United States

Background: Type 1 Diabetes affects over 2.1 million patients in the United States and cost the healthcare system $14.4B in 2016. The current clinical standard for Type 1 Diabetes is daily glucose monitoring and exogenous insulin administration, which is medically and financially intensive. Islet cell transplantation could provide a curative solution but requires intense immunosuppression to avoid graft rejection.
Rapamycin, one part of this immunosuppressive protocol, delivered directly to antigen-presenting cells (APCs) maintains them in an immature state that leads to “co-stimulation blockade”, leading to anergy of T-cells. Polyethylene glycol- b-polypropylene sulfide polymers self-assemble into nanovesicles (PS) that can be loaded with hydrophobic drugs such as rapamycin (rPS). When injected subcutaneously, rPS is preferentially uptaken by macrophages, leading to targeted costimulation blockade4.
Burke et al. (2022) demonstrate that rPS induces extended survival of MHC- mismatched islet allografts and normoglycemia in a drug-induced diabetic mouse model4. We seek to validate these results in a non-obese diabetic (NOD) mouse model that replicates the inflammatory and autoimmune environment of Type 1 Diabetes pathology. Studies (Table 1) show that certain gut microbiome bacteria have increased populations in the states of immune tolerance.

Methods: NOD mice (age = 12 weeks) were injected with varying concentrations of rPS (0 mg/kg [PBS], 0.5 mg/kg, 1 mg/kg, 2 mg/kg, n =5 for each group) every 3 days for 18 days (total 6 doses). After the final dosing, mice were euthanized and their brachial/pancreatic lymph nodes, spleen, and cecal content were harvested. Cecal content was sent to Zymo Research for microbiological sequencing while lymph node and spleen samples were processed for flow cytometry.

Results: rPS exhibits a significant and positive dose dependent effect on the prevalence of the Blautia genus associated with induction of regulatory T cells and allograft survival. In the Lactobacillus genus, a statistically non-significant increase in prevalence is seen in the rPS 2 mg/kg group. Genus Alistipes was significantly decreased in prevalence in the 0.5 mg/kg rPS group.
Many rejection associated bacteria were not prevalent at all in the microbiota of both the controls and treatments.

Conclusions: The significant and dose associated effect of rPS on the Blautia genus shows that one mechanism of rPS’s tolerogenic effects may be through change of the gut microbiome. These results agree with previous pharmacologic characterization of rPS in significantly changing the immune population of CD80/86+ APCs and regulatory T cells.
The mechanism by which rPS affects the gut microbiome still needs to be elucidated. It is unclear whether rPS modulates the microbiome directly or if rPS’s previously established effects on the immune system allow for bacterial species associated with tolerance to flourish. In addition, each experimental group was not adequately powered to find significant associations in species outside of the Blautia genus. A larger study is required to confirm these results and establish the mechanism of causality.

AMA Research Challenge 2024 

Novel nanomedicine increases tolerance-associated species in the gut microbiota of non-obese diabetic mice

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Biosafety of Intramuscular Autoinjection of Sulfanegen, a New Cyanide Antidote, in a Porcine Model
Deepali Shrivastava, Arreh Jain, Steven E. Patterson, Walt Tollison, John Carney, David Beebe, Kumar G. Belani
Background: Sulfanegen is a potent antidote to severe cyanide toxicity and can be administered intramuscularly. A proprietary intramuscular autoinjector has been developed for rapid administration during emergencies. This study investigated the safety of sulfanegen administered via the autoinjector in a porcine model, focusing on its systemic biochemical and metabolic toxicity and local tissue reaction.
Methods: After IACUC approval, eight healthy juvenile Yorkshire pigs (16-20 kg) were sedated with Tiletemine/Zolazepam (2-7 mg/kg) and Xylazine (0.2-1 mg/kg). Monitoring in these spontaneously breathing pigs included continuous EKG, pulse oximetry, respiratory rate, blood pressure, and temperature. Surface warming ensured normothermia. Blood samples were collected via peripheral venous blood before sulfanegen injection with a novel automatic injection system. The calculated body weight dose of Sulfanegen (75 mg/kg) was divided between two injectors and injected simultaneously into each of the hind thigh muscles. Hemodynamic parameters such as heart rate, respiratory rate, oxygen saturation, and core temperature were monitored throughout the procedure. Pre- and post-injection blood samples were collected for biochemical evaluation. After the Sulfanegen injection, the pigs recovered and observed for 7 days. They were then sedated again with the tiletamine/zolazepam and Xylazine mixture to collect metabolic blood samples and humanely euthanized for a necropsy. The muscle injection sites were grossly examined. Hemodynamic and biochemical data were analyzed using SPSS v27.
Results: All the pigs survived the Sulfanegen injection. Hemodynamics and biochemical parameters remained stable during and immediately following the injection without significant changes. Following emergence from anesthesia, all pigs were active and feeding appropriately. At necropsy, the local muscle tissue at the injection sites showed only minimal inflammation and no necrosis. Liver function, hematological, and metabolic tests at necropsy were within normal range.
Conclusion: In this porcine model, the intramuscular injection of Sulfanegen using the proprietary autoinjector device did not exert any adverse biochemical, hematological, or hemodynamic effects. There was only minimal local irritation at the injection sites. The next steps would be to examine the effects of increased doses of sulfanegen on muscle tissue in this model.


