2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, ß-adrenergic receptor antagonists (also known as ß-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.

Increased dopaminergic neurotransmission results in ethanol dependent sedative behaviors in Caenorhabditis elegans.

Ethanol is a widely used drug, excessive consumption of which could lead to medical conditions with diverse symptoms. Ethanol abuse causes dysfunction of memory, attention, speech and locomotion across species. Dopamine signaling plays an essential role in ethanol dependent behaviors in animals ranging from C. elegans to humans. We devised an ethanol dependent assay in which mutants in the dopamine autoreceptor, dop-2, displayed a unique sedative locomotory behavior causing the animals to move in circles while dragging the posterior half of their body. Here, we identify the posterior dopaminergic sensory neuron as being essential to modulate this behavior. We further demonstrate that in dop-2 mutants, ethanol exposure increases dopamine secretion and functions in a DVA interneuron dependent manner. DVA releases the neuropeptide NLP-12 that is known to function through cholinergic motor neurons and affect movement. Thus, DOP-2 modulates dopamine levels at the synapse and regulates alcohol induced movement through NLP-12.

Caffeine intoxication treated with hemodialysis.

INTRODUCTION: Caffeine overdose, while uncommon, can be life threatening with hemodynamic and neurological complications and often requires intensive monitoring and critical management. CASE REPORT: We report a case of a 23-year-old male who ingested approximately 24 g of caffeine in a suicidal attempt and developed cardiopulmonary complications. He was resuscitated, and hemodialysis was performed with successful recovery. CONCLUSION: Hemodialysis appears to effectively remove caffeine from the blood system and can be lifesaving in severe caffeine overdose.

Claudins in the brain: Unconventional functions in neurons.

Bonafide claudin proteins are functional and structural components of tight junctions and are largely responsible for barrier formation across epithelial and endothelial membranes. However, current advances in the understanding of claudin biology have revealed their unexpected functions in the brain. Apart from maintaining blood-brain barriers in the brain, other functions of claudins in neurons and at synapses have been largely elusive and are just coming to light. In this review, we summarize the functions of claudins in the brain and their association in neuronal diseases. Further, we go on to cover some recent studies that show that claudins play signaling functions in neurons by regulating trafficking of postsynaptic receptors and controlling dendritic morphogenesis in the model organism Caenorhabditis elegans.

The C-terminal of CASY-1/Calsyntenin regulates GABAergic synaptic transmission at the Caenorhabditis elegans neuromuscular junction.

The C. elegans ortholog of mammalian calsyntenins, CASY-1, is an evolutionarily conserved type-I transmembrane protein that is highly enriched in the nervous system. Mammalian calsyntenins are strongly expressed at inhibitory synapses, but their role in synapse development and function is still elusive. Here, we report a crucial role for CASY-1 in regulating GABAergic synaptic transmission at the C. elegans neuromuscular junction (NMJ). The shorter isoforms of CASY-1; CASY-1B and CASY-1C, express and function in GABA motor neurons where they regulate GABA neurotransmission. Using pharmacological, behavioral, electrophysiological, optogenetic and imaging approaches we establish that GABA release is compromised at the NMJ in casy-1 mutants. Further, we demonstrate that CASY-1 is required to modulate the transport of GABAergic synaptic vesicle (SV) precursors through a possible interaction with the SV motor protein, UNC-104/KIF1A. This study proposes a possible evolutionarily conserved model for the regulation of GABA synaptic functioning by calsyntenins.

A Case of Unintentional Opioid (U-47700) Overdose in a Young Adult After Counterfeit Xanax Use.

ABSTRACT: We report the case of a young adult who became unresponsive after insufflating what he believed to be "crushed Xanax." Naloxone was administered, reversing his altered mental status and respiratory depression. Clinicians suspected opioid toxicity; however, the patient adamantly denied opioid use. Because of unclear etiology of his symptoms, blood and urine specimens were obtained. A urine specimen was split and then submitted for a clinical comprehensive drug screen using gas chromatography-mass spectrometry. The blood specimen and the remaining urine specimen were sent to a reference laboratory for analysis using liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography tandem mass spectrometry. The standard, clinical gas chromatography-mass spectrometry urine drug testing procedure only detected caffeine; however, analysis by liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography tandem mass spectrometry confirmed the presence of U-47700 (a high-potency clandestine opioid) and its metabolites in the urine and blood. These findings implicate U-47700 as the agent responsible for the patient's signs of opioid toxicity. In this case, a young adult intending to use alprazolam encountered U-47700 with life-threatening effect. Clinicians must remain vigilant for symptoms consistent with opioid overdose, especially with increasing prevalence of counterfeit drugs containing clandestine opioids. Clinicians must also consider obtaining specimens for appropriate analytical testing to improve surveillance and facilitate public health interventions.

