Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses.

Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that several metabolic pathways exhibit sex differences including glycolysis, fatty acid metabolism, nucleotide metabolism, and xenobiotics metabolism. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we find several subsystems with differential expression overlap with the sex-altered pathways such as fatty acid metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the pentose phosphate pathway and other metabolic pathways. These results suggest potential sex differences in the contribution of the pentose phosphate pathway to oxidative stress, and we recommend further research into how these reactions respond to hepatotoxic pharmaceuticals.

Suspected Suicide Attempts by Self-Poisoning Among Persons Aged 10-19 Years During the COVID-19 Pandemic - United States, 2020-2022.

The World Health Organization declared COVID-19 a global pandemic on March 11, 2020 (1). As strategies to mitigate the pandemic were implemented, concerns were raised that the containment efforts through quarantine and social distancing practices were negatively affecting the mental and physical health of children and adolescents (2). Suicide is a growing public health problem in the United States. In 2020, suicide was the second leading cause of death among persons aged 10-14 years and the third leading cause among those aged 15-24 years (3). The National Poison Data System (NPDS) database was used to examine trends in suspected suicide attempts by self-poisoning among persons aged 10-19 years before and during the COVID-19 pandemic. Compared with 2019 (prepandemic), during 2021, the overall rate of suspected suicide attempts by self-poisoning increased by 30.0% (95% CI = 28.6%-30.9%), rates among children aged 10-12 years, adolescents aged 13-15 years, and females increased 73.0% (67.4%-80.0%), 48.8% (46.7%-50.9%), and 36.8% (35.4%-38.2%), respectively, and these trends continued into the third quarter of 2022. Substances most frequently involved in overdoses were acetaminophen, ibuprofen, sertraline, fluoxetine, and diphenhydramine. Acetaminophen-involved overdoses increased 71% (67.4%-74.9%) in 2021 and 58.0% (54.5%-61.6%) in 2022. Diphenhydramine-involved overdoses increased 24.2% (19.9%-28.7%) in 2021 and 35.8% (31.2%-40.5%) in 2022. A comprehensive public health approach to suicide prevention, focused on children and adolescents and involving a partnership between families, school teachers, mental health professionals, and public health leadership is needed. The 9-8-8 Suicide and Crisis Lifeline provides crisis support for persons experiencing mental health-related distress and assists community members who are concerned about persons experiencing a mental health crisis.

Using an Exposure Call Center to Help Mitigate Outbreaks, Such as COVID-19, on a University Campus.

Rapid identification and management of close contacts is an important component of an effective university mitigation strategy for highly contagious infectious diseases such as measles and coronavirus disease-2019 (COVID-19). Institutions of higher education must plan for an associated large influx of calls that can overwhelm standard student health and local public health operations. In fall 2020, a large state public university's Department of Student Health and Wellness created a dedicated exposure call center (ECC), in close collaboration with the local public health department, to quickly assess students who learned of a COVID-19 exposure outside of the formal contact tracing process. The ECC operated 7 days a week and fielded 3361 calls: 3187 from students and 174 from staff, faculty, and parents. The ECC provided rapid assessment and guidance for students with COVID-19 exposure, allowing for prompt quarantine and medical assessment when warranted. Call centers can increase the bandwidth of university health centers and also reduce the burden on health care providers and other public health resources during periods of crisis or high demand.

A Membrane-Modulated Centrifugal Microdevice for Enzyme-Linked Immunosorbent Assay-Based Detection of Illicit and Misused Drugs.