Biosafety of Intramuscular Autoinjection of Sulfanegen, a New Cyanide Antidote, in a Porcine Model

Background
Electroconvulsive therapy (ECT) is a procedure involving controlled seizures induced by electrical currents through the brain, all while a patient is under anesthesia and muscle paralysis. It is used to treat mental health conditions, including major depressive disorder, bipolar disorder, schizophrenia, and catatonia. Despite its effectiveness, ECT is underutilized, with only about 0.25% of mood disorder patients receiving it due to cost and stigma. Common anesthetics for ECT include etomidate and propofol. This research aims to further compare etomidate and propofol, and to find adequate evidence to support that etomidate is the better choice.

Methods
The narrative review employed a systematic search strategy to identify relevant studies on the use of Etomidate and Propofol as anesthetic agents in ECT. The search, conducted on January 21, 2024, utilized PubMed and Web of Science databases with key terms derived from MeSH and combined using Boolean operators. Inclusion criteria encompassed studies published until January 2024, accessed through PubMed, Scopus, and Web of Science, with reference lists of selected studies reviewed for additional relevant articles. Inclusion and exclusion criteria are outlined in this section. The review adheres to reporting standards outlined in the Scale for the Assessment of Narrative Review Articles.

Results
The tables present various study characteristics and results related to the use of different anesthetic agents in ECT. Table 1 outlines study details such as including medication dosages, exclusions, and patient populations across different countries and years. Table 2 provides population characteristics, including sample sizes and age ranges, mean ages, and gender distributions. Table 3 summarizes the results and conclusions of each study, highlighting findings such as induction times, seizure durations, hemodynamic stability, and incidence of myoclonus with different anesthetic agents. These tables collectively demonstrate the comparative effectiveness and safety profiles of Propofol, Etomidate, Thiopentone, and other anesthetic agents in ECT induction.

Conclusion
The narrative review examined the effects of Propofol and Etomidate on ECT. Propofol showed superiority over Etomidate in terms of shorter induction time, decreased seizure duration, and improved recovery times. Additionally, Propofol was associated with stable hemodynamics, shorter induction times, decreased seizure durations, and improved recovery times, along with stable hemodynamics. However, Etomidate was found to be more suitable for elderly patients due to quicker cognitive function recovery. Despite these findings’ differences, both drugs showed similar overall efficacy, indicating a need for further research, particularly exploring combined drug approaches for optimized treatment outcomes in ECT.


Comparison of Propofol or Etomidate in Electroconvulsive Therapy: A Narrative of Randomized Control Trials

Propofol in a Cardiac Setting: Recent Findings in Clinical Applicability and Protective Mechanisms

Researchers: Nizam Ali Karim B.S. Justin Viet Quang Le B.S.A. Zahir Malik Amin B.S. Harmandeep Singh B.S. Winston Tawiah B.S.
The University of Texas Medical Branch (UTMB) John Sealy School of Medicine, Galveston, TX

Background: Propofol is a widely used intravenous anesthetic agent known for its rapid onset and short duration of action. Beyond its primary anesthetic role, propofol has been found to possess cardioprotective properties. This study aims to investigate the mechanisms underlying these cardioprotective effects and evaluate their clinical applicability in cardiac medicine.