Differential Regulation of Innate and Learned Behavior by Creb1/Crh-1 in Caenorhabditis elegans.

Memory formation is crucial for the survival of animals. Here, we study the effect of different crh-1 [Caenorhabditis elegans homolog of mammalian cAMP response element binding protein 1 (CREB1)] isoforms on the ability of C. elegans to form long-term memory (LTM). Null mutants in creb1/crh-1 are defective in LTM formation across phyla. We show that a specific isoform of CREB1/CRH-1, CRH-1e, is primarily responsible for memory related functions of the transcription factor in C. elegans Silencing of CRH-1e-expressing neurons during training for LTM formation abolishes the LTM of the animal. Further, CRH-1e expression in RIM neurons is sufficient to rescue LTM defects of creb1/crh-1-null mutants. We go on to show that apart from being LTM defective, creb1/crh-1-null animals show defects in innate chemotaxis behavior. We further characterize the amino acids K247 and K266 as responsible for the LTM related functions of CREB1/CRH-1 while being dispensable for its innate chemotaxis behavior. These findings provide insight into the spatial and temporal workings of a crucial transcription factor that can be further exploited to find CREB1 targets involved in the process of memory formation.SIGNIFICANCE STATEMENT This study elucidates the role of a specific isoform of CREB1/CRH-1, CRH-1e, in Caenorhabditis elegans memory formation and chemosensation. Removal of this single isoform of creb1/crh-1 shows defects in long-term memory formation in the animal and expression of CREB1/CRH-1e in a single pair of neurons is sufficient to rescue the memory defects seen in the mutant animals. We further show that two specific amino acids of CRH-1 are required for the process of memory formation in the animal.

Pediatric Poisonings in a Rural Ugandan Emergency Department.

OBJECTIVE: This study aims to describe pediatric poisonings presenting to a rural Ugandan emergency department (ED), identifying demographic factors and causative agents. METHODS: This retrospective study was conducted in the ED of a rural hospital in the Rukungiri District of Uganda. A prospectively collected quality assurance database of ED visits was queried for poisonings in patients under the age of 5 who were admitted to the hospital. Cases were included if the chief complaint or final diagnosis included anything referable to poisoning, ingestion, or intoxication, or if a toxicologic antidote was administered. The database was coded by a blinded investigator, and descriptive statistics were performed. RESULTS: From November 9, 2009, to July 11, 2014, 3428 patients under the age of 5 were admitted to the hospital. A total of 123 cases (3.6%) met the inclusion criteria. Seventy-two patients were male (58.5%). The average age was 2.3 (SD, 0.97) years with 45 children (36.6%) under the age of 2 years. There were 19 cases (15.4%) lost to 3-day follow-up. The top 3 documented exposures responsible for pediatric poisonings were cow tick or organophosphates (36 cases, 29.2%), general poison or drug overdose (26 cases, 21.1%), and paraffin or hydrocarbon (24 cases, 19.5%).Of the admitted patients, 1 died in the ED and 2 died at 72-hour follow-up, for an overall 72-hour mortality of 2.4%. Patients who died were exposed to iron, cow tick, and rat poison. CONCLUSIONS: Pediatric poisoning affects patients in rural sub-Saharan Africa. The mortality rate at one rural Ugandan hospital was greater than 2%.

FLP-18 Functions through the G-Protein-Coupled Receptors NPR-1 and NPR-4 to Modulate Reversal Length in Caenorhabditis elegans.

