; for penetrating trauma, c-collars were applied to 50% of patients with C-spine injuries and only 8% without. Among penetrating trauma patients with C-spine injury, all patients either arrived quadriplegic or did not require emergent neurosurgical intervention. The proportion of patients receiving a c-collar decreased in both blunt and penetrating traumas from 2014 to 2021 (blunt-82% in 2014 to 68% in 2021; penetrating-24% in 2014 to 6% in 2021). CONCLUSIONS: Unnecessary C-spine stabilization has decreased from 2014 to 2021. However, c-collars are still being applied to patients who do not need them, both in blunt and in penetrating trauma cases, while not being applied to patients who would benefit from them.

Temporal changes in the prehospital management of trauma patients: 2014-2021.

INTRODUCTION: Aggressive prehospital interventions (PHI) in trauma may not improve outcomes compared to prioritizing rapid transport. The aim of this study was to quantify temporal changes in the frequency of PHI performed by EMS. METHODS: Retrospective chart review of adult patients transported by EMS to our trauma center from January 1, 2014 to 12/31/2021. PHI were recorded and annual changes in their frequency were assessed via year-by-year trend analysis and multivariate regression. RESULTS: Between the first and last year of the study period, the frequency of thoracostomy (6% vs. 9%, p â€‹= â€‹0.001), TXA administration (0.3% vs. 33%, p â€‹< â€‹0.001), and whole blood administration (0% vs. 20%, p â€‹< â€‹0.001) increased. Advanced airway procedures (21% vs. 12%, p â€‹< â€‹0.001) and IV fluid administration (57% vs. 36%, p â€‹< â€‹0.001) decreased. ED mortality decreased from 8% to 5% (p â€‹= â€‹0.001) over the study period. On multivariate regression, no PHI were independently associated with increased or decreased ED mortality. CONCLUSION: PHI have changed significantly over the past eight years. However, no PHI were independently associated with increased or decreased ED mortality.

Structural Racism, Residential Segregation, and Exposure to Trauma: The Persistent Impact of Redlining.

INTRODUCTION: As part of New Deal era federal housing policy, the Home Owners Loan Corporation (HOLC) developed maps grading US neighborhoods by perceived financial security. Neighborhoods with high concentrations of racial and ethnic minorities were deemed financially unstable and denied federal investment, a practice colloquially known as redlining. The aim of this study was to assess the association of historical redlining within Austin, Texas to spatial patterns of penetrating traumatic injury. METHODS: Retrospective cross sectional study utilizing data from violent penetrating trauma admissions between January 1, 2014 - December 31, 2021, at the single Level 1 trauma center in Austin, Texas. Using ArcGIS, addresses where the injury took place were geocoded and spatial joining was used to match them to their corresponding census tract, for which 1935 HOLC financial designations are classified as: "Hazardous", "Definitely Declining", "Still Desirable", "Best", or "Non HOLC Graded". Tracts with designations of "Hazardous" and "Definitely Declining" were categorized as Redlined. The adjusted incidence rate ratio comparing rates of penetrating trauma among historically Redlined vs. Not Redlined and Not Graded census tracts was calculated. RESULTS: 1,404 violent penetrating trauma admissions were identified for the study period, of which 920 occurred within the county of interest. Among these, 5% occurred in census tracts that were Not Redlined, 13% occurred in Redlined tracts, and 82% occurred in non HOLC graded tracts. When adjusting for differences in current census tract demographics and social vulnerability, historically Redlined areas experienced a higher rate of penetrating traumatic injury (Not Redlined IRR = 0.42, 95% CI 0.19-0.94, p = 0.03; Not Graded IRR = 0.15, 95% CI 0.07-0.29, p < 0.001). CONCLUSIONS: Neighborhoods unfavorably classified by HOLC in 1935 continue to experience a higher incidence rate of violent penetrating trauma today. These results underscore the persistent impacts of structural racism and of historical residential segregation policies on exposure to trauma. LEVEL OF EVIDENCE: Level IV, Prognostic and Epidemiological.

The more you have, the more you lose: Muscle mass changes in trauma patients with prolonged hospitalizations.