Increased opioid use and misuse have imposed large analytical demands across clinical and forensic sectors. Due to the absence of affordable, accurate, and simple on-site tests (e.g., point of interdiction and bedside), analysis is primarily conducted in centralized laboratories via time-consuming, labor-intensive methods. Many healthcare facilities do not have such analytical capabilities and must send samples to commercial laboratories, increasing turnaround time and care costs, as well as delaying public health warnings regarding the emergence of specific substances. Enzyme-linked immunosorbent assays (ELISAs) are used ubiquitously, despite lengthy workflows that require substantial manual intervention. Faster, reliable analytics are desperately needed to mitigate the mortality and morbidity associated with the current substance use epidemic. We describe one such alternative─a portable centrifugal microfluidic ELISA system that supplants repetitive pipetting with rotationally controlled fluidics. Embedded cellulosic membranes act as microvalves, permitting flow only when centrifugally generated hydraulic pressure exceeds their liquid entry pressure. These features enable stepwise reagent introduction, incubation, and removal simply by tuning rotational frequency. We demonstrate the success of this platform through sensitive, specific colorimetric detection of opiates, a subclass of opioids naturally derived from the opium poppy. Objective image analysis eliminated subjectivity in human color perception and permitted reliable detection of opiates in buffer and artificial urine at the ng/µL range. Opiates were clearly differentiated from other drug classes without interference from common adulterants known to cause false positive results in current colorimetric field tests. Eight samples were simultaneously analyzed in under 1 h, a marked reduction from the traditional multiday timeline. This approach could permit rapid, automatable ELISA-based drug detection outside of traditional laboratories by nontechnical personnel.

COVID-19 Isolation and Quarantine Experience for Residential Students at a Large Four-Year Public University.

Rapid identification and management of students with COVID-19 symptoms, exposure, or disease are critical to halting disease spread and protecting public health. We describe the interdisciplinary isolation and quarantine program of a large, public university, the University of Virginia, Charlottesville. The program provided students with wraparound services, including medical, mental health, academic, and other support services during their isolation or quarantine stay. The program successfully accommodated 844 cases during the fall 2020 semester, thereby decreasing exposure to the rest of the university and the local community. (Am J Public Health. 2021;111(10):1772-1775. https://doi.org/10.2105/AJPH.2021.306424).

Opioid Exposures Reported to U.S. Poison Centers.

OBJECTIVE: Opioid-related deaths are a leading cause of accidental deaths in the United States (U.S.). This study aims to examine the national trends in opioid exposures reported to U.S. poison centers (PCs). METHODS: The National Poison Data System (NPDS) was queried for opioid exposures between 2011 and 2018. We descriptively assessed the demographic and clinical characteristics. Trends in opioid frequencies and rates were analyzed using Poisson regression. Independent predictors of serious adverse events in opioid exposures were studied. RESULTS: There were a total of 604,183 opioid exposure calls made to the PCs during the study period. The frequency of opioid exposures decreased by 28.9% (95% CI: -29.6%, -28.1%; p < 0.001), and the rate of opioid exposures decreased by 21.2% (95% CI: -24.7%, -16.9%; p < 0.001). Multiple substance exposures accounted for 48.9% cases. The most frequent age group was 20-29 years (19.3%). Suspected suicides accounted for 34.9% cases. There were 7,246 deaths in our study sample, with 6.8% of cases demonstrating major effects. Hydrocodone was the most frequently observed opioid causing a toxic exposure and naloxone was used in 20.6% cases. Important predictors of a serious adverse event were age, gender, multi-substance exposures, and reasons for exposure. CONCLUSIONS: Analysis of calls to PCs indicated a decreasing trend of opioid exposures. However, the proportion of SAEs due to such exposures increased. There was a high proportion of intentional exposures and occurred in older age groups. PCs are a vital component of real-time public health surveillance of overdoses in the current opioid crisis.

The Efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(ab')2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.

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.

Epidemiologic Trends in Loperamide Abuse and Misuse.

STUDY OBJECTIVE: Loperamide abuse has been increasing in the United States as a potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects of opioid use. In June 2016, the Food and Drug Administration warned health care providers and the general public about potential serious adverse outcomes, including cardiac dysrhythmias and death. The purpose of this study is to determine recent trends in intentional loperamide abuse and misuse, reported clinical effects and management, and medical outcomes as reported to poison centers across the United States. METHODS: Loperamide exposures reported to the National Poison Data System indicating intentional misuse, abuse, and suspected suicide between January 1, 2010, and December 31, 2015, were assessed. Demographic and temporal trends, as well as reported clinical effects, medical management, and health outcomes, were analyzed. RESULTS: There was a 91% increase in reported exposures from 2010 to 2015, of which half were single-agent loperamide use only. Loperamide exposures reported to the National Poison Data System increased at approximately 38 cases per year (95% confidence interval [CI] 32.5 to 42.9; P<0.0001). Fifteen deaths were reported during this time frame, of which 8 involved single-agent loperamide abuse. CONCLUSION: Loperamide abuse and misuse are projected to increase in the absence of any methods to reduce exposure or curb abuse. Health care providers should consider the potential for loperamide toxicity when managing patients with opioidlike toxicity.