Methods: A systematic review was conducted using PubMed to ascertain published studies in the English language over the period of 2021-2024 using the appropriate search terms. The primary papers of interest were those that examined the cardioprotective effect of the intravenous anesthetic propofol. The search criteria yielded a total of 26 articles, which were then examined by three researchers for inclusion in the study. A total of 15 articles met the inclusion criteria and were included.

Results: The systematic review evaluated the cardioprotective effects of propofol in various preclinical and clinical settings. The studies reviewed included experiments on H9c2 rat-derived cardiac cells subjected to hypoxia/reoxygenation conditions, animal models of myocardial ischemia/reperfusion (I/R) injury, and clinical trials involving cardiac surgery patients. Propofol postconditioning (P-PostC) significantly reduced hypoxia/reoxygenation-induced apoptosis and autophagy in H9c2 cells. This effect was mediated by the upregulation of forkhead transcription factors FoxO1 and FoxO3a. Silencing these transcription factors reversed the cardioprotective effects, indicating their critical role in propofol's mechanism. Additionally, propofol alleviated oxidative stress, as evidenced by decreased reactive oxygen species (ROS) levels. In rat models, propofol pretreatment reduced myocardial infarct size, improved cardiac function, and decreased markers of myocardial injury such as lactate dehydrogenase (LDH) and creatine kinase (CK). Propofol also inhibited mast cell degranulation by reducing calcium influx through store-operated Ca2+ channels (SOCs) and activated the PI3K/AKT/Bcl-2 pathway, enhancing cell survival. Furthermore, in patients undergoing off-pump coronary artery bypass grafting (OPCABG), both volatile anesthetics and propofol demonstrated cardioprotective effects. However, volatile anesthetics slightly outperformed propofol in reducing myocardial injury markers such as troponin. Despite this, no significant difference in overall mortality or major morbidity was observed between these anesthetics.

Conclusion: Propofol exhibits significant cardioprotective effects through multiple mechanisms, including modulation of molecular pathways, inhibition of mast cell degranulation, activation of survival pathways, antioxidant activity, modulation of calcium homeostasis, and reduction of ischemia-reperfusion injury. Utilizing these effects, propofol can improve the quality of care in patients with cardiovascular conditions. Although its benefits in cardiac surgery are well-documented, further clinical research is warranted to optimize its use in non-surgical cardiac interventions.

Propofol in a Cardiac Setting: Recent Findings in Clinical Applicability and Protective
Mechanisms

Title: A Tale of Two Sexes: Exploring Differences in Right-Sided Heart Failure in a Porcine Model

Introduction: Right-sided heart failure (RHF) exhibits notable sex-based differences, with females generally demonstrating better right ventricular (RV) function compared to males. These disparities have significant prognostic implications, especially in RV-centric diseases like
pulmonary hypertension (PH), where RV dysfunction is linked to poor patient outcomes. Despite these observations, there are no therapies that specifically target the failing RV, and potential sex-based differences are understudied. Therefore, we evaluated the cellular and molecular responses to RHF in male and female pigs to identify potential sex-based differences.

Methods: 4-week-old male and female piglets underwent pulmonary artery banding (PAB) for six weeks to induce right ventricular dysfunction. Cardiac MRI changes in RV structure, function, volume, and mass. Wheat Germ Agglutinin evaluated cardiomyocyte hypertrophy. Super resolution confocal micrographs were analyzed using FIJI. Proteomics and metabolomics quantified RV metabolites and proteins.
Results: Despite having the same right ventricular ejection fraction, PAB-females had greater relative RV hypertrophy and dilation as assessed by cardiac MRI. Histologically, PAB-females had a nearly two-fold increase in RV cardiomyocyte cross sectional area compared to PAB-males. All four experimental groups clustered separately on hierarchical cluster analysis, suggesting significant groupwise differences in metabolomic profiles. Levels of triacylglycerols
and diacylglycerols were reduced in PAB-males and PAB-females compared to their controls. However, PAB-males had increased abundances of acylcarnitines, the mitochondrial form of fatty acids, compared to their controls, suggesting reduced fatty acid metabolism in PAB-males. Proteomics revealed reduced protein abundances in metabolic pathways in PAB-males, but not PAB-females. In addition, proteomics identified proteins in the cardiac muscle contraction
pathway are upregulated in PAB-males, compared to control males, but these proteins are mostly unchanged in PAB-females compared to control females.

