IntroductionSnakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes.MethodsThis double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours.ResultsAmong 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred.ConclusionFor emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration.

There are several pathophysiological outcomes associated with substance abuse including metabolic disbalance, neurodegeneration, and disordered redox. Drug use in pregnant women is a topic of great concern due to developmental harm which may occur during gestation and the associated complications in the neonate after delivery. We sought to determine what the trajectory of drug use is like in children aged 0–4 years and mothers of neonates. Urine drug screen (UDS) results were obtained of our target demographic during 1998–2011 and 2012–2019 from LSU Health Sciences Center in Shreveport (LSUHSC-S). Statistical analysis was performed using R software. We observed an increase in cannabinoid-positive UDS results in both Caucasian (CC) and African American (AA) groups between 1998–2011 and 2012–2019 periods. Cocaine-positive UDS results decreased in both cohorts. CC children had higher UDS positive results for opiates, benzodiazepines, and amphetamines, while AA children had a higher percentage for illicit drugs such as cannabinoids and cocaine. Neonate’s mothers had similar UDS trends to that in children during 2012–2019. Overall, while percentage of positive UDS results for both AA and CC 0–4 year old children started to decline for opiate, benzodiazepine, and cocaine during 2012–2019, cannabinoid- and amphetamine (CC)-positive UDS steadily increased. These results suggest a shift in the type of drug use by mothers from opiates, benzodiazepines, and cocaine to cannabinoids and/or amphetamines. We also observed that 18-year-old females who tested positive for opiates, benzodiazepine, or cocaine had higher than average chances of testing positive for cannabinoids later in life.

Louisiana State University Health Sciences Center at Shreveport (LSUHSC-S) serves a largely minority-based, urban population. This study aims to identify trends in urine drug screen (UDS) results among females aged 18–35 visiting State University during 1998–2011 and 2012–2019. Using two databases extracted from the electronic medical record system, we performed statistical analysis of demographics and UDS results. Young females aged 18–35 mostly tested positive for cannabinoids and opiates during both periods, 1998–2011 and 2012–2019. African-American females had a higher percentage of positive UDS for illicit drugs, such as cannabinoids and cocaine, while Caucasian females had a higher rate for prescription drugs such as opiates, benzodiazepines, and amphetamine. Between 1998–2011 and 2012–2019, trends in drug screen results changed in both populations, with Caucasian females showing a drastic increase in amphetamines and African-American females showing increase in opiates and cannabinoids during 2012–2019. GatewayNet analysis (sequential-rule mining for inducing causation) for 2012–2019 indicated that a positive screen for amphetamines is likely preceded by a positive screen for cannabinoids, and benzodiazepines may be preceded by opiates. Our results emphasize the importance of drug use monitoring among young females of childbearing age. GatewayNet analysis implies a sequential nature to drug positivity on urine drug screening in this population.

The development of targeted anticancer drugs has been one of the most challenging goals of current research. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that stimulates mRNA translation via binding to the 5' endcap structure. It is well documented that eIF4E is overexpressed in many cancers including breast, prostate, head and neck, and stomach malignancies and leads to oncogenic transformation and metastasis. One approach to block eIF4E function in cancer cells is based on the disruption of the interaction between eIF4E and the 5' mRNA cap structure using cap analog inhibitors. Since analogs are cell-impermeable due to their anionic nature, we used a cell penetrating peptide (CPP) for delivery of model cap analogs into cancer cells. The human immunodeficiency virus I (HIV-1) transactivator of transcription derived peptide (TAT) was conjugated with the analogs m7GMP and m7GpppG using click chemistry methodology. We observed that both conjugates (m7GMP-TAT and m7GpppG-TAT), contrary to TAT alone, did not translocate through the artificial phospholipid membrane of giant unilamellar vesicles. This suggests that passive transport is not the mechanism by which translocation of cap analogs occurs. In contrast, synthesized fluorescently labeled m7GpppG-TAT translocated into the human breast adenocarcinoma cancer cell line MCF-7. Furthermore, we demonstrated that m7GMP-TAT and m7GpppG-TAT inhibited cap-dependent translation up to 30% both in vivo and in vitro while simultaneously not affecting cell growth and viability. These results demonstrate the usefulness of cell penetration peptides as carriers for the internalization of cap analogs.