Lyme Disease: What the Wilderness Provider Needs to Know.

Lyme disease is a multisystem tickborne illness caused by the spirochete Borrelia burgdorferi and is the most common vectorborne disease in the United States. Prognosis after initiation of appropriate antibiotic therapy is typically good if treated early. Wilderness providers caring for patients who live in or travel to high-incidence Lyme disease areas should be aware of the basic biology, epidemiology, clinical manifestations, and treatment of Lyme disease.

Evaluation of the initiation of urine drug screens intended for use in transfer patients.

OBJECTIVE: The objective of this study was to determine if signs of clinical intoxication were present in patients who had transfer urine drug screens (UDS) performed and to determine the proportion of patients with UDS orders who were actually transferred to another facility. METHODS: Of all emergency department (ED) patient visits who had a transfer UDS ordered from November 19, 2011, to December 31, 2012, 54% of the population was randomly selected for review by 1 of 3 study investigators. For quality assurance, a random sample of 100 patient charts was independently reviewed by all 3 investigators to assure consistency in interpreting data. Demographics, clinical characteristics and history, disposition, and laboratory results were recorded. RESULTS: Of the 639 patients included in this study, only 18% were transferred to another psychiatric facility. Pediatric patients and those with presenting with suicidal ideation were more likely to be transferred to an outside facility. Thirty-six percent of the UDS were positive for at least one substance. Marijuana was the most common substance (23%), followed by cocaine (7%) and opiates (7%). There was no evidence that the UDS changed acute management decisions. CONCLUSIONS: Few (<6%) patients demonstrated any clinical characteristics that were consistent with an acute intoxication. Less than 20% of patients who had a transfer UDS were actually transferred to an outside facility corresponding with more than 80% not ordered appropriately according to the ED established guidelines. This number of inappropriate tests represented more than $152 000 of avoidable UDS cost during the study period.

Increasing severity of medical outcomes and associated substances in cases reported to United States poison centers.

INTRODUCTION: Poison centers provide free expert recommendations on the treatment of a wide variety of toxicological emergencies. Prior studies have called attention to the increasing complexity of cases reported to poison centers. We aimed first, to evaluate the trends in medical outcome severity, over a 15-year period in both the adult and pediatric populations. Second, we described the most frequently reported substances associated with major effect or death. METHODS: This is a retrospective review of exposures reported to the National Poison Data System from 1 January 2007 through 31 December 2021. All closed cases, for human exposures, reported during the study period were included. We assessed trends in frequencies and rates of medical outcomes and level of care received, among the adult (age greater than 19 years) and pediatric (age 19 years and younger) populations by reason for exposure. RESULTS: During the study period, the number of adult unintentional exposures resulting in major effect (37.4 percent) and death (65.3 percent) increased. The number of adult intentional exposures resulting in death increased by 233.9 percent and those resulting in a major effect increased by 133.1 percent. The rates of exposures resulting in major effect and death increased among both intentional and unintentional adult exposures. The number of pediatric unintentional exposures resulting in a major effect increased by 76.6 percent and the number of pediatric intentional exposures resulting in death and major effect increased by 122.7 and 190.1 percent, respectively. Moderate, major effect, and death rates increased in pediatric unintentional exposures and moderate and major effect rates increased in pediatric intentional exposures. CONCLUSIONS: We found a worsening severity of medical outcomes in adult and pediatric cases reported to poison centers. Poison centers are increasingly managing complex cases. Monitoring trends in which substances are associated with severe outcomes is imperative for future strategic prevention efforts.

Psilocybin Exposures Reported to U.S. Poison Centers: National Trends Over a Decade.

PURPOSE: We describe trends in psilocybin exposures among adolescents and young adults as reported to US poison centers over the past decade. METHODS: We queried the National Poison Data System for cases involving psilocybin during January 1, 2013-December 31, 2022. Persons aged 13-25 years were included. We examined exposures to psilocybin by demographics, clinical effects, level of care, and medical outcome. RESULTS: During the 10-year study period, 4,055 psilocybin-involved exposures were reported among adolescents and young adults, 2,667 (65.8%) being single substance exposures. Most single substance cases received medical attention (adolescents: 75.3% [n = 1,176], young adults: 72.1% [n = 797]). We did not find significant change in the number of cases during 2013-2018. Cases started increasing in 2019. In 2022, cases more than tripled among adolescents and more than doubled among young adults, compared to 2018 (p < .0001). DISCUSSION: Continued national surveillance is critical to determine the impact of psilocybin exposures on youth as it becomes increasingly available.