Conclusion: Male and female piglets exhibit different cellular and molecular responses to PAB, despite similar levels of RV dysfunction. Females have a greater hypertrophic response, less metabolic/energetic derangements, and less relative sarcomeric protein upregulation compared to male pigs.

A Tale of Two Sexes: Exploring Right Sided Heart Failure in a Porcine Model

Air Pollution Induces Atrial Fibrosis via CARD9-Mediated Immune Response

Background
Exposure to ambient fine particulate matter (PM) triggers systemic inflammation and is associated with atrial fibrosis (AF) and cardiac arrhythmia. The cytosolic adaptor caspase recruitment domain 9 (CARD9) is crucial for macrophage function and innate immune response. This study aimed to investigate the role of CARD9-dependent immune response in PM-induced macrophage-mediated inflammation and the detrimental effects of PM on the heart atrium, exploring the underlying mechanisms.

Methods
Male C57BL/6 wild type (WT) mice (4-6 months old, n=8-12) and age- and sex-matched CARD9 knockout (CARD9-/-) mice (n=8-12) were intranasally exposed to PM for 1, 2, 7, 14, and 28 days. Serum levels of TNF-α, IL-1β, IL-6, and IL-10 were measured using ELISA. Total macrophage populations and M1/M2 subpopulations in bone marrow (BM) and blood were analyzed in mice with and without PM exposure. BM macrophages were cultured for 48 hours in M0, M1, or M2 medium to analyze their populations and cytokine production with or without PM exposure. Phosphorylated Akt (p-Akt), p-Erk, and Ankyrin-B levels were determined in atrial cardiomyocytes using immunoblotting. AF area was measured with Masson’s trichrome staining.

Results
PM exposure significantly elevated serum levels of TNF-α, IL-1β, and IL-6 in WT mice within 24 hours, but not in CARD9-/- mice. In CARD9-/- mice, PM exposure increased the M2 macrophage population and IL-10 levels compared to WT mice, with similar findings observed in vitro using BM cells cultured in M0, M1, and M2 media. PM-induced AF was linked to reduced atrial p-Akt and Ankyrin-B levels, effects that were mitigated in CARD9-/- mice compared to WT mice.

Conclusion
PM exposure-induced AF may be linked to an enhanced macrophage inflammatory response through CARD9-mediated reduction in IL-10 secretion, resulting in a decreased M2 macrophage polarization from M0 macrophage.

Air Pollution Induces Atrial Fibrosis via CARD9-Mediated Immune Response

Background: Excessive fibrosis can alter the electrical conduction in the atrial tissue leading to atrial fibrillation (AFib). However, the underlying mechanisms driving atrial fibrosis and the development of AFib remain incompletely understood. We hypothesized that atrial fibrosis could result due to coronary microvascular vasodilator dysfunction. 

Methods: Right human atrial appendages were collected during cardiac surgeries. Coronary arterioles (~100 µm) were dissected, cannulated, and pressurized (80 mmHg). Using video-microscopy, endothelium-dependent vasodilation was assessed by bradykinin (BK) and smooth muscle-dependent vasodilation was measured using sodium nitroprusside (SNP). Atrial tissue was then paraffin embedded and, via Masson’s Trichrome staining, the collagen content was quantified by ImageJ.

Results: When submitted to cumulative increases of bradykinin, AFib patients showed a significant reduced maximum vasodilation compared to the control patient with sinus rhythm (p=0.021), whereas no significant changes were recorded in SNP-induced vasodilator response. This decrease in BK-induced vasodilatory response was accompanied by a trend in increasing collagen content in the AFib patients, when compared to the control group (p=0.133). 

Conclusion: The collected data shows that patients with AFib have an increased collagen content in association with impaired endothelium-dependent vasodilatory response. Together, these data show that coronary microvascular dysfunction is accompanied by increased fibrosis, which may lead to hypoxia and AFib. 

