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Monkeypox virus (MPXV) can spread among humans through direct contact with lesions, scabs, or saliva; via respiratory secretions; and indirectly from fomites; via percutaneous injuries; and by crossing the placenta to the fetus during pregnancy. Since 2022, most patients with mpox in the United States have experienced painful skin lesions, and some have had severe illness. During 2021-2022, CDC initiated aircraft contact investigations after receiving reports of travelers on commercial flights with probable or confirmed mpox during their infectious period. Data were collected 1) during 2021, when two isolated clade II mpox cases not linked to an outbreak were imported into the United States by international travelers and 2) for flights arriving in or traveling within the United States during April 30-August 2, 2022, after a global clade II mpox outbreak was detected in May 2022. A total of 113 persons (100 passengers and 13 crew members) traveled on 221 flights while they were infectious with mpox. CDC developed definitions for aircraft contacts based on proximity to mpox cases and flight duration, sent information about these contacts to U.S. health departments, and received outcome information for 1,046 (68%) of 1,538 contacts. No traveler was found to have acquired mpox via a U.S. flight exposure. For persons with mpox and their contacts who had departed from the United States, CDC forwarded contact information as well as details about the exposure event to destination countries to facilitate their own public health investigations. Findings from these aircraft contact investigations suggest that traveling on a flight with a person with mpox does not appear to constitute an exposure risk or warrant routine contact tracing activities. Nonetheless, CDC recommends that persons with mpox isolate and delay travel until they are no longer infectious., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

We report 3 complicated and prolonged cases of mpox in people with advanced human immunodeficiency virus (HIV) not on antiretroviral therapy (ART) at mpox diagnosis. Multiple medical countermeasures were used, including prolonged tecovirimat treatment and immune optimization with ART initiation. Immunofluorescence of skin biopsies demonstrated a dense immune infiltrate of predominantly myeloid and CD8+ T cells, with a strong type I interferon local response. RNAscope detected abundant replication of monkeypox virus (MPXV) in epithelial cells and dendritic cells. These data suggest that prolonged mpox in people with advanced HIV may be due to ongoing MPXV replication, warranting aggressive medical countermeasures and immune optimization., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: The diagnosis of toxic alcohol poisoning is often based on clinical presentation and nonspecific surrogate laboratory studies due to limited testing availability. Fomepizole is the recommended antidote and often administered empirically. The objective of this study is to identify substances that mimic toxic alcohols and compare key clinical factors between toxic alcohol and non-toxic alcohol exposures when fomepizole was administered., Methods: This study was a retrospective evaluation using the National Poison Data System from January 1, 2010 through December 31, 2021. Exposures were included if fomepizole was administered. Toxic alcohol exposures had ethylene glycol or methanol as a coded substance. For exposures not coded as a toxic alcohol, the first substance was described. Paracetamol (acetaminophen) exposures from 2020 and 2021 were excluded., Results: Fomepizole was reportedly used 25,110 times over 12 years. Use increased from 1,955 in 2010 to 2,710 in 2021. Most administrations were for reported toxic alcohol poisoning (60 percent) but use in reported non-toxic alcohol poisoning was greater starting in 2020. Toxic alcohol exposures were older (43.3 versus 39.8 years; P  < 0.001) and more likely male (65.7 percent versus 58.2 percent). Level of care was mostly a critical care unit (67.7 percent), which was less common in toxic alcohol (63.3 percent) than non-toxic alcohol exposures (74.2 percent). The most common non-toxic alcohol substances were ethanol (24.9 percent) or an unknown drug (17.5 percent). Acidosis, increased creatinine concentration, anion gap, and osmolal gap, and kidney failure were coded in a lower proportion of toxic alcohol exposures than non-toxic alcohol exposures ( P  < 0.001)., Discussion: The inability to provide rapid clinical confirmation of toxic alcohol poisoning results in the empiric administration of fomepizole to many patients who will ultimately have other diagnoses. Although fomepizole is relative well tolerated we estimated that this practice costs between $1.5 to $2.5 million. The major limitations of this work include the biases associated with retrospective record review, and the inability to confirm the exposures which may have resulted in allocation error., Conclusion: Most fomepizole use was for a presumed toxic alcohol. This recently shifted to greater use in likely non-toxic alcohol poisoning. Key difference between the groups suggest fomepizole administration was likely due to the difficulty in diagnosis of toxic alcohol poisoning along with the efficacy and safety of fomepizole. Increased toxic alcohol laboratory testing availability could improve timely diagnosis, reserving fomepizole use for toxic alcohol poisoning.