Survival of acute hypernatremia due to massive soy sauce ingestion.

BACKGROUND: Intentional massive sodium chloride ingestions are rare occurrences and are often fatal. OBJECTIVES: There are a variety of treatment recommendations for hypernatremia, ranging from dialysis to varying rates of correction. We report a case of acute severe hypernatremia corrected with rapid free-water infusions that, to our knowledge, has not been previously reported. CASE REPORT: A 19-year-old man presented to the Emergency Department in a comatose state with seizure-like activity 2 hours after ingesting a quart of soy sauce. He was administered 6 L of free water over 30 min and survived neurologically intact without clinical sequelae. Corrected for hyperglycemia, the patient's peak serum sodium was 196 mmol/L, which, to our knowledge, is the highest documented level in an adult patient to survive an acute sodium ingestion without neurologic deficits. CONCLUSION: Emergency physicians should consider rapidly lowering serum sodium with hypotonic intravenous fluids as a potential management strategy for acute severe hypernatremia secondary to massive salt ingestion.

Metabolic modeling of sex-specific tissue predicts mechanisms of differences in toxicological responses.

Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact effect of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that androgen, ether lipid, glucocorticoid, tryptophan, and xenobiotic metabolism have more activity in the male liver, and serotonin, melatonin, pentose, glucuronate, and vitamin A metabolism have more activity in the female liver. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we see little response in those sex-altered subsystems, and the largest differences are in subsystems related to lipid metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the import of bile acids and salts. This result suggests that the sexually dimorphic behavior of the liver may be caused by differences in enterohepatic recirculation, and we suggest an investigation into sex-specific microbiome composition as an avenue of further research. Author Summary: Male-bias in clinical testing of drugs has led to a disproportionate number of hepatotoxic events in women. Previous works use gene-by-gene differences in biological sex to explain this discrepancy, but there is little focus on the systematic interactions of these differences. To this end, we use a combination of gene expression data and metabolic modeling to compare metabolic activity between the male and female liver and treated and untreated hepatocytes. We find several subsystems with differential activity in each sex; however, when comparing these subsystems with those pathways altered by hepatotoxic agents, we find little overlap. To explore these differences on a reaction-by-reaction basis, we use the same sex-specific transcriptomic data to contextualize the previously published Human1 human cell metabolic model. In these models we find a difference in flux for the import of bile acids and salts, suggesting a potential difference in enterohepatic circulation. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population.

Identifying vulnerable populations at a university during the COVID-19 pandemic.

Objective: Persons with high-risk for severe COVID-19 illness require special attention when considering university operations during the novel coronavirus pandemic. The objective of this study was to determine the number of students who fall within a high-risk category according to Centers for Disease Control and Prevention (CDC) guidelines using linked databases. Participants: Students enrolled at a large public University and who accessed the student health center between 2016 and 2020. Methods: Clinical data were linked with both university student enrollment and disability services databases to provide a comprehensive, de-identified dataset of students at higher medical risk of severe COVID-19 illness. Results: 1902 unique students (14% of the student health center population) were identified as having one or more high-risk condition. Conclusions: Utilizing a large and longitudinally linked student database provides universities with valuable information to make critical administrative decisions about how best to accommodate high-risk students to reduce their medical risk when returning to in-person instruction.

Hyperthermia and multiorgan failure after abuse of "bath salts" containing 3,4-methylenedioxypyrovalerone.

"Bath salts" are being increasingly used as drugs of abuse. These products have been found to contain a variety of compounds, including 3,4-methylenedioxypyrovalerone (MDPV). We present a case of a 25-year-old man who injected bath salts and acutely developed severe agitation, hyperthermia, and tachycardia. Despite aggressive early medical management, including dialysis, he progressed to multiorgan system failure, although he ultimately recovered after a prolonged hospital course. The only chemical substance detected on comprehensive toxicologic testing was MDPV, a synthetic cathinone analogue. According to our case, MDPV abuse may result in adverse multisystem organ effects, including rhabdomyolysis, cardiac injury, hepatic injury, and renal failure. It is unknown whether these end-organ effects were due to direct cellular toxicity induced by MDPV or a result of the patient's marked agitation and hyperthermia. Acute management should focus on the rapid identification of organ injury and appropriate supportive care.