Relevance for Patient Care: These data show a possible link between coronary microvascular dysfunction and Afib, which allows us to better understand AFib. 

Strengths/limitations: Limitations of this study include small sample size (n=8). The strength of these data is that these are samples taken from patients. 

Ethical Permissions: Ethical Approval was obtained for biological sample use.

Coronary Microvascular Dysfunction is Associated with Atrial Fibrosis in Patients with Atrial Fibrillation

Background: Abdominal aortic aneurysm (AAA) is a potentially lethal vascular disease lacking non-surgical treatments. AAA is associated with decreased expression of estrogen receptor alpha (ERα) in the aorta. The significance of this finding and the mechanisms by which lack of ERα signaling contributes to AAA pathogenesis have not been examined. In this investigation, we test the hypothesis that ERα signaling protects against AAA by decreasing endothelin-1 (ET-1) production and regulating inflammation.

Methods: AAA was induced in endothelial cell-specific ERα knockout (eERαKO) male mice and their littermates (ERαFL2) (n=6-11) by administering β-Aminopropionitrile (BAPN) via drinking water (1 mg/ml, 0.15 g/kg/d) 3 days before angiotensin II (Ang II; 1 µg/kg/day) infusion for 2 weeks. Development of AAA was assessed by in vivo ultrasound measurement of aortic luminal dilation. Relevant molecular mechanisms were examined in abdominal aortic tissues, human aortic endothelial cells (HAECs) and mouse bone marrow-derived macrophages (BMDMs). 

Results: BAPN/Ang II increased abdominal aortic diameter in ERαFL2 and eERαKO mice compared to control. Lack of ERα further augmented the BAPN/Ang II-induced increase in aortic diameter and AAA incidence compared to ERαFL2 mice. Immunohistochemical staining revealed that BAPN/Ang II co-infusion significantly upregulates ET-1 expression and macrophage infiltration of the abdominal aorta in eERαKO mice compared to ERαFL2 mice. In vitro studies in HAECs demonstrated that treatment with ERα agonist, β-estradiol (100 nM, 24 h), decreases TNFα (15 ng/ml)-induced ET-1 production, while treatment with ERα-specific antagonist, methylpiperidinopyrazole (1 µM, 24 h), increases ET-1 production. Additionally, BMDMs obtained from the eERαKO mice exhibited increased production of the pro-inflammatory cytokine monocyte chemoattractant protein-1 compared to macrophages from ERαFL2 mice.

Conclusion: Our findings demonstrate a protective effect of endothelial ERα signaling against AAA in male mice likely through decreased ET-1 production and reduced pro-inflammatory macrophage activation of the aorta. Further studies are needed to delineate the crosstalk between endothelial ET-1 with macrophage phenotype and their impact in AAA pathogenesis.

Role of Estrogen Receptor Alpha and Endothelin-1 in Pathogenesis of Abdominal Aortic Aneurysm in Male Mice

Background: Age and biological sex are well-known cardiovascular risk factors. Advanced age is correlated with vascular stenosis and turbulent flow, and studies suggest females experience increased coronary flow and vascular shear stress compared to males. These conditions increase risks for coronary calcification and luminal surface alterations, and subsequently, hemodynamic changes. Understanding the impact of age and sex on calcification and luminal surface topography in coronary arteries will yield insight not only on the mechanical pathophysiology of hemodynamic changes over time and between sexes, but also on refining risk stratification for cardiovascular diseases. In this study, we aim to detect, quantify, and compare the extent of calcification and luminal surface differences between age groups and sexes in cadaveric left anterior descending arteries (LADs) using a relatively novel approach–surface metrology. We hypothesized that LAD calcification and luminal surface complexity would increase in higher age groups and in the female sex. 

Methods: LADs (n=18) were harvested from cadaveric hearts using a systematic dissection approach. To quantify the extent of calcification, each specimen was scanned using the Bruker Skyscan 1173 microCT scanner and subsequently underwent threshold-based image segmentation on Dragonfly by Object Research Systems. To quantify luminal surface complexity, each specimen was splayed open to expose their luminal surfaces and up to 15 scans were performed at 20X magnification using the Sensofar S Neox optical profiler. Each scan subsequently underwent surface metrologic scale-sensitive fractal analyses in SensoMap 10. 