Since May 2022, mpox has been identified in 108 countries without endemic disease; most cases have been in gay, bisexual, or other men who have sex with men. To determine number of missed cases, we conducted 2 studies during June-September 2022: a prospective serologic survey detecting orthopoxvirus antibodies among men who have sex with men in San Francisco, California, and a retrospective monkeypox virus PCR testing of swab specimens submitted for other infectious disease testing among all patients across the United States. The serosurvey of 225 participants (median age 34 years) detected 18 (8.0%) who were orthopoxvirus IgG positive and 3 (1.3%) who were also orthopoxvirus IgM positive. The retrospective PCR study of 1,196 patients (median age 30 years; 54.8% male) detected 67 (5.6%) specimens positive for monkeypox virus. There are likely few undiagnosed cases of mpox in regions where sexual healthcare is accessible and patient and clinician awareness about mpox is increased.

The relative contribution of the respiratory route to transmission of mpox (formerly known as monkeypox) is unclear. We review the evidence for respiratory transmission of monkeypox virus (MPXV), examining key works from animal models, human outbreaks and case reports, and environmental studies. Laboratory experiments have initiated MPXV infection in animals via respiratory routes. Some animal-to-animal respiratory transmission has been shown in controlled studies, and environmental sampling studies have detected airborne MPXV. Reports from real-life outbreaks demonstrate that transmission is associated with close contact, and although it is difficult to infer the route of MPXV acquisition in individual case reports, so far respiratory transmission has not been specifically implicated. Based on the available evidence, the likelihood of human-to-human MPXV respiratory transmission appears to be low; however, studies should continue to assess this possibility., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Historical targets for country-level animal rabies testing volumes were abandoned due to ethical and welfare concerns, and interpretation challenges of testing healthy animals. To-date, no quantitative threshold has been established for evaluating adequate surveillance capacity specific to suspected rabid animals. The purpose here is to establish quantitative testing thresholds for rabies suspected animals to assess a country's rabies surveillance capacity. Animal rabies testing data was obtained from official and unofficial rabies surveillance platforms from 2010 to 2019 and supplemented with official country reports and published literature. Testing rates were determined for all-animal and domestic animals, and standardized per 100,000 estimated human population; the domestic animal rate was also standardized per 100,000 estimated dog population. There were 113 countries that reported surveillance data eligible for analysis. Countries reporting the most data were under WHO categories as having endemic human rabies or no dog rabies. The annual median all-animal testing rate for all countries was 1.53 animals/100,000 human population (IQR 0.27-8.78). Three proposed testing rate thresholds are an all-animal rate of 1.9 animals/100,000 humans, a domestic animal per human rate of 0.8 animals/100,000 humans, and a domestic animal per dog rate of 6.6 animals/100,000 dogs. These three peer-derived rabies testing thresholds for passive surveillance can be used to facilitate assessment of a country's rabies surveillance capacity., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Monkeypox (mpox) is a disease caused by infection with Monkeypox virus (MPXV), an Orthopoxvirus (OPXV) in the same genus as Variola virus, which causes smallpox. During 2022, a global outbreak involving mpox clade IIb was recognized, primarily among gay, bisexual, and other men who have sex with men.* Most affected patients have been immunocompetent and experienced ≤10 rash lesions (1). CDC has recommended supportive care including pain control. † However, some patients have experienced severe mpox manifestations, including ocular lesions, neurologic complications, myopericarditis, complications associated with mucosal (oral, rectal, genital, and urethral) lesions, and uncontrolled viral spread due to moderate or severe immunocompromise, particularly advanced HIV infection (2). Therapeutic medical countermeasures (MCMs) are Food and Drug Administration (FDA)-regulated drugs and biologics that are predominantly stockpiled by the U.S. government; MCMs developed for smallpox preparedness or shown to be effective against other OPXVs (i.e., tecovirimat, brincidofovir, cidofovir, trifluridine ophthalmic solution, and vaccinia immune globulin intravenous [VIGIV]) have been used to treat severe mpox. During May 2022-January 2023, CDC provided more than 250 U.S. mpox consultations. This report synthesizes data from animal models, MCM use for human cases of related OPXV, unpublished data, input from clinician experts, and experience during consultations (including follow-up) to provide interim clinical treatment considerations. Randomized controlled trials and other carefully controlled research studies are needed to evaluate the effectiveness of MCMs for treating human mpox. Until data gaps are filled, the information presented in this report represents the best available information concerning the effective use of MCMs and should be used to guide decisions about MCM use for mpox patients., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