Fatalities from venomous and nonvenomous animals in the United States (1999-2007).

OBJECTIVE: To review recent (1999-2007) US mortality data from deaths caused by nonvenomous and venomous animals and compare recent data with historic data. METHODS: The CDC WONDER Database was queried to return all animal-related fatalities between 1999 and 2007. Rates for animal-related fatalities were calculated using the estimated 2003 US population. Inclusion criteria included all mortalities that were a consequence of bite, contact, attack, or envenomation (ICD-10 codes W53-W59 and X20-X29). RESULTS: There were 1802 animal-related fatalities with the majority coming from nonvenomous animals (60.4%). The largest percentage (36.4%) of animal-related fatalities was attributable to "other mammals," which is largely composed of farm animals. Deaths attributable to Hymenoptera (hornets, wasps, and bees) have increased during the past 60 years in the United States and now account for more than 79 fatalities per year and 28.2% of the total animal-related fatalities from 1999 to 2007. Dog-related fatalities have increased in the United States, accounting for approximately 28 fatalities per year and 13.9% of the total animal-related fatalities. CONCLUSIONS: Prevention measures aimed at minimizing injury from animals should be directed at certain high-risk groups such as farmworkers, agricultural workers, and parents of children with dogs.

The epidemiology of caving injuries in the United States.

OBJECTIVE: Caving is a demanding sport practiced throughout the world. Currently, there are no collective data analyzing injury mechanism or type in these austere environments. This study is a retrospective analysis of caving incidents documented by the National Speleological Society (NSS)-American Caving Accidents (ACA) annual publication. METHODS: This study retrospectively analyzes 877 incident reports collected between 1980 and 2008 by NSS-ACA. For each victim, the month, year, location, age, gender, incident type, injury zone of the body, injury type, the result of the incident, and time intervals for rescue were extracted. RESULTS: A total of 1356 victims were identified; 83% of victims were male, 17% were female. Ages ranged from 2 to 69 years old, with an average of 27 years. The greatest number of events occurred in summer months, peaking in July. The most common incident leading to traumatic injury was a caver fall (74%), also contributing to 30% of caver fatalities. Lower extremities were most commonly injured (29%), followed by the upper extremities and head (21% and 15%, respectively). Fractures comprised 41% of injuries, followed by lacerations (13%), bruise, hematoma, and abrasions (12%), and sprains and strains (7%). CONCLUSIONS: The majority of injuries were not life threatening; however, over the course of 28 years there were 81 documented fatalities. Similar to other studies of wilderness injuries, fractures, soft tissue injuries, and lacerations were prominent in this study. In general, the overall precipitating event leading to injuries is falling, leading to orthopedic trauma. To better prepare cave rescue teams we have attempted to describe the characteristics of caving injuries in the United States.

Utilizing the Toxicology Laboratory in the Poisoned Patient.

When evaluating a potentially poisoned patient, there is no substitute for a thorough history and physical examination. Clues from the examination are generally more likely to be helpful than a "shotgun" laboratory approach that involves indiscriminate testing of blood or urine for multiple agents. When used appropriately, diagnostic tests may be of help in the management of the intoxicated patient. When a specific toxin or even class of toxins is suspected, requesting qualitative or quantitative levels may be appropriate. The purpose of this review is to examine the role of common diagnostic tests in the evaluation of the poisoned patient.

Chemical Agents Encountered in Protests.

The most common chemicals used in riot control agents are chlorobenzylidene malononitrile, chloroacetophenone, dibenz[b,f]-[1,4]-oxazepine, and oleoresin capsicum. They cause ocular, respiratory, and dermal effects usually within seconds to minutes of exposure, but delayed effects have been reported. In addition, the canisters containing these chemicals can cause traumatic injuries when launched as projectiles. Although most effects are mild, some may be serious, especially in those with preexisting respiratory disease. Treatment consists of removing the patient from the source of exposure, removing contaminated clothes, and copiously irrigating the affected areas with water.