Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma.

PURPOSE: Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in patients with melanoma, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. METHODS: Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. RESULTS: We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions and ulcerated lesions and was associated with shorter survival in primary and metastatic tumors. On multivariable analysis, Breslow thickness, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. CONCLUSION: Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Assessing the one-month mortality impact of civilian-setting prehospital transfusion: A systematic review and meta-analysis.

BACKGROUND: Based on convincing evidence for outcomes improvement in the military setting, the past decade has seen evaluation of prehospital transfusion (PHT) in the civilian emergency medical services (EMS) setting. Evidence synthesis has been challenging, due to study design variation with respect to both exposure (type of blood product administered) and outcome (endpoint definitions and timing). The goal of the current meta-analysis was to execute an overarching assessment of all civilian-arena randomized controlled trial (RCT) evidence focusing on administration of blood products compared to control of no blood products. METHOD: The review structure followed the Cochrane group's Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). Using the Transfusion Evidence Library (transfusionevidencelibrary.com), the multidatabase (e.g. PubMed, EMBASE) Harvard On-Line Library Information System (HOLLIS), and GoogleScholar, we accessed many databases and gray literature sources. RCTs of PHT in the civilian setting with a comparison group receiving no blood products with 1-month mortality outcomes were identified. RESULTS: In assessing a single patient-centered endpoint-1-month mortality-we calculated an overall risk ratio (RR) estimate. Analysis of three RCTs yielded a model with acceptable heterogeneity (I2 = 48%, Q-test p = 0.13). Pooled estimate revealed civilian PHT results in a statistically nonsignificant (p = 0.38) relative mortality reduction of 13% (RR 0.87, 95% CI 0.63-1.19). CONCLUSIONS: Current evidence does not demonstrate 1-month mortality benefit of civilian-setting PHT. This should give pause to EMS systems considering adoption of civilian-setting PHT programs. Further studies should not only focus on which formulations of blood products might improve outcomes but also focus on which patients are most likely to benefit from any form of civilian-setting PHT.

Natural Experiment Outcomes Studies in Rotor Wing Air Medical Transport: Systematic Review and Meta-Analysis of Before-and-After and Helicopter-Unavailable Publications From 1970 to 2022.

OBJECTIVE: Helicopter emergency medical services (HEMS) is widely used for prehospital and interfacility transport, but there is a paucity of HEMS outcomes data from studies using randomized controlled trial designs. In the absence of robust randomized controlled trial evidence, judgments regarding HEMS potential benefit must be informed by observational data. Within the study design set of observational analyses, the natural experiment (NE) is notable for its high potential methodologic quality; NE designs are occasionally denoted "quasi-experimental." The aim of this study is to examine all NE outcomes studies in the HEMS literature and to discern what lessons can be learned from these potentially high-quality observational data. METHODS: HEMS NE studies were identified during the development of a new HEMS Outcomes Assessment Research Database (HOARD). HOARD was constructed using a broad-ranging search of published and gray literature resources (eg, PubMed, Embase, and Google Scholar) that used variations of the terms "helicopter EMS," "air ambulance," and "air medical transport." Among the 221 studies ultimately included in HOARD, 16 NE publications describing 13 sets of observational data comprising myriad diagnostic groups were identified. Of these 16 HEMS NEs, 4 HEMS NE studies assessing trauma outcomes were used in a meta-analysis. A meta-analysis was also performed of 4 HEMS NE studies. RESULTS: Although the disparity of studies (in terms of both case mix and end points) precluded the generation of a pooled effect estimate of an adjusted mortality benefit of HEMs versus ground emergency medical services, HEMS was found to be associated with outcomes improvement in 8 of the 13 cohorts. CONCLUSION: The weight of the NE evidence supports a conclusion of some form of HEMS-mediated outcomes improvement in a variety of patient types. Meta-analysis of 4 HEMS NE studies assessing trauma outcomes generated a model with acceptable heterogeneity (I2 = 43%, Q test: P = .16), which significantly (P < .01) favored HEMS use with a pooled HEMS survival odd ratio estimate of 1.66 (95% confidence interval, 1.23-2.22).

Applications of Artificial Intelligence in Helicopter Emergency Medical Services: A Scoping Review.