Background Opioids are the most effective drugs commonly prescribed to treat pain. Due to their addictive nature, opioid pain relievers are now second to marijuana, ahead of cocaine with respect to dependence. Ours and other studies suggest potential toxic effects of chronic opioid administration leading to neuronal degeneration. It has been suggested that protein carbonylation may represent a sensitive biomarker of cellular degeneration. To evaluate whether prolonged oxycodone administration is associated with accumulation of protein aggregates that may contribute to neuronal degeneration we measured protein carbonylation levels in brain and also in blood plasma of rats after 30-days of 15 mg/kg daily oxycodone administration. Results We observed a significant increase in the level of carbonylated proteins in rat brain cortex after 30-days of oxycodone treatment compare to that in water treated animals. Also, oxycodone treated rats demonstrated accumulation of insoluble carbonyl-protein aggregates in blood plasma. Conclusions Our data suggests that tests detecting insoluble carbonyl-protein aggregates in blood may serve as an inexpensive and minimally invasive method to monitor neuronal degeneration in patients with a history of chronic opioid use. Such methods could be used to detect toxic side effects of other medications and monitor progression of aging and neurodegenerative diseases.

Study objective: The antivenom currently available for treatment of systemic black widow envenomation (latrodectism) is composed of equine whole immunoglobin. Although considered effective, it has been associated with anaphylaxis and 2 reported fatalities. We test the efficacy and safety of new equine antivenom composed of purified F(ab')(2) antibody fragments. Methods: A randomized, double-blind, placebo-controlled trial was conducted at 16 sites across the United States. Subjects aged 10 years or older with moderate to severe pain because of black widow spider envenomation received F(ab')(2) antivenom or placebo. The primary outcome measure was treatment failure, which was defined as failure to achieve and maintain clinically significant reduction in pain for 48 hours posttreatment. Secondary measures of pain intensity differences and summed pain intensity difference were computed. Adverse events were recorded. Results: Sixty patients were treated (29 antivenom and 31 placebo). The mean age was 39 years and 68% were male. There were 15 treatment failures in the antivenom group and 24 in the placebo group (P=.019). Differences in pain intensity difference between groups were lower at each postbaseline point, and the mean summed pain intensity difference was greater for the antivenom group (difference 2,133; 95% confidence interval 177 to 4,090). No deaths or serious drug-related adverse events were detected. Conclusion: The F(ab')(2) antivenom met the predefined primary outcome of reduced treatment failures. Secondary outcomes of pain intensity difference and summed pain intensity difference also supported efficacy. The rate of symptom improvement in the placebo group was higher than expected, which may be related to enrollment criteria or placebo effect.

BackgroundThe gateway hypothesis (and particularly the prediction of developmental stages in drug abuse) has been a subject of protracted debate since the 1970s. Extensive research has gone into this subject, but has yielded contradictory findings. We propose an algorithm for detecting both association and causation relationships given a discrete sequence of events, which we believe will be useful in addressing the validity of the gateway hypothesis.To assess the gateway hypothesis, we developed the GatewayNet algorithm, a refinement of sequential rule mining called initiation rule mining. After a brief mathematical definition, we describe how to perform initiation rule mining and how to infer causal relationships from its rules (gateway rules).We tested GatewayNet against data for which relationships were known. After constructing a transaction database using a first-order Markov chain, we mined it to produce a gateway network. We then discuss various incarnations of the gateway network.We then evaluated the performance of GatewayNet on urine drug screening data collected from the emergency department at LSU Health Sciences Center in Shreveport. A de-identified database of urine drug screenings ordered by the department between August 1998 and June 2011 was collected and then restricted to patients having at least one screening succeeding their first positive drug screening result.ResultsIn the synthetic data, a chain of gateway rules was found in the network which demonstrated causation. We did not find any evidence of gateway rules in the empirical data, but we were able to isolate two documented transitions into benzodiazepine use.ConclusionsWe conclude that GatewayNet may show promise not only for substance use data, but other data involving sequences of events. We also express future goals for GatewayNet, including optimizing it for speed.