In late August 2021, a boy aged 7 years was bitten by a bat while he was playing outside his apartment home in Medina County, Texas. He informed his parents; however, no rabies postexposure prophylaxis (PEP) was sought because there were no visible bite marks, and the family was unaware that contact with a bat, including in the absence of visible bite marks, might cause rabies. Approximately 2 months later, the child was hospitalized for altered mental status, seizures, and hypersalivation and ultimately received a diagnosis of rabies. Experimental therapies were attempted; however, the child died 22 days after symptom onset. Fifty-seven persons who met criteria for suspected or known exposure to infectious secretions in this case were advised to consult with a medical provider about the need for rabies PEP in accordance with Advisory Committee on Immunization Practices (ACIP) guidelines (1). Rabies, an acute, progressive neuroencephalitis, is nearly always fatal. Although dogs are the most common source of human rabies deaths worldwide and account for an estimated 59,000 annual cases of human rabies globally (2), bats are the most common source of domestically acquired rabies in the United States and have been implicated in 31 (81.6%) of 38 human infections since 2000 (3). Attempts to prevent death or poor neurologic outcomes once rabies symptoms develop have been largely unsuccessful (4). Administration of rabies PEP, comprising rabies immunoglobulin and a series of doses of rabies vaccine, is critical to preventing rabies after an exposure; enhanced public education about the risk posed by bats, and the availability of PEP to prevent rabies, is needed., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

As of October 21, 2022, a total of 27,884 monkeypox cases (confirmed and probable) have been reported in the United States. § Gay, bisexual, and other men who have sex with men have constituted a majority of cases, and persons with HIV infection and those from racial and ethnic minority groups have been disproportionately affected (1,2). During previous monkeypox outbreaks, severe manifestations of disease and poor outcomes have been reported among persons with HIV infection, particularly those with AIDS (3-5). This report summarizes findings from CDC clinical consultations provided for 57 patients aged ≥18 years who were hospitalized with severe manifestations of monkeypox ¶ during August 10-October 10, 2022, and highlights three clinically representative cases. Overall, 47 (82%) patients had HIV infection, four (9%) of whom were receiving antiretroviral therapy (ART) before monkeypox diagnosis. Most patients were male (95%) and 68% were non-Hispanic Black (Black). Overall, 17 (30%) patients received intensive care unit (ICU)-level care, and 12 (21%) have died. As of this report, monkeypox was a cause of death or contributing factor in five of these deaths; six deaths remain under investigation to determine whether monkeypox was a causal or contributing factor; and in one death, monkeypox was not a cause or contributing factor.** Health care providers and public health professionals should be aware that severe morbidity and mortality associated with monkeypox have been observed during the current outbreak in the United States (6,7), particularly among highly immunocompromised persons. Providers should test all sexually active patients with suspected monkeypox for HIV at the time of monkeypox testing unless a patient is already known to have HIV infection. Providers should consider early commencement and extended duration of monkeypox-directed therapy †† in highly immunocompromised patients with suspected or laboratory-diagnosed monkeypox. §§ Engaging all persons with HIV in sustained care remains a critical public health priority., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Siobhán M. O’Connor reports US Patent Application #20190212345 and #20150140670 for kits and methods for determining physiologic levels and ranges of hemoglobin or disease state. Nicola A. Hanania reports institutional support from GSK, Sanofi, Genentech, AstraZeneca, and Teva; consulting fees from AstraZeneca, GSK, Boehringer Ingelheim, Sanofi, Genentech, Teva, and Amgen; and service as editor in chief of Respiratory Medicine. Jerry Clay Goodman reports payment from the American Academy of Neurology for a course in neuropathology at the annual meeting. No other potential conflicts of interest were disclosed.

