Pigs provide a sensitive and quantitative animal model of non-IgE-mediated(pseudoallergic) hypersensitivity reactions (HSRs) caused by liposomes and many other nanoparticulate drugs or drug-carrier nanosystems (nanomedicines). The rapidly arising symptoms, including cardiopulmonary, hemodynamic, hematological, blood chemistry and skin changes, resemble the clinical picture in man undergoing infusion reactions toreactogenic nanoparticles. In addition to summarizing the basic features of the pig CARPA model, thereviewconsiderssome of the advantages and disadvantages of using the modelforpreclinical evaluation of nanomedicine safety.

Environmental heat stress represents a pervasive threat to warfighters, athletes, and occupational workers, impacting performance and increasing the risk of injury. Exertional heat illness (EHI) is a spectrum of clinical disorders of increasing severity. While frequently predictable, EHI can occur unexpectedly and may be followed by long-term comorbidities, including cardiovascular dysfunction and exercise intolerance. The objective of this study was to assess genetic factors contributing to EHI. Whole-exome sequencing was performed in a cohort of 53 cases diagnosed with EHI. Rare variants in prioritized gene sets were analyzed and classified per published guidelines. Clinically significant pathogenic and potentially pathogenic variants were identified in 30.2% of the study cohort. Variants were found in 14 genes, including the previously known RYR1 and ACADVL genes and 12 other genes (CAPN3, MYH7, PFKM, RYR2, TRPM4, and genes for mitochondrial disorders) reported here for the first time in EHI. Supporting structural and functional studies of the TRPM4 p.Arg905Trp variant show that it impairs the thermal sensitivity of the TRPM4 channel, revealing a potentially new molecular mechanism contributing to EHI susceptibility. Our study demonstrates associations between EHI and genes implicated in muscle disorders, cardiomyopathies, thermoregulation, and oxidative phosphorylation deficiencies. These results expand the genetic heterogeneity of EHI and shed light on its molecular pathogenesis.

Purpose The Coronavirus Disease 2019 (COVID-19) pandemic may cause an acute shortage of ventilators. Standard noninvasive bilevel positive airway pressure devices with spontaneous and timed respirations (bilevel PAP ST) could provide invasive ventilation but evidence on their effectiveness in this capacity is limited. We sought to evaluate the ability of bilevel PAP ST to effect gas exchange via invasive ventilation in a healthy swine model. Methods Two single limb respiratory circuits with passive filtered exhalation were constructed and evaluated. Next, two bilevel PAP ST devices, designed for sleep laboratory and home use, were tested on an intubated healthy swine model using these circuits. These devices were compared to an anesthesia ventilator. Results We evaluated respiratory mechanics, minute ventilation, oxygenation, and presence of rebreathing for all of these devices. Both bilevel PAP ST devices were able to control the measured parameters. There were noted differences in performance between the two devices. Despite these differences, both devices provided effective invasive ventilation by controlling minute ventilation and providing adequate oxygenation in the animal model. Conclusions Commercially available bilevel PAP ST can provide invasive ventilation with a single limb respiratory circuit and in-line filters to control oxygenation and ventilation without significant rebreathing in a swine model. Further study is needed to evaluate safety and efficacy in clinical disease models. In the setting of a ventilator shortage during the COVID-19 pandemic, and in other resource-constrained situations, these devices may be considered as an effective alternative means for invasive ventilation.

Background/Objective: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, the underlying mechanisms specific to the ER are not universally known within humans. This study aimed to evaluate whether patients with ER exhibited transcriptional signatures that were significantly different from those of healthy individuals. Methods: This study utilized RNA sequencing on skeletal muscle samples from 19 human patients with ER history, collected at a minimum of six months after the most recent ER event, and eight healthy controls to investigate the transcriptomic landscape of ER. To identify any alterations in biological processes between the case and control groups, functional pathway analyses were conducted. Results: Functional pathway enrichment analyses of differentially expressed genes revealed strong suppression of mitochondrial function. This suppression included the “aerobic electron transport chain” and “oxidative phosphorylation” pathways, indicating impaired energy production. Conversely, there was an upregulation of genes associated with adhesion and extracellular matrix-related pathways, indicating active restoration of muscle function in ER cases. Conclusions: The study demonstrated that muscle tissue exhibited signs of suppressed mitochondrial function and increased extracellular matrix development. Both of these facilitate muscle recovery within several months after an ER episode.