The emergency department (ED) at Louisiana State University-Health Science Center in Shreveport (LSUHSC-S) serves an urban population with a large rural catchment area. This study focuses on demographic variables in substance abuse trends in this region based on urine drug screen (UDS) results. A database of de-identified UDSs ordered in the ED at LSUHSC-S between 1998 and 2011 was analyzed. Samples were tested for the presence of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), methadone, methamphetamine, opiates, phencyclidine, and propoxyphene. The patient population was categorized by age group, gender, and race. The majority of tests were performed on African-American and Caucasian patients ages 18 to 54 followed by the 0 to 11-year-old group. Of the drugs tested, cannabinoids represented the highest percentage of positive results in both the African-American and Caucasian populations. Opiates returned the highest percent of positive results among all prescription drugs. The Caucasian population predominated in positive tests for prescription drugs (opiates and benzodiazepines), while the African-American population predominated in results positive for illicit drugs (cannabinoids and cocaine). The increasing presence of opiates and cannabinoids, particularly in very young patients, should prompt policy makers and healthcare providers to develop intervention strategies to protect the most vulnerable populations.

Chronic opioid therapy for non-malignant pain conditions has significantly increased over the last 15 years. Recently, the correlation between opioid analgesics and alternations in brain structure, such as leukoencephalopathy, axon demyelination, and white matter lesions, has been demonstrated in patients with a history of long-term use of prescription opioids. The exact mechanisms underlying the neurotoxic effect of opioids on the central nervous system are still not fully understood. We investigated the effect of chronic opioids using an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days. In addition we tested oxycodone, morphine and DAMGO in breast adenocarcinoma MCF7 cells, which are known to express the μ-opioid receptor.

Cardiovascular toxicity, including sudden hypertension, tachycardia, coronary arterial vasoconstriction, and/ or dysrhythmia, may arise from cocaine or methamphetamine use. Treatment options should be considered carefully based upon the unique pharmacology of these different stimulants. We report a rare case of acute cardiovascular toxicity from concomitant use of cocaine and methamphetamine in a 24-year-old male presenting to the emergency department with chest pain. He arrived hypertensive, tachycardic, anxious, and diaphoretic. His initial electrocardiogram showed tachycardia, ST- depression, and prominent T- waves. Hewas initially administered two doses of 1 mg of intravenous lorazepam, which resulted in anxiety, agitation, and worsening vital signs suggestive of paradoxical agitation. He was then given two 5 mg doses of intravenous labetalol. This rapidly resolved his chest pain, anxiety, diaphoresis, hypertension, and tachycardia. He was later discharged without further sequelae. A second electrocardiogram demonstrated reversal of the prior abnormal ST- segment and T- wave findings. We believe clinicians should be aware of the potential for cardiovascular toxicity from concomitant cocaine and methamphetamine use, and that labetalol represents a potential initial treatment. Unlike benzodiazepines, labetalol directly counters the pharmacologic effects of cocaine and methamphetamine and does not cause respiratory depression, sedation, or paradoxical agitation. Labetalol, with its mixed beta 1/ beta 2/ alpha 1- blocking properties, also may reduce concern for " unopposed alpha stimulation."

Oxycodone (6‐deoxy‐7,8‐dehydro‐14‐hydroxy‐3‐O‐methyl‐6‐oxomorphine) is a strong semi‐synthetic opioid. It is prescribed to treat different types of pain especially when other opioids are ineffective. Oxycodone has close structural similarity to morphine and heroin and binds not only m‐ but also k‐opioid receptors. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to develop analgesic tolerance, withdrawal, and addiction. Recently, another concern regarding the effect of chronic or over‐dose opioid exposure has emerged: their effect on neuronal degeneration. Leukoencephalopathy or damage of white matter has been described as one of the effects that heroin abusers develop, and was recently documented in a patient after morphine and oxycodone administration. The exact mechanisms underlying the neurotoxic effect of opioids on the Central Nervous System are still not fully understood. To investigate the effect of opioid treatment on rat white matter we used an animal model in which female rats were gavaged with 15 mg/kg oxycodone every 24 hours for 30 days. In our study we observed that chronic oxycodone exposure induces oxidative/nitrosidative stresses in three brain areas in rats: nucleus accumbens, cortex and brain stem. We demonstrated activation of pro‐apoptotic machinery in rat brains after oxycodone treatment. Interestingly, activated caspase 3 was predominantly localized in areas containing white matter suggesting increased axonal damages after chronic oxycodone exposure. The increased level of a‐synuclein aggregates and amyloid precursor protein (APP) in oxycodone‐exposed cerebellum confirmed the axonal injury. We also demonstrated induction of pro‐apoptotic protein Bax by oxycodone, morphine and DAMGO in breast carcinoma cells MCF7, which are known to express the m‐opioid receptor. Support or Funding Information LMS was supported by Grant No. 2R01GM20818 from the National Institute of General Medical Sciences.