OBJECTIVE: Recent systematic reviews of acute care medicine applications of artificial intelligence (AI) have focused on hospital and general prehospital uses. The purpose of this scoping review was to identify and describe the literature on AI use with a focus on applications in helicopter emergency medical services (HEMS). METHODS: A literature search was performed with specific inclusion and exclusion criteria. Articles were grouped by characteristics such as publication year and general subject matter with categoric and temporal trend analyses. RESULTS: We identified 21 records focused on the use of AI in HEMS. These applications included both clinical and triage uses and nonclinical uses. The earliest study appeared in 2006, but over one third of the identified studies have been published in 2021 or later. The passage of time has seen an increased likelihood of HEMS AI studies focusing on nonclinical issues; for each year, the likelihood of a nonclinical focus had an odds ratio of 1.3. CONCLUSION: This scoping review provides overview and hypothesis-generating information regarding AI applications specific to HEMS. HEMS AI may be ultimately deployed in nonclinical arenas as much as or more than for clinical decision support. Future studies will inform future decisions as to how AI may improve HEMS systems design, asset deployment, and clinical care.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

Nation-Wide Variation in Presence of Legislation or Protocols for EMS Care of Operational Canines.

BACKGROUND & AIMS: Deployment of law enforcement operational canines (OpK9s) risks injuries to the animals. This study's aim was to assess the current status of states' OpK9 (veterinary Emergency Medical Services [VEMS]) laws and care protocols within the United States. METHODS: Cross-sectional standardized review of state laws/regulations and OpK9 VEMS treatment protocols was undertaken. For each state and for the District of Columbia (DC), the presence of OpK9 legislation and/or care protocols was ascertained. Information was obtained through governmental records and from stakeholders (eg, state EMS medical directors and state veterinary boards).The main endpoints were proportions of states with OpK9 laws and/or treatment protocols. Proportions are reported with 95% confidence intervals (CIs). Fisher's exact test (P <.05) assessed whether presence of an OpK9 law in a given jurisdiction was associated with presence of an OpK9 care protocol, and whether there was geographic variation (based on United States Census Bureau regions) in presence of OpK9 laws or protocols. RESULTS: Of 51 jurisdictions, 20 (39.2%) had OpK9 legislation and 23 (45.1%) had state-wide protocols for EMS treatment of OpK9s. There was no association (P = .991) between presence of legislation and presence of protocols. There was no association (P = .144) between presence of legislation and region: Northeast 66.7% (95% CI, 29.9-92.5%), Midwest 50.0% (95% CI, 21.1-78.9%), South 29.4% (95% CI, 10.3-56.0%), and West 23.1% (95% CI, 5.0-53.8%). There was significant (P = .001) regional variation in presence of state-wide OpK9 treatment protocols: Northeast 100.0% (95% CI, 66.4-100.0%), Midwest 16.7% (95% CI, 2.1-48.4%), South 47.1% (95% CI, 23.0-72.2%), and West 30.8% (95% CI, 9.1-61.4%). CONCLUSION: There is substantial disparity with regard to presence of OpK9 legal and/or clinical guidance. National collaborative guidelines development is advisable to optimize and standardize care of OpK9s. Additional attention should be paid to educational and training programs to best utilize the limited available training budgets.

Update on Biomarkers in Renal Cell Carcinoma.

Immune checkpoint inhibitors have significantly transformed the treatment paradigm for metastatic renal cell carcinoma (RCC), offering prolonged overall survival and achieving remarkable deep and durable responses. However, given the multiple ICI-containing, standard-of-care regimens approved for RCC, identifying biomarkers that predict therapeutic response and resistance is of critical importance. Although tumor-intrinsic features such as pathological characteristics, genomic alterations, and transcriptional signatures have been extensively investigated, they have yet to provide definitive, robust predictive biomarkers. Current research is exploring host factors through in-depth characterization of the immune system. Additionally, innovative technological approaches are being developed to overcome challenges presented by existing techniques, such as tumor heterogeneity. Promising avenues in biomarker discovery include the study of the microbiome, radiomics, and spatial transcriptomics.

A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better.

BACKGROUND: Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. METHODS: We employed a Simon's two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. RESULTS: Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. CONCLUSIONS: Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03502330.

Melanocortin 1 receptor (MC1R) expression as a marker of progression in melanoma.

Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in melanoma patients, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions, ulcerated lesions, and mucosal melanomas compared to cutaneous melanomas and was associated with shorter survival in primary and metastatic tumors. On multi-variable analysis, Breslow thickness, ulceration, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. In the metastatic melanoma cohort, MC1R expression and mucosal melanomas were independent predictors of inferior overall survival. Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Survivorship With Incrementally Faster Times to Primary Percutaneous Coronary Intervention (SWIFT-PPCI): A Systematic Review and Meta-Analysis.