INTRODUCTION: Sarcopenia is a clinically relevant loss of muscle mass with implications of increased morbidity and mortality in adult trauma populations.  Our study aimed to evaluate loss of muscle mass change in adult trauma patients with prolonged hospital stays. METHODS: Retrospective analysis using institutional trauma registry to identify all adult trauma patients with hospital length of stay >14 days admitted to our Level 1 center between 2010 and 2017. All CT images were reviewed, and cross-sectional area (cm2) of the left psoas muscle was measured at the level of the third lumbar vertebral body to determine total psoas area (TPA) and Total Psoas Index (TPI) normalized for patient stature.  Sarcopenia was defined as a TPI on admission below gender specific thresholds of 5.45(cm2/m2) in men and 3.85(cm2/m2) in women.  TPA, TPI, and rates of change in TPI were then evaluated and compared between sarcopenic and non-sarcopenic adult trauma patients. RESULTS: There were 81 adult trauma patients who met inclusion criteria. The average change in TPA was -3.8 cm2 and TPI was -1.3 cm2. On admission, 23% (n = 19) of patients were sarcopenic while 77% (n = 62) were not. Non-sarcopenic patients had a significantly greater change in TPA (-4.9 vs. -0.31, p<0.0001), TPI (-1.7 vs. -0.13, p<0.0001), and rate of decrease in muscle mass (p = 0.0002). 37% of patients who were admitted with normal muscle mass developed sarcopenia during admission.  Older age was the only risk factor independently associated with developing sarcopenia (OR: 1.04, 95%CI 1.00-1.08, p = 0.045). CONCLUSION: Over a third of patients with normal muscle mass at admission subsequently developed sarcopenia with older age as the primary risk factor. Patients with normal muscle mass at admission had greater decreases in TPA and TPI, and accelerated rates of muscle mass loss compared to sarcopenic patients.

Racial and Ethnic Disparity in Prehospital Pain Management for Trauma Patients.

BACKGROUND: Although evidence suggests that racial and ethnic minority (REM) patients receive inadequate pain management in the acute care setting, it remains unclear whether these disparities also occur during the prehospital period. The aim of this study is to assess the impact of race and ethnicity on prehospital analgesic use by emergency medical services (EMS) in trauma patients. STUDY DESIGN: Retrospective chart review of adult trauma patients aged 18 to 89 years old transported by EMS to our American College of Surgeons-verified level 1 trauma center from 2014 to 2020. Patients who identified as Black, Asian, Native American, or Other for race and/or Hispanic or Latino or Unknown for ethnicity were considered REM. Patients who identified as White, non-Hispanic were considered White. Groups were compared in univariate and multivariate analysis. The primary outcome was prehospital analgesic administration. RESULTS: A total of 2,476 patients were transported by EMS (47% White and 53% REM). White patients were older on average (46 years vs 38 years; p < 0.001) and had higher rates of blunt trauma (76% vs 60%; p < 0.001). There were no differences in Injury Severity Score (21 vs 20; p = 0.22). Although REM patients reported higher subjective pain rating (7.2 vs 6.6; p = 0.002), they were less likely to get prehospital pain medication (24% vs 35%; p < 0.001), and that difference remained significant after controlling for baseline characteristics, transport method, pain rating, prehospital hypotension, and payor status (adjusted odds ratio [95% CI], 0.67 [0.47 to 0.96]; p = 0.03). CONCLUSIONS: Patients from racial and ethnic minority groups were less likely to receive prehospital pain medication after traumatic injury than White patients. Forms of conscious and unconscious bias contributing to this inequity need to be identified and addressed.

An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization.

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against Leishmania amazonensis axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC50 values from 50 to 480 nM. Concentration-response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium falciparum, suggesting broad antiparasitic activity. We explored structure-activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20-5000 nM) against axenic Leishmania amastigotes. Compared to MMV676477, our most potent analog, SW41, had ∼5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts Leishmania tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays with purified Leishmania and porcine tubulin demonstrated that MMV676477 promoted leishmanial tubulin polymerization in a concentration-dependent manner. Analogs' antiparasitic activity correlated with their ability to facilitate purified Leishmania tubulin polymerization. Chemical cross-linking demonstrated binding of the MMV676477 scaffold to purified Leishmania tubulin, and competition studies established a correlation between binding and antileishmanial activity. Our studies demonstrate that MMV676477 is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity.

Advances in infectious disease control strategies through genetic manipulation of insect microbiomes have heightened interest in microbially produced small molecules within mosquitoes. Herein, 33 mosquito-associated bacterial genomes were mined and over 700 putative biosynthetic gene clusters (BGCs) were identified, 135 of which belong to known classes of BGCs. After an in-depth analysis of the 135 BGCs, iron-binding siderophores were chosen for further investigation due to their high abundance and well-characterized bioactivities. Through various metabolomic strategies, eight siderophore scaffolds were identified in six strains of mosquito-associated bacteria. Among these, serratiochelin A and pyochelin were found to reduce female Anopheles gambiae overall fecundity likely by lowering their blood-feeding rate. Serratiochelin A and pyochelin were further found to inhibit the Plasmodium parasite asexual blood and liver stages in vitro. Our work supplies a bioinformatic resource for future mosquito-microbiome studies and highlights an understudied source of bioactive small molecules.