Animal behavior is critically dependent on the activity of neuropeptides. Reversals, one of the most conspicuous behaviors in Caenorhabditis elegans, plays an important role in determining the navigation strategy of the animal. Our experiments on hermaphrodite C. elegans show the involvement of a neuropeptide FLP-18 in modulating reversal length in these hermaphrodites. We show that FLP-18 controls the reversal length by regulating the activity of AVA interneurons through the G-protein-coupled neuropeptide receptors, NPR-4 and NPR-1. We go on to show that the site of action of these receptors is the AVA interneuron for NPR-4 and the ASE sensory neurons for NPR-1. We further show that mutants in the neuropeptide, flp-18, and its receptors show increased reversal lengths. Consistent with the behavioral data, calcium levels in the AVA neuron of freely reversing C. elegans were significantly higher and persisted for longer durations in flp-18, npr-1, npr-4, and npr-1 npr-4 genetic backgrounds compared with wild-type control animals. Finally, we show that increasing FLP-18 levels through genetic and physiological manipulations causes shorter reversal lengths. Together, our analysis suggests that the FLP-18/NPR-1/NPR-4 signaling is a pivotal point in the regulation of reversal length under varied genetic and environmental conditions.SIGNIFICANCE STATEMENT In this study, we elucidate the circuit and molecular machinery required for normal reversal behavior in hermaphrodite Caenorhabditis elegans We delineate the circuit and the neuropeptide receptors required for maintaining reversal length in C. elegans Our work sheds light on the importance of a single neuropeptide, FLP-18, and how change in levels in this one peptide could allow the animal to change the length of its reversal, thereby modulating how the C. elegans explores its environment. We also go on to show that FLP-18 functions to maintain reversal length through the neuropeptide receptors NPR-4 and NPR-1. Our study will allow for a better understanding of the complete repertoire of behaviors shown by freely moving animals as they explore their environment.

The Claudin-like Protein HPO-30 Is Required to Maintain LAChRs at the C. elegans Neuromuscular Junction.

Communications across chemical synapses are primarily mediated by neurotransmitters and their postsynaptic receptors. There are diverse molecular systems to localize and regulate the receptors at the synapse. Here, we identify HPO-30, a member of the claudin superfamily of membrane proteins, as a positive regulator for synaptic localization of levamisole-dependent AChRs (LAChRs) at the Caenorhabditis elegans neuromuscular junction (NMJ). The HPO-30 protein localizes at the NMJ and shows genetic and physical association with the LAChR subunits LEV-8, UNC-29, and UNC-38. Using genetic and electrophysiological assays in the hermaphrodite C. elegans, we demonstrate that HPO-30 functions through Neuroligin at the NMJ to maintain postsynaptic LAChR levels at the synapse. Together, this work suggests a novel function for a tight junction protein in maintaining normal receptor levels at the NMJ.SIGNIFICANCE STATEMENT Claudins are a large superfamily of membrane proteins. Their role in maintaining the functional integrity of tight junctions has been widely explored. Our experiments suggest a critical role for the claudin-like protein, HPO-30, in maintaining synaptic levamisole-dependent AChR (LAChR) levels. LAChRs contribute to <20% of the acetylcholine-mediated conductance in adult Caenorhabditis elegans; however, they play a significant functional role in worm locomotion. This study provides a new perspective in the study of LAChR physiology.

C. elegans Locomotion: Finding Balance in Imbalance.

The excitation-inhibition (E-I) imbalance in neural circuits represents a hallmark of several neuropsychiatric disorders. The tiny nematode Caenorhabditis elegans has emerged as an excellent system to study the molecular mechanisms underlying this imbalance in neuronal circuits. The C. elegans body wall muscles receive inputs from both excitatory cholinergic and inhibitory GABAergic motor neurons at neuromuscular junctions (NMJ), making it an excellent model for studying the genetic and molecular mechanisms required for maintaining E-I balance at the NMJ. The cholinergic neurons form dyadic synapses wherein they synapse onto ipsilateral body wall muscles allowing for muscle contraction as well as onto GABAergic motor neurons that in turn synapse on the contralateral body wall muscles causing muscle relaxation. An alternating wave of contraction and relaxation mediated by excitatory and inhibitory signals maintains locomotion in C. elegans. This locomotory behavior requires an intricate balance between the excitatory cholinergic signaling and the inhibitory GABAergic signaling mechanisms.Studies on the C. elegans NMJ have provided insights into several molecular mechanisms that could regulate this balance in neural circuits. This review provides a discussion on multiple genetic factors including neuropeptides and their receptors, cell adhesion molecules, and other molecular pathways that have been associated with maintaining E-I balance in C. elegans motor circuits. Further, it also discusses the implications of these studies that could help us in understanding the role of E-I balance in mammalian neural circuits and how changes in this balance could give rise to brain disorders.

Recognition and Management of Pediatric Salt Toxicity.