In the United States, there are approximately 750,000 ST-elevation myocardial infarction cases each year. Streamlined care and rapid delivery for primary percutaneous coronary intervention (PPCI) is associated with improved survival. This systematic review and meta-analysis aimed to generate a practical estimate of mortality savings for every notional 30-minute decrease in the time to achieving PPCI. Included studies were those that provided a specific absolute risk reduction for a specific reduction in pre-PPCI time. The eligible studies evaluated the survival benefit from pre-PPCI time savings measured in any interval ending with PPCI and commencing with objectively recorded timing, such as initial emergency call, first medical contact, or hospital arrival. Study planning called for the reporting of data as individual study results, with a pooled effect estimate of relative risk calculated with random-effects meta-analysis. A total of 1,088 records were eligible for review; 52 were reviewed in full text, with 4 studies (total patient n = 235,814, overall mortality 4.7% to 7.8%) included in the final analysis. All 4 studies reported significant time-related survival benefit over the study focus window of 60 to 180 minutes pre-PPCI. The number of lives saved per 100 cases for each 30-minute pre-PPCI time savings ranged from 0.8 to 1.9. The overall effect estimate generated was 0.753 (95% confidence interval 0.712 to 0.796), with acceptable heterogeneity (I2 = 36%). In conclusion, a pooled effect calculation estimated a 24.7% relative risk reduction for each 30 minutes of time savings. For cases that underwent PPCI within 60 to 180 minutes of initial presentation with known baseline mortality risk, the time savings in 30-minute epochs can be leveraged to estimate a specific number of lives saved; this may be useful for those involved in the organization of medical care who make systemwide plans and individual patient triage decisions.

First-Pass Success of Intubations Using Video Versus Direct Laryngoscopy in Children With Limited Neck Mobility.

OBJECTIVE: It is not clear whether video laryngoscopy (VL) is associated with a higher first-pass success rate in pediatric patients with limited neck mobility when compared with direct laryngoscopy (DL). We sought to determine the association between the laryngoscopy method and first-pass success. METHODS: In this retrospective cohort study, we examined intubation data extracted from 2 prospectively collected, multicenter, airway management safety databases (National Emergency Airway Registry and the National Emergency Airway Registry for children), obtained during the years 2013-2018 in the emergency department. Intubations were included if patients were aged younger than 18 and had limited neck mobility. We compared first-pass success rates for ED intubations that were performed using VL versus DL. We built a structural causal model to account for potential confounders such as age, disease category (medical or trauma condition), other difficult airway characteristics, use of sedatives/paralytics, and laryngoscopist training level. We also analyzed adverse events as a secondary outcome. RESULTS: Of 34,239 intubations (19,071 in the National Emergency Airway Registry and 15,168 in the National Emergency Airway Registry for children), a total of 341 intubations (1.0%) met inclusion criteria; 168 were performed via VL and 173 were performed via DL. The median age of patients was 124 months (interquartile range, 48-204). There was no difference in first-pass success between VL and DL (79.8% vs 75.7%, P = 0.44). Video laryngoscopy was not associated with higher first-pass success (odds ratio, 1.11; 95% confidence interval 0.84-1.47, with DL as a comparator) when a structural causal model was used to account for confounders. There was no difference in the adverse events between VL and DL groups (13.7% vs 8.7%, P = 0.19). CONCLUSION: In children with limited neck mobility receiving tracheal intubation in the ED, neither VL nor DL was associated with a higher first-pass success rate.

Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases.

BACKGROUND: The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized. METHODS: We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases. RESULTS: We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation. CONCLUSIONS: Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.

Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments antitumor activity in melanoma.

Targeting tumor-associated blood vessels to increase immune infiltration may enhance treatment effectiveness, yet limited data exist regarding anti-angiogenesis effects on the tumor microenvironment (TME). We hypothesized that dual targeting of angiogenesis with immune checkpoints would improve both intracranial and extracranial disease. We used subcutaneous and left ventricle melanoma models to evaluate anti-PD-1/anti-VEGF and anti-PD-1/lenvatinib (pan-VEGFR inhibitor) combinations. Cytokine/chemokine profiling and flow cytometry were performed to assess signaling and immune-infiltrating populations. An in vitro blood-brain barrier (BBB) model was utilized to study intracranial treatment effects on endothelial integrity and leukocyte transmigration. Anti-PD-1 with either anti-VEGF or lenvatinib improved survival and decreased tumor growth in systemic melanoma murine models; treatment increased Th1 cytokine/chemokine signaling. Lenvatinib decreased tumor-associated macrophages but increased plasmacytoid DCs early in treatment; this effect was not evident with anti-VEGF. Both lenvatinib and anti-VEGF resulted in decreased intratumoral blood vessels. Although anti-VEGF promoted endothelial stabilization in an in vitro BBB model, while lenvatinib did not, both regimens enabled leukocyte transmigration. The combined targeting of PD-1 and VEGF or its receptors promotes enhanced melanoma antitumor activity, yet their effects on the TME are quite different. These studies provide insights into dual anti-PD-1 and anti-angiogenesis combinations.

Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma.

INTRODUCTION: Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib, are approved for first-line treatment of metastatic renal cell carcinoma (mRCC). Pembrolizumab/axitinib is associated with superior progression free survival (PFS), objective response rate (ORR), and overall survival over sunitinib. However, to date, the activity and safety of pembrolizumab/axitinib in later lines of therapy has not been reported. MATERIALS AND METHODS: Clinical data of consecutive patients receiving pembrolizumab/axitinib in the second-line or beyond for mRCC at Yale-New Haven Hospital were retrospectively collected. Best objective response was assessed using RECIST 1.1 criteria. Kaplan-Meier function was used to analyze survival. RESULTS: Thirty-eight patients were included. Median age was 64, 92.1% had clear cell mRCC, 18.4% had sarcomatoid dedifferentiation; 94.7% had prior ICI and 39.5% had prior VEGF-R-TKI. Pembrolizumab/axitinib was administered as second-line therapy in 21 (55.5%) patients, third-line in 5 (13.2%) and beyond in 12 (30.2%). Adverse events (AEs) occurred in 86.8% of patients. Grade 3-4 AEs attributed to pembrolizumab and axitinib were seen in 18.4% and 6.4% of patients, respectively. No grade 5 AEs occurred. At a median follow up of 17.1 months, median PFS was 9.7 months (95% CI, 4.1-15.3). Amongst 36 response evaluable patients, the ORR was 25.0% (all partial) and disease control rate (including stable disease for at least 6 months) was 66.6%. The most frequent treatment sequence was first-line nivolumab/ipilimumab followed by second-line pembrolizumab/axitinib (n = 17, 44.7%); among this cohort, median PFS with pembrolizumab/axitinib was 11.1 (95% CI, 8.4-13.7) months, with an ORR of 31.4%. CONCLUSION: Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line. Prospective studies evaluating ICI-VEGF-R-TKI combinations beyond first-line are warranted to identify the most beneficial treatment sequencing in mRCC.

A Pragmatic Cluster-Randomized Trial of Provider Education and Community Health Worker Support for Tobacco Cessation.

OBJECTIVE: Individuals with serious mental illness have a high prevalence of tobacco use disorder and related early mortality but underutilize smoking cessation medication. The authors determined whether clinician-delivered education to primary care providers regarding safety, efficacy, and importance of cessation medication (provider education [PE]) alone or combined with community health worker (CHW) support would increase tobacco abstinence in this population, compared with usual care. METHODS: All adult current tobacco smokers receiving psychiatric rehabilitation for serious mental illness through two community agencies in Greater Boston were eligible, regardless of readiness to quit smoking. Primary care clinics were cluster randomized to PE or usual care, with a nested, participant-level randomization to CHW or no CHW in PE-assigned clinics. The primary outcome was blindly assessed, biochemically verified tobacco abstinence at year 2. RESULTS: Overall, 1,010 eligible participants were enrolled. PE was delivered to providers in 53 of 55 assigned clinics; 220 of 336 CHW-assigned participants consented to CHW support. Year 2 abstinence rates were significantly higher among participants assigned to PE+CHW versus usual care (12% vs. 5%; adjusted odds ratio [AOR]=2.40, 95% confidence interval [CI]=1.20-4.79) or PE alone (12% vs. 7%; AOR=1.84, 95% CI=1.04-3.24). No effect of PE alone on abstinence was detected. Compared with participants assigned to usual care, those assigned to PE+CHW had greater odds of varenicline use (OR=2.77, 95% CI=1.61-4.75), which was associated with higher year 2 abstinence (OR=1.97, 95% CI=1.16-3.33). CONCLUSIONS: Combined PE and CHW tobacco cessation support increased tobacco abstinence rates among adults with serious mental illness.

State-by-state estimates of avoidable trauma mortality with early and liberal versus delayed or restricted administration of tranexamic acid.