Oxycodone is an opioid that is prescribed to treat multiple types of pain, especially when other opioids are ineffective. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to lead to development of analgesic tolerance, withdrawal, and addiction. Studies demonstrate that chronic opioid exposure, including oxycodone, alters gene expression profiles and that these changes contribute to opioid-induced analgesic effect, tolerance and dependence. However, very little is known about opioids altering the translational machinery of the central nervous system. Considering that opioids induce clinically significant levels of hypoxia, increase intracellular Ca2+ levels, and induce the production of nitric oxide and extracellular glutamate transmission, we hypothesize that opioids also trigger a defensive mechanism called the integrated stress response (ISR). The key event in the ISR activation, regardless of the trigger, is phosphorylation of translation initiation factor 2 alpha (eIF2α), which modulates expression and translational activation of specific mRNAs important for adaptation to stress. To test this hypothesis, we used an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days.

1 East Carolina University Brody School of Medicine/Vidant Medical Center, Greenville, NC, USA 2 Banner Good Samaritan Medical Center, Phoenix, AZ, USA 3 University of New Mexico Health Sciences Center, Albuquerque, NM, USA 4 Scott and White Memorial Hospital, Temple, TX, USA 5 Saint Josephs Hospital, Bryan, TX, USA 6 Louisiana State University Health Sciences Center, Shreveport, LA, USA 7 University of California Medical Center, San Diego, CA, USA 8 Paul L. Foster School of Medicine/Texas Tech University Health Sciences Center, El Paso, TX, USA 9 Northwest Medical Center, Tucson, AZ, USA 10 UF Health Jacksonville, Jacksonville, FL, USA 11 Arizona Poison & Drug Information Center, Tucson, AZ, USA 12 Tucson Medical Center, Tucson, AZ, USA 13 Maricopa Medical Center, Phoenix, AZ, USA 14 Instituto Bioclon, M é xico Distrito Federal, Mexico 15 UNAM, Avenida Universidad 2001, Cuernavaca, Mexico 16 University of Arizona Health Sciences Center, Tucson, AZ, USA

Emergency room (ER) crowding has become a widespread problem in hospitals across the United States. Two main reasons can be cited. First, emergency medicine is the only specialty in the "House of Medicine" that has a federal mandate to provide care to any patients requesting treatment. Second, primary care providers are in short supply, forcing sick people to seek medical care in ERs. Once seen as an "ER problem," crowding has become more appropriately recognized as a "hospital problem," related to factors beyond the doors of the ER. This realization has led many regulating agencies to launch corrective attempts, some of which have actually been effective. Now, the lack of ER crowding is considered a measure of the success of a hospital or system. This review considers the complex causative factors that contribute to ER crowding and explores corrective measures that may prove helpful in alleviating this paralyzing condition.

