Significance of temperature in antimuscarinic toxicity: a case-control study.

INTRODUCTION: Antimuscarinic toxicity can result in temperature dysregulation, but the clinical significance of this is unclear. The objective of this study was to compare peak temperatures between antimuscarinic patients with and without severe clinical outcomes. METHODS: This was a case-control analysis at two large, urban, academic medical centers from January 1, 2016, through December 31, 2021. We compared peak temperature (Tmax) amongst antimuscarinic patients who experienced severe outcomes with those who did not. Severe outcome was defined as seizure, ventricular dysrhythmia, hypotension, or intubation. RESULTS: Fifty-six patients met inclusion criteria of which 23 developed severe outcomes: 16 seizures, 9 cases with hypotension, 5 intubations, and 2 ventricular dysrhythmias. Tmax amongst all patients ranged from 36.4-39.2 °C. There were no fatalities. There was no difference in Tmax in the emergency department or throughout hospitalization between groups, and Tmax was not predictive for the development of severe outcomes. DISCUSSION: Maximum temperatures did not differ between patients with and without severe outcomes in the setting of antimuscarinic toxicity, and temperature was poorly predictive of outcomes. Our findings suggest that mild temperature dysregulation in antimuscarinic toxicity is not a key prognostic indicator for severe outcome. Further study is needed to assess implication of severe hyperthermia.

Management and Associated Toxicokinetics of Massive Valproic Acid Ingestion with High Flow Continuous Venovenous Hemodiafiltration.

INTRODUCTION: Valproic acid (VPA) toxicity commonly results in a self-limited state of CNS depression that is managed with supportive care and levocarnitine. In massive overdose, patients can develop toxic encephalopathy, shock, multisystem organ failure, and death. We present a case with relevant toxicokinetics of a patient presenting with a profoundly elevated VPA concentration resulting in survival, treated with supportive care including high-dose continuous venovenous hemodiafiltration (CVVHDF). CASE REPORT: A 17-year-old female presented to an emergency department after being found unresponsive at home with concern for massive VPA ingestion. She arrived obtunded and hypotensive with initial VPA concentration of 2226 mg/L, estimated 9 h post-ingestion. Her early hospital course was marked by hypotension requiring multiple vasopressors, and her workup was notable for multiple severe metabolic derangements. High-dose CVVHDF was initiated upon transfer to a tertiary children's hospital with the aim to enhance VPA removal and normalize metabolic derangements. At that time, her VPA concentration was 1071 mg/L. Apparent half-life of VPA improved modestly with extracorporeal treatment, but her metabolic derangements and hemodynamic instability corrected rapidly. Her clinical course was complicated by necrotizing pancreatitis, pancytopenia requiring transfusions of multiple cell lines, coma, and seizures. She ultimately recovered with normal neurological function.

Emergency department management of traumatic brain injuries: A resource tiered review.

INTRODUCTION: Traumatic brain injury is a leading cause of death and disability globally with an estimated African incidence of approximately 8 million cases annually. A person suffering from a TBI is often aged 20-30, contributing to sustained disability and large negative economic impacts of TBI. Effective emergency care has the potential to decrease morbidity from this multisystem trauma. OBJECTIVES: Identify and summarize key recommendations for emergency care of patients with traumatic brain injuries using a resource tiered framework. METHODS: A literature review was conducted on clinical care of brain-injured patients in resource-limited settings, with a focus on the first 48 h of injury. Using the AfJEM resource tiered review and PRISMA guidelines, articles were identified and used to describe best practice care and management of the brain-injured patient in resource-limited settings. KEY RECOMMENDATIONS: Optimal management of the brain-injured patient begins with early and appropriate triage. A complete history and physical can identify high-risk patients who present with mild or moderate TBI. Clinical decision rules can aid in the identification of low-risk patients who require no neuroimaging or only a brief period of observation. The management of the severely brain-injured patient requires a systematic approach focused on the avoidance of secondary injury, including hypotension, hypoxia, and hypoglycaemia. Most interventions to prevent secondary injury can be implemented at all facility levels. Urgent neuroimaging is recommended for patients with severe TBI followed by consultation with a neurosurgeon and transfer to an intensive care unit. The high incidence and poor outcomes of traumatic brain injury in Africa make this subject an important focus for future research and intervention to further guide optimal clinical care.

Canonical and atypical E2Fs regulate the mammalian endocycle.

The endocycle is a variant cell cycle consisting of successive DNA synthesis and gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals.

Atypical E2F repressors and activators coordinate placental development.

The evolutionarily ancient arm of the E2f family of transcription factors consisting of the two atypical members E2f7 and E2f8 is essential for murine embryonic development. However, the critical tissues, cellular processes, and molecular pathways regulated by these two factors remain unknown. Using a series of fetal and placental lineage-specific cre mice, we show that E2F7/E2F8 functions in extraembryonic trophoblast lineages are both necessary and sufficient to carry fetuses to term. Expression profiling and biochemical approaches exposed the canonical E2F3a activator as a key family member that antagonizes E2F7/E2F8 functions. Remarkably, the concomitant loss of E2f3a normalized placental gene expression programs, corrected placental defects, and fostered the survival of E2f7/E2f8-deficient embryos to birth. In summary, we identified a placental transcriptional network tightly coordinated by activation and repression through two distinct arms of the E2F family that is essential for extraembryonic cell proliferation, placental development, and fetal viability.

Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development.

The E2f7 and E2f8 family members are thought to function as transcriptional repressors important for the control of cell proliferation. Here, we have analyzed the consequences of inactivating E2f7 and E2f8 in mice and show that their individual loss had no significant effect on development. Their combined ablation, however, resulted in massive apoptosis and dilation of blood vessels, culminating in lethality by embryonic day E11.5. A deficiency in E2f7 and E2f8 led to an increase in E2f1 and p53, as well as in many stress-related genes. Homo- and heterodimers of E2F7 and E2F8 were found on target promoters, including E2f1. Importantly, loss of either E2f1 or p53 suppressed the massive apoptosis in double-mutant embryos. These results identify E2F7 and E2F8 as a unique repressive arm of the E2F transcriptional network that is critical for embryonic development and control of the E2F1-p53 apoptotic axis.