Results: We established 4 age groups: 60-69, 70-79, 80-89, and 90-99, and categorized our data to the corresponding age and sex groups. Our microCT findings demonstrated statistically significant reductions in LAD calcification in females compared to males, but no differences between age groups. Our surface metrology findings demonstrated statistically significant reductions in fractal complexity (Lsfc) and fractal dimension (Dls) in the highest age group compared to each of the lower age groups, but no differences in smooth rough crossover (SRC) and the scale of maximum complexity (Smfc) between each group. Additionally, no statistically significant differences were observed in SRC, Lsfc, Dls, and Smfc between males and females. 

Conclusions: Our data suggests that males are significantly more prone to LAD calcification than females. Moreover, LAD luminal surfaces may increase in smoothness at a high age (>90) relative to lower ages (>60, but <90). Future studies will involve modeling blood flow across these surfaces using smooth particle hemodynamics (SPH) to evaluate the resulting hemodynamic changes.

The effects of age and sex on calcification and luminal surface complexity in
cadaveric left anterior descending arteries

Intro: Melanoma is the most aggressive and deadly form of skin cancer, especially at later stages. There is currently no excellent diagnostic test established for the diagnosis of melanoma; however, circulating microRNAs (miRNAs) have shown some promise. We seek to conduct a systematic review and meta-analysis to establish the clinical utility of circulating miRNAs in diagnosing melanoma.
Methods: PubMed, Wiley, and Web of Science were searched for studies that determined miRNA sensitivity and specificity in patients with melanoma. The included studies were assessed in Stata, and the sensitivity, specificity, summary receiver operating characteristic (SROC), positive likelihood ratio, negative likelihood ratio, and the area under the SROC curve (AUC) were calculated.
Results: 9 studies with 898 melanoma patients were included in the meta-analysis. The circulating miRNAs showed high diagnostic accuracy with a sensitivity of 0.89 (p < 0.001), specificity of 0.85 (p < 0.001), diagnostic odds ratio of 45, and an area under the curve of 0.93.
Conclusion: Circulating miRNAs have shown a high diagnostic power in detecting melanoma.

Circulating miRNAs as biomarkers for the diagnosis in patients with melanoma: a meta-analysis

Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common form of non-melanoma skin cancer, with both genetic and non-genetic factors influencing its development. Recent evidence suggests that commonly used medications may impact cSCC progression through previously unidentified mechanisms affecting keratinocyte stem cell differentiation and protein synthesis. This study investigates the effects of several widely prescribed drugs - lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032 - on these cellular processes, aiming to improve risk assessment and potentially develop new therapeutic strategies for cSCC. Primary keratinocytes and cSCC cells were treated with various medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, PLX-4032, and Dabrafenib) and analyzed using RT-qPCR, western blotting, immunofluorescence, flow cytometry, and m7-GTP pull-down assays. These techniques were used to assess changes in mRNA levels, protein abundance, protein synthesis activity, and the availability of translation initiation factors. Common medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032) significantly reduce KRT10 mRNA levels in keratinocyte stem cells after 24 hours of calcium-induced differentiation. These medications also decrease Keratin 10 protein abundance in differentiating keratinocytes, suggesting a potential impairment of early differentiation processes. Common medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032) significantly reduce KRT10 mRNA levels in keratinocyte stem cells after 24 hours of calcium-induced differentiation. These medications also decrease Keratin 10 protein abundance in differentiating keratinocytes, suggesting a potential impairment of early differentiation processes. Common medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032) impair keratinocyte stem cell differentiation by reducing both mRNA and protein levels of early differentiation markers. BRAF kinase inhibitors (PLX-4032 and Dabrafenib) decrease global protein synthesis in keratinocyte stem cells by reducing the availability of translation initiation factors, particularly affecting cells entering early differentiation. These findings suggest that commonly prescribed medications may increase cSCC risk by altering keratinocyte stem cell differentiation and protein synthesis, highlighting the need for careful consideration of these drugs in high-risk patients.

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Biosafety of Intramuscular Autoinjection of Sulfanegen, a New Cyanide Antidote, in a Porcine Model

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