ContextTeaching 12-lead electrocardiogram (ECG) interpretation to students and residents is a challenge for medical educators. To date, few studies have compared the effectiveness of different techniques used for ECG teaching.ObjectivesThis study aimed to determine if common teaching techniques, such as those involving workshops, lectures and self-directed learning (SDL), increase medical students' ability to correctly interpret ECGs. It also aimed to compare the effectiveness of these formats.MethodsThis was a prospective randomised study conducted over a 28-month period. Year 4 medical students were randomised to receive teaching in ECG interpretation using one of three teaching formats: workshop, lecture or SDL. All three formats covered the same content. Students were administered three tests: a pre-test (before teaching); a post-test (immediately after teaching), and a retention test (1 week after teaching). Each tested the same content using 25 questions worth 1 point each. A mixed-model repeated-measures analysis of variance (anova) with least squares post hoc analysis was conducted to determine if differences in test scores between the formats were statistically significant.ResultsOf the 223 students for whom data were analysed, 79 were randomised to a workshop, 82 to a lecture-based format and 62 to SDL. All three teaching formats resulted in a statistically significant improvement in individual test scores (p < 0.001). Comparison of the lecture- and workshop-based formats demonstrated no difference in test scores (marginal mean [MM] for both formats = 12.4, 95% confidence interval [95% CI] 11.7-13.2]; p = 0.99). Test scores of students using SDL (MM = 10.7, 95% CI 9.8-11.5) were lower than those of students in the workshop (p = 0.003) and lecture (p = 0.002) groups.ConclusionsCompared with those taught using workshop- and lecture-based formats, medical students learning ECG interpretation by SDL had lower test scores.

Objective: The objective of the study was to determine if balanced electrolyte solution (BES) prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis (DKA).Methods: This is a prospective, randomized, double-blind study. A convenience sample of DKA patients aged 18 to 65 years with serum bicarbonate less than or equal to 15 and anion gap greater than or equal to 16 was enrolled at "Louisiana State University Health Sciences Center-Shreveport" an capitalize Emergency Department over a 24-month period (2006-2008). Patients were randomized to standardized resuscitation with normal saline (NS) or BES (Plasma-Lyte A pH 7.4; Baxter International, Deerfield, IL). Every 2 hours, serum chloride and bicarbonate were measured until the patient's anion gap decreased to 12. An intention-to-treat analysis was performed on patients who met inclusion criteria and received at least 4 hours of study fluid. Chloride and bicarbonate measurements from the BES and NS groups were compared using unpaired and paired Student t tests.Results: Of 52 patients enrolled, 45 (22 in BES group and 23 in NS group) met inclusion criteria and received 4 hours of fluid. The mean postresuscitation chloride was 111 mmol/L (95% confidence interval [CI] = 110-112) in the NS group and 105 mmol/L (95% CI = 103-108) in the BES group (P <= .001). The mean postresuscitation bicarbonate was 17 mmol/L (95% CI = 15-18) in the NS group and 20 mmol/L (95% CI = 18-21) in the BES group (P = .020).Conclusions: Resuscitation of DKA patients with BES results in lower serum chloride and higher bicarbonate levels than patients receiving NS, consistent with prevention of hyperchloremic metabolic acidosis. (C) 2011 Elsevier Inc. All rights reserved.

BACKGROUND:Studies have shown that vein size is an important predictor of successful ultrasound-guided vascular access. The objective of this study is to evaluate maneuvers designed to increase basilic vein size, which could be used to facilitate ultrasound-guided peripheral intravenous access (USGPIV) in the Emergency Department (ED) setting.METHODS:This was a prospective non-randomized trial. Healthy volunteers aged 18-65 were enrolled. Basilic veins were identified and the cross-sectional area measured sonographically. Following baseline measurement, the following maneuvers were performed: application of a tourniquet, inflation of a blood pressure (BP) cuff, application of a tourniquet with the arm lowered, and BP cuff inflation with the arm lowered. Following each maneuver there was 30 s of recovery time, and a baseline measurement was repeated to ensure that the vein had returned to baseline. Change in basilic vein size was modeled using mixed model analysis with a Tukey correction for multiple comparisons to determine if significant differences existed between different maneuvers.RESULTS:Over the 5-month study period, 96 basilic veins were assessed from 52 volunteers. All of the maneuvers resulted in a statistically significant increase in basilic vein size from baseline (p < 0.001). BP cuff inflation had the greatest increase in vein size from baseline 17%, 0.87 mm 95% CI (0.70-1.04). BP cuff inflation statistically significantly increased vein size compared to tourniquet placement by 3%, 0.16 mm 95% CI (0.02-0.30).CONCLUSIONS:The largest increase in basilic vein size was due to blood pressure cuff inflation. BP cuff inflation resulted in a statistically significant increase in vein size compared to tourniquet application, but this difference may not be clinically significant.