OBJECTIVE: Early administration of tranexamic acid (TXA) has been shown to save lives in trauma patients, and some U.S. emergency medical systems (EMS) have begun providing this therapy prehospital. Treatment protocols vary from state to state: Some offer TXA broadly to major trauma patients, others reserve it for patients meeting vital sign criteria, and still others defer TXA entirely pending a hospital evaluation. The purpose of this study is to compare the avoidable mortality achievable under each of these strategies, and to report on the various approaches used by EMS. METHODS: We used the National Center for Health Statistics Underlying Cause of Death data to identify a TXA-naïve population of trauma patients who died from 2007 to 2012 due to hemorrhage. We estimated the proportion of deaths where the patient was hypotensive or tachycardic using the National Trauma Data Bank. We used avoidable mortality risk ratios from the landmark CRASH 2 study to calculate lives saved had TXA been given within one hour of injury based on a clinician's gestalt the patient was at risk for significant hemorrhage; had it been reserved only for hypotensive or tachycardic patients; or had it been given between hours one to three of injury, considered here as a surrogate for deferring the question to the receiving hospital. RESULTS: Had TXA been given within 1 hour of injury, an average of 3409 deaths per year could have been averted nationally. Had TXA been given between one and three hours after injury, 2236 deaths per year could have been averted. Had TXA only been given to either tachycardic or hypotensive trauma patients, 1371 deaths per year could have been averted. Had TXA only been given to hypotensive trauma patients, 616 deaths per year could have been averted. Similar trends are seen at the individual state level. A review of EMS practices found 15 statewide protocols that allow EMS providers to administer TXA for trauma. CONCLUSION: Providing early TXA to persons at risk of significant hemorrhage has the potential to prevent many deaths from trauma, yet most states do not offer it in statewide prehospital treatment protocols.

Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance.

While great strides have been made in the treatment of advanced renal cell carcinoma (RCC) with the emergence of immune checkpoint inhibitors (ICIs) and VEGFR-targeting drugs, sizable proportions of patients still do not respond to upfront therapy and long-term responses only occur in a minority of patients. There is therefore a great need for the development of better predictors of response and an increased understanding of mechanisms of resistance to these therapies. Alternative immune checkpoints outside the PD-1/PD-L1 axis, such as LAG3, have been implicated as one mechanism of resistance to ICIs. These checkpoints thus represent attractive therapeutic targets, and indeed the LAG3 inhibitor relatlimab was recently approved for the treatment of metastatic melanoma in combination with anti-PD-1 therapy. LAG3 inhibitors are being evaluated for RCC as well. In this context, a better understanding of LAG3 expression patterns in RCC and how they relate to clinicopathologic features of disease and response to immunotherapy may give insight into mechanisms of resistance to PD-1 inhibitors and aid in the identification of subgroups of patients more likely to benefit from certain drug regimens. In this study, we assessed LAG3 protein levels in leukocytes in normal kidney adjacent to RCC, primary RCC tumors, and matched metastatic tumors, including large numbers of brain metastases. We found that LAG3 protein levels are on average lower at metastatic sites compared to matched primary tumors, and that the difference was more pronounced in patients with high-risk clinical characteristics, including those with larger primary tumor size, grade 4 tumors, IMDC poor-risk disease, and initial presentation with brain metastases. We further saw that the prognostic value of LAG3 levels varies depending on the tissue site queried (i.e., primary tumor versus metastases), and that relatively higher LAG3 levels at metastatic sites may predict a better response to immunotherapy and longer overall survival after the development of metastatic disease. These findings may have important implications for the design of future studies involving LAG3 or other immunotherapies in RCC.

Triple Threat: A Case of Erysipelothrix rhusiopathiae Septicemia Complicated by Multi-Valvular Endocarditis, Spinal Osteomyelitis, and Septic Embolic Stroke.

Erysipelothrix rhusiopathiae is a Gram-positive rod associated with zoonotic infections, most commonly the soft tissues. It can be present in several ways, though most commonly as erysipeloid. Rarely, it may manifest systemically with septic organ involvement such as endocarditis or osteomyelitis. Here, we present the case of a 71-year-old male who presented to the hospital with back pain and neurological deficits. He was found to be bacteremic with E. rhusiopathiae, and imaging demonstrated the presence of multi-valvular endocarditis, spinal osteomyelitis with epidural abscess, and septic embolic stroke. Though such complications of E. rhusiopathiae septicemia have been documented in the literature, this is the first reported case of all three manifestations in one patient.