OBJECTIVES: Immediate recognition of salt toxicity and aggressive resuscitative measures are critical in the treatment of this lethal poisoning. Despite heroic measures, pediatric deaths due to salt toxicity still occur from irreversible neurological damage. The objective of this article is to review the relevant literature and offer a therapeutic algorithm for the management of pediatric patients presenting with salt toxicity. METHODS: A literature search for cases of salt toxicity was conducted. Articles in English that were available electronically through PubMed and Google Scholar were reviewed. RESULTS: Nineteen cases and case series of salt toxicity were located using our search strategy. Salt poisoning has a distinct pathophysiology compared with hypernatremia, most notable for the lack of formation of idiogenic osmoles. CONCLUSIONS: The approach to treatment differs between salt toxicity and hypernatremia, focusing on rapid correction of serum osmolality rather than gradual normalization of serum sodium concentrations. Consultation of nephrology and child protection services are strongly recommended in the comprehensive treatment approach.

Energy Drinks: A Contemporary Issues Paper.

Since their introduction in 1987, energy drinks have become increasingly popular and the energy drink market has grown at record pace into a multibillion-dollar global industry. Young people, students, office workers, athletes, weekend warriors, and service members frequently consume energy drinks. Both health care providers and consumers must recognize the difference between energy drinks, traditional beverages (e.g., coffee, tea, soft drinks/sodas, juices, or flavored water), and sports drinks. The research about energy drinks safety and efficacy is often contradictory, given the disparate protocols and types of products consumed: this makes it difficult to draw firm conclusions. Also, much of the available literature is industry-sponsored. After reports of adverse events associated with energy drink consumption, concerns including trouble sleeping, anxiety, cardiovascular events, seizures, and even death, have been raised about their safety. This article will focus on energy drinks, their ingredients, side effects associated with their consumption, and suggested recommendations, which call for education, regulatory actions, changes in marketing, and additional research.

Preventing iatrogenic overdose: a review of in-emergency department opioid-related adverse drug events and medication errors.

STUDY OBJECTIVE: We describe characteristics of patients with in-emergency department (ED) opioid-related adverse drug events, medication errors, and harm resulting from medication errors; identify patient-, provider-, and system-based factors associated with in-ED opioid-related medication errors and harm; and create a list of strategies to prevent future events. METHODS: This retrospective study was conducted at 2 urban academic EDs. Potential iatrogenic opioid overdoses were identified by querying the ED electronic medical record for cases when naloxone was administered after an opioid was administered in the ED. Cases involving medication errors resulting in harm were reviewed qualitatively for common patient-, provider-, and systems-based factors that might have contributed to the event. RESULTS: Of 73 ED patients with in-ED opioid-related adverse events that required reversal with naloxone, 43 had a medication error resulting in harm. Patient-, provider-, and systems-based factors that might have contributed to the events included chronic health conditions that could predispose an individual to an opioid-related adverse event, failure to adjust opioid dosing in the elderly and for hepatic or renal impairment, multiple doses and routes of administration of opioids, coadministration of opioids with other sedating medications, and systems-based problems with patient handoffs and pharmacy oversight. CONCLUSION: We identified patient-, provider-, and systems-based factors related to opioid-related adverse drug events and medication errors among ED patients who had received naloxone. The results from our assessment can be used to inform educational and policy initiatives aimed to prevent in-ED opioid-related adverse drug events and medication errors.

Lack of association between Press Ganey emergency department patient satisfaction scores and emergency department administration of analgesic medications.

STUDY OBJECTIVE: We explore the relationship between Press Ganey emergency department (ED) patient satisfaction scores and ED administration of analgesic medications, including amount of opioid analgesics received, among patients who completed a patient satisfaction survey. METHODS: We conducted a secondary data analysis of Press Ganey ED patient satisfaction surveys from patients discharged from 2 academic, urban EDs October 2009 to September 2011. We matched survey responses to data on opioid and nonopioid analgesics administered in the ED, demographic characteristics, and temporal factors from the ED electronic medical records. We used polytomous logistic regression to compare quartiles of overall Press Ganey ED patient satisfaction scores to administration of analgesic medications, opioid analgesics, and number of morphine equivalents received. We adjusted models for demographic and hospital characteristics and temporal factors. RESULTS: Of the 4,749 patients who returned surveys, 48.5% received analgesic medications, and 29.6% received opioid analgesics during their ED visit. Mean overall Press Ganey ED patient satisfaction scores for patients receiving either analgesic medications or opioid analgesics were lower than for those who did not receive these medications. In the univariable polytomous logistic regression analysis, receipt of analgesic medications, opioid analgesics, and a greater number of morphine equivalents were associated with lower overall scores. However, in the multivariable analysis, receipt of analgesic medications or opioid analgesics was not associated with overall scores, and receipt of greater morphine equivalents was inconsistently associated with lower overall scores. CONCLUSION: Overall Press Ganey ED patient satisfaction scores were not primarily based on in-ED receipt of analgesic medications or opioid analgesics; other factors appear to be more important.