Data on monkeypox in children and adolescents aged <18 years are limited (1,2). During May 17–September 24, 2022, a total of 25,038 monkeypox cases were reported in the United States, † primarily among adult gay, bisexual, and other men who have sex with men (3). During this period, CDC and U.S. jurisdictional health departments identified Monkeypox virus (MPXV) infections in 83 persons aged <18 years, accounting for 0.3% of reported cases. Among 28 children aged 0–12 years with monkeypox, 64% were boys, and most had direct skin-to-skin contact with an adult with monkeypox who was caring for the child in a household setting. Among 55 adolescents aged 13–17 years, most were male (89%), and male-to-male sexual contact was the most common presumed exposure route (66%). Most children and adolescents with monkeypox were non-Hispanic Black or African American (Black) (47%) or Hispanic or Latino (Hispanic) (35%). Most (89%) were not hospitalized, none received intensive care unit (ICU)–level care, and none died. Monkeypox in children and adolescents remains rare in the United States. Ensuring equitable access to monkeypox vaccination, testing, and treatment is a critical public health priority. Vaccination for adolescents with risk factors and provision of prevention information for persons with monkeypox caring for children might prevent additional infections., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Since May 2022, approximately 20,000 cases of monkeypox have been identified in the United States, part of a global outbreak occurring in approximately 90 countries and currently affecting primarily gay, bisexual, and other men who have sex with men (MSM) (1). Monkeypox virus (MPXV) spreads from person to person through close, prolonged contact; a small number of cases have occurred in populations who are not MSM (e.g., women and children), and testing is recommended for persons who meet the suspected case definition* (1). CDC previously developed five real-time polymerase chain reaction (PCR) assays for detection of orthopoxviruses from lesion specimens (2,3). CDC was granted 510(k) clearance for the nonvariola-orthopoxvirus (NVO)-specific PCR assay by the Food and Drug Administration. This assay was implemented within the Laboratory Response Network (LRN) in the early 2000s and became critical for early detection of MPXV and implementation of public health action in previous travel-associated cases as well as during the current outbreak (4-7). PCR assays (NVO and other Orthopoxvirus laboratory developed tests [LDT]) represent the primary tool for monkeypox diagnosis. These tests are highly sensitive, and cross-contamination from other MPXV specimens being processed, tested, or both alongside negative specimens can occasionally lead to false-positive results. This report describes three patients who had atypical rashes and no epidemiologic link to a monkeypox case or known risk factors; these persons received diagnoses of monkeypox based on late cycle threshold (Ct) values ≥34, which were false-positive test results. The initial diagnoses were followed by administration of antiviral treatment (i.e., tecovirimat) and JYNNEOS vaccine postexposure prophylaxis (PEP) to patients' close contacts. After receiving subsequent testing, none of the three patients was confirmed to have monkeypox. Knowledge gained from these and other cases resulted in changes to CDC guidance. When testing for monkeypox in specimens from patients without an epidemiologic link or risk factors or who do not meet clinical criteria (or where these are unknown), laboratory scientists should reextract and retest specimens with late Ct values (based on this report, Ct ≥34 is recommended) (8). CDC can be consulted for complex cases including those that appear atypical or questionable cases and can perform additional viral species- and clade-specific PCR testing and antiorthopoxvirus serologic testing., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Brian Pope reports travel support and provision of laboratory equipment from the Association for Public Health Laboratories and unpaid participation for service on the Awards and Nominations Committee for the Pan American Society for Clinical virology. Heba H. Mostafa reports grant support from the Maryland Department of Health, and research contract support from BioRad, DiaSorin, and Hologic. No other potential conflicts of interest were disclosed.

In May 2022, the Salt Lake County Health Department reported two real-time polymerase chain reaction (PCR)-confirmed travel-associated cases of monkeypox to the Utah Department of Health and Human Services (UDHHS). The two persons with monkeypox (patients A and B) lived together without other housemates. Both persons experienced prodromal symptoms (e.g., fatigue and body aches). Eight days after symptom onset, patient A experienced penile lesions; lesions spread to the lips, hands, legs, chest, and scalp by day 10. Patient B experienced prodromal symptoms 8 days after illness onset of patient A; patient B experienced a lesion on the foot which spread to the leg and finger by day 11. Although both patients had lesions in multiple anatomic areas, the overall number of lesions was small, and lesions varied in presentation from "pimple-like" or ulcerated, to characteristically well-circumscribed and centrally umbilicated. Both patients had mild illness. The time from symptom onset to resolution was approximately 30 days for patient A and approximately 22 days for patient B., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Purpose: Describe a dose rounding strategy for rabies immune globulin (RIG) administration., Methods: Multicenter, retrospective, observational review of patients that received RIG following an exposure from an animal with potential to transmit rabies infection in one health-system from March 2011 through December 2021. The primary outcome was to describe the RIG dose rounding strategy and population of patients that received RIG rounded to the nearest vial size compared to those that did not. Secondary outcomes evaluated additional costs and RIG international units (IU) wasted that could have occurred (rounded group) or did occur (not rounded group), re-presentation to the ED or primary care provider (PCP) within 7 days due to RIG related complaint, and occurrence of rabies infection. Data collection included patient demographics, exposure information, and RIG dose administered. Descriptive data and univariate analyses are reported. Cost and RIG IU wasted were calculated for the dosing strategies., Results: 426 patients were included; 373 (88%) had RIG rounded to the nearest vial size and 53 (12%) did not (mean age 36.1 years ±20.5, 51.6% male, most common exposures were bats [50%], type was bite [58%], and category III exposures [92%]). Those that had RIG rounded were younger and had lower total RIG doses, but similar IU/kg doses to those not rounded. A cost savings of $144,815 and prevention of 40,572 RIG IU wasted was calculated from those patients that had RIG rounded. There was no difference in the rate of re-presentation within 7 days and no cases of human rabies infection in the region during the study period., Conclusions: RIG dose rounding to the nearest vial size is associated with cost savings and prevention of wasting RIG IU. There was no association with re-presentation to the ED or PCP with RIG related issues within 7 days from administration., Competing Interests: Declaration of Competing Interest NMA, EU, DD and FSM have no conflicts of interest to report., (Copyright © 2022 Elsevier Inc. All rights reserved.)

On May 17, 2022, the Massachusetts Department of Public Health (MDPH) Laboratory Response Network (LRN) laboratory confirmed the presence of orthopoxvirus DNA via real-time polymerase chain reaction (PCR) from lesion swabs obtained from a Massachusetts resident. Orthopoxviruses include Monkeypox virus, the causative agent of monkeypox. Subsequent real-time PCR testing at CDC on May 18 confirmed that the patient was infected with the West African clade of Monkeypox virus. Since then, confirmed cases* have been reported by nine states. In addition, 28 countries and territories, † none of which has endemic monkeypox, have reported laboratory-confirmed cases. On May 17, CDC, in coordination with state and local jurisdictions, initiated an emergency response to identify, monitor, and investigate additional monkeypox cases in the United States. This response has included releasing a Health Alert Network (HAN) Health Advisory, developing interim public health and clinical recommendations, releasing guidance for LRN testing, hosting clinician and public health partner outreach calls, disseminating health communication messages to the public, developing protocols for use and release of medical countermeasures, and facilitating delivery of vaccine postexposure prophylaxis (PEP) and antivirals that have been stockpiled by the U.S. government for preparedness and response purposes. On May 19, a call center was established to provide guidance to states for the evaluation of possible cases of monkeypox, including recommendations for clinical diagnosis and orthopoxvirus testing. The call center also gathers information about possible cases to identify interjurisdictional linkages. As of May 31, this investigation has identified 17 § cases in the United States; most cases (16) were diagnosed in persons who identify as gay, bisexual, or men who have sex with men (MSM). Ongoing investigation suggests person-to-person community transmission, and CDC urges health departments, clinicians, and the public to remain vigilant, institute appropriate infection prevention and control measures, and notify public health authorities of suspected cases to reduce disease spread. Public health authorities are identifying cases and conducting investigations to determine possible sources and prevent further spread. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy. ¶ ., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: Previous literature suggests a laboratory interference of n-acetylcysteine (NAC) with prothrombin time (PT) and the international normalized ratio (INR). Early publications focused on this interaction in the setting of an acetaminophen overdose and evaluated the INR of patients receiving intravenous NAC. However, there is limited literature describing the concentration-effect relationship of NAC to INR measurement in the absence of acetaminophen-induced hepatotoxicity at therapeutic NAC concentrations. The purpose of the study is to quantify the degree of interference of NAC on INR values at therapeutic concentrations correlating to each infusion of the regimen (ex. bag 1: 550 mcg/mL, bag 2: 200 mcg/mL, bag 3: 35 mcg/mL, double bag 3: 70 mcg/mL) and at supratherapeutic concentrations in vitro ., Methods: Blood samples were obtained from study volunteers. Each blood sample was transferred into vials containing 0.3 mL buffered sodium citrate 3.2% and spiked with various concentrations of NAC for final concentrations of 0, 35, 70, 200, 550, 1000, 2000, and 4000 mcg/mL. The samples were centrifuged and tested to determine PT and INR on two separate machines: Siemens CS-2500 and Stago SN1114559. We would require a sample size of 6 to achieve a power of 80% and a level of significance of 1.7% (two-sided). Differences between INRs at varying concentrations were determined by Friedman's test. For multiple comparisons, post hoc analysis was performed using Wilcoxon signed-rank test with Bonferroni adjustment. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC)., Results: Participants included 11 healthy subjects: 8 males, 3 females, median age 30 years (range 25 - 58). Median and interquartile ranges (IQR) INR for the baseline samples were 1.09 (IQR 1.05, 1.16) for Siemens and 1.03 (IQR 0.99, 1.11) for Stago analyzers. There was a significant difference in INR between the therapeutic concentrations (baseline, 35, 70,200, or 550 µg/mL) (Siemens p  = .0008, Stago p  < .0001). The 550 µg/mL concentration with the Siemens analyzer was the only one compared separately and found to be significantly greater than the baseline (1.07 vs 1.22, p  = .02). For the Stago analyzer the 200 µg/mL and 500 µg/mL were compared and found to be significantly different from baseline (1.00 vs 1.07 and 1.19, adjusted p  = .02 and p  = .03, respectively). The largest INR increase seen was in one subject from a baseline of 1.07-1.32 with the 550 µg/mL concentration. Increases in concentrations to supratherapeutic levels resulted in a statistically significant non-linear increase in INR for all concentrations (Siemens p  < .0001, Stago p  < .0001). All of these concentrations were found to be significantly different from baseline (all adjusted p  < .05)., Conclusion: Although it was found that at therapeutic concentrations the in vitro presence of NAC affects INR measurements on two different machines, the change is of little clinical relevance. Supratherapeutic concentrations of NAC affect INR significantly, but the clinical utility of those results is limited by the rarity of those concentrations being measured.

Background: Limited data describe poisoning exposures in pregnant women. Previous studies are limited to inpatient populations, those seen only by toxicologists, or single poison centers. This study aimed to describe poison exposures reported to U.S. poison control centers in pregnant patients compared to non-pregnant controls., Methods: This was a retrospective observational study of exposures reported to the American Association of Poison Control Centers National Poison Data System from 2000 through 2019. Pregnant patients were included from 15-44 years along with a random sampling of 5:1 age and year matched control group of non-pregnant exposures. Demographics, primary substance, and known medical outcomes were described. Chi square analysis was performed for comparisons., Results: From 2000 to 2019, a total of 131,619 pregnant cases and 658,095 non-pregnant controls were identified. The median age was 27 years (IQR: 22, 31) for the matched groups. For known trimester of pregnancy: 29.8, 37.0, and 28.2% were in the first, second, and third trimester, respectively. Most common exposures were analgesics and cleaning products. Intentional exposures were more common in non-pregnant compared to pregnant cases (41.2 vs 21.9%; OR 2.71, 95% CI 2.67-2.75), mostly self-harm attempts (31.5 vs. 15.8%). Notably, there was a large discrepancy in the proportion of environmental exposures, with fewer in non-pregnant controls compared with pregnant cases (3.8 vs. 12.1%; OR 0.29, 95% CI 0.28-0.29). More non-pregnant cases had multiple substance exposures compared with pregnant cases (22.2 vs. 10.9%; OR 2.34, 95% CI 2.29-2.38). There were more moderate effect outcomes in non-pregnant compared with pregnant cases (13.2 vs. 6.3%; OR 2.25, 95% CI 2.20-2.30)., Conclusions: Outcomes of poisoning exposures in pregnant patients reported to U.S. poison centers are less serious compared to non-pregnant controls, likely due to the lower rates of intentional abuse and self-harm exposures and greater number of minimally toxic environmental exposures.

Introduction: Perampanel is indicated for partial onset seizures in children and adults. The mechanism is unique among antiepileptic agents as it inhibits glutamate activity on AMPA receptors. Currently, there are few published case reports describing overdose., Methods: This is a retrospective observational study of all single substance perampanel ingestions from January 2014 to December 2019 reported to the national poison data system (NPDS). The primary outcome is to describe the clinical effects of perampanel exposures. Secondary outcomes include evaluation of management and investigation of a dose-effect relationship for the purpose of triaging acute unintentional exposures., Results: A total of 138 exposures were reported to NPDS since the release of the agent. Median age was 20 years (IQR 10-38) with 68 (49.3%) males. The reason for exposure was most commonly therapeutic error (80, 58.0%), followed by exploratory ingestion (24, 17.4%), and suicidal ingestion (14, 10.1%). A total of six (4.3%) patients developed major effects, 20 (14.5%) moderate, 32 (23.2%) minor effects and 22 (15.9%) no effect. An additional 54 (39.1%) cases were not followed. Almost half of cases were managed at home. Of those that were in a healthcare facility (HCF) ( n  = 72), most were treated/evaluated and released (31, 43.1%), followed by admission to a non-critical care unit (20, 27.8%), and critical care unit (13, 18.1%). Most frequently reported symptoms were drowsiness (27, 19.6%), agitation (20, 14.5%), ataxia (13, 9.4%), and confusion (12, 8.7%). The most common therapies provided in a HCF were intravenous fluids (22,30.6%), followed by benzodiazepines (14, 19.4%), then other types of sedation (9, 12.5%). There were too few cases to determine a dose cut off for triaging., Conclusions: While drowsiness, agitation, ataxia, and confusion were the most often reported symptoms, close to 19% developed moderate/major effects and almost 4% of patients received potentially life-saving interventions.

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Abstract: Amphetamine toxicity typically presents with hypertension and tachycardia. Conversely, clonidine acts as an agonist at central α2 and imidazoline receptors, which may cause brief initial hypertension followed by hypotension and bradycardia in overdose. We report a case of mixed ingestion resulting in posterior reversible encephalopathy syndrome (PRES) successfully treated with phentolamine.A 17-year-old male adolescent presented to the emergency department 2 hours after ingesting up to 25 each of clonidine 0.1-mg tablets and dextroamphetamine 10 mg extended-release capsules. He reported nausea and fatigue with initial blood pressure (BP) 145/95 mm Hg and heart rate (HR) 52 beats per minute (bpm). Nine hours postingestion (HPI), the patient developed headache, photophobia, and confusion with BP 182/111 mm Hg and HR 48 bpm. A computed tomography scan of the head revealed generalized fullness of the cerebellum, upward bulging of the tentorial leaflets, effacement of the fourth ventricle, and crowding of the foramen magnum, suspicious for an atypical presentation of PRES. The patient's systolic BP rose over 200 mm Hg and treated with 2 mg of intravenous phentolamine at 14 HPI. Blood pressure decreased to 133/82 mm Hg, and HR increased to 56 bpm with improvements in headache. Following repeat doses of phentolamine, nicardipine was initiated and increased to 2.5 mg/h for 12 hours. The patient was stable with normal vital signs at 36 HPI.The delayed presentation of hypertensive emergency with PRES may have been due to the actions of extended-release dextroamphetamine and the α2-agonistic effects of clonidine. Phentolamine was chosen for its α1-antagonism and was effective in managing symptoms., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Benzonatate is a commonly prescribed medication that can be lethal in acute overdose of a small number of capsules., Objective: This was a systematic review to describe the course of severe poisoning and deaths from benzonatate supplemented with the National Poison Data System (NPDS) fatalities module., Methods: The NPDS was queried from 2000 to 2018 for benzonatate fatalities. Pubmed, Cochrane, Embase, and Google Scholar were searched for combinations of benzonatate and "poisoning," "overdose," and "toxicity." References of relevant articles were searched for additional publications. Articles were included if they described the clinical course of at least one patient suffering from benzonatate poisoning and available in English. Dual independent review and extraction were performed., Results: Seventeen cases from NPDS and 19 published reports met the inclusion criteria resulting in 36 cases, mostly (28/36) self-harm ingestions. Most patients were young [17 (11-29), median (IQR)] and female (22). Onset of toxicity was rapid at <5 min (9). Most common symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Return of spontaneous circulation was achieved in 23/28 patients, but most had significant neurologic deficits or other end organ damage and 5 survived with a good neurologic outcome., Conclusion and Relevance: Overdose ingestions of benzonatate can cause significant toxicity with a rapid onset. Interventions performed were generally supportive in nature. Duration of directly toxic effects is short, but dramatic with neurologic devastation and resuscitated patients often still have a poor outcome.

Objective: Opioids are high-risk medications in the inpatient setting because of their potential for significant patient harm. The primary objective was to identify risk factors that predispose inpatients to develop opioid-related adverse drug events (ORADE) requiring the use of naloxone., Methods: In a retrospective case-control study, patients were included according to the following criteria: 18 years or older, 1 administered opioid doses or more, and admitted for 24 hours or more. Patients were excluded if they had a prehospital drug overdose, other indications for naloxone use, or were admitted to an intensive care unit, psychiatric medical unit, or in the emergency department. Patients were classified as cases if naloxone was administered and a selection of controls were frequency matched 2:1 based on medical or surgical status. A logistic regression model was used to evaluate for risk factors for ORADE., Results: A total of 275 cases and 592 control patients were included into the final analysis. Variables that were associated with greater odds of naloxone administration included age of 65 years or older, female, length of stay, pulmonary diagnoses, use of gabapentinoids, and patient-controlled analgesia use. Antihistamines, continuous infusion, and intermittent nurse administered intravenous bolus routes had a negative association with naloxone use., Conclusions: Several risk factors were found to be associated with ORADE supporting many of the previously described risk factors, and the discovery of potential new ones, such as gabapentinoid use. Health care providers should consider the risk factors for hospitalized patients receiving opioids who may warrant lower doses, additional monitoring, or alternative agents., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This is a descriptive study evaluating fatal iatrogenic and in-hospital medication errors reported to United States poison centers., Methods: A retrospective evaluation of the National Poison Data System from 2000-2017 of all therapeutic errors with a scenario coded as iatrogenic/healthcare professional or occurring in a healthcare facility. Death abstracts were reviewed for details of the exposure and therapeutic error scenarios were recoded or added to the case as appropriate. Cases, where death was considered not related to the exposure, were excluded. Additionally, we created one additional scenario (rate-