Commercial Delta-8 THC Products: an Analysis of Content and Labeling.

INTRODUCTION: ∆-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid and structural isomer of ∆-9 THC that is technically legal under United States Federal law. Commercial ∆-8-THC products being sold are currently unregulated. This study aims to (1) describe the advertising and labeling of Δ-8 THC retail products; (2) compare the advertised amount of Δ-8 THC for each product to that found during independent laboratory analysis; and (3) evaluate the presence and amount of other cannabinoids in those products. METHODS: Twenty ∆-8 THC products were purchased from retail stores in Pittsburgh, PA, USA. Samples were analyzed to determine cannabinoid content using a validated UPLC-MS/MS method. Descriptive statistics were calculated for all variables. Spearman's rank order correlation was calculated for the labeled ∆-8 THC content compared to ∆-8 THC content found on our analysis. Differences in continuous variables were compared using ANOVA, Wilcoxon Rank Sum, or Kruskal-Wallis tests. RESULTS: ∆-8 THC was detected in 95% (N=19) of the sample products. A weakly positive correlation (Spearman's rho =0.40) was found between the advertised ∆-8 THC content and our analysis results. Factors associated with decreased difference in these variables included (1) solid matrix (chocolate, gummies) and (2) absence of a "lab-tested" label. Δ-9 THC was found in 35% (N=7) of the products, and CBD was found in one. CONCLUSION: A majority of the products analyzed contained ∆-8 THC in amounts that could cause intoxication. The range of ∆-8 THC content on independent analysis was wide and weakly correlated to the advertised content. ∆-8 THC, ∆-9 THC, and CBD were the only cannabinoids detected.

EYA protein complex is required for Wntless retrograde trafficking from endosomes to Golgi.

Retrograde transport of WLS (Wntless) from endosomes to trans-Golgi network (TGN) is required for efficient Wnt secretion during development. However, the molecular players connecting endosomes to TGN during WLS trafficking are limited. Here, we identified a role for Eyes Absent (EYA) proteins during retrograde trafficking of WLS to TGN in human cell lines. By using worm, fly, and zebrafish models, we found that the EYA-secretory carrier-associated membrane protein 3 (SCAMP3) axis is evolved in vertebrates. EYAs form a complex and interact with retromer on early endosomes. Retromer-bound EYA complex recruits SCAMP3 to endosomes, which is necessary for the fusion of WLS-containing endosomes to TGN. Loss of EYA complex or SCAMP3 leads to defective transport of WLS to TGN and failed Wnt secretion. EYA mutations found in patients with hearing loss form a dysfunctional EYA-retromer complex that fails to activate Wnt signaling. These findings identify the EYA complex as a component of retrograde trafficking of WLS from the endosome to TGN.

Development of a predictive algorithm for patient survival after traumatic injury using a five analyte blood panel.

Severe trauma can induce systemic inflammation but also immunosuppression, which makes understanding the immune response of trauma patients critical for therapeutic development and treatment approaches. By evaluating the levels of 59 proteins in the plasma of 50 healthy volunteers and 1000 trauma patients across five trauma centers in the United States, we identified 6 novel changes in immune proteins after traumatic injury and further new variations by sex, age, trauma type, comorbidities, and developed a new equation for prediction of patient survival. Blood was collected at the time of arrival at Level 1 trauma centers and patients were stratified based on trauma level, tissues injured, and injury types. Trauma patients had significantly upregulated proteins associated with immune activation (IL-23, MIP-5), immunosuppression (IL-10) and pleiotropic cytokines (IL-29, IL-6). A high ratio of IL-29 to IL-10 was identified as a new predictor of survival in less severe patients with ROC area of 0.933. Combining machine learning with statistical modeling we developed an equation ("VIPER") that could predict survival with ROC 0.966 in less severe patients and 0.8873 for all patients from a five analyte panel (IL-6, VEGF-A, IL-21, IL-29, and IL-10). Furthermore, we also identified three increased proteins (MIF, TRAIL, IL-29) and three decreased proteins (IL-7, TPO, IL-8) that were the most important in distinguishing a trauma blood profile. Biologic sex altered phenotype with IL-8 and MIF being lower in healthy women, but higher in female trauma patients when compared to male counterparts. This work identifies new responses to injury that may influence systemic immune dysfunction, serving as targets for therapeutics and immediate clinical benefit in identifying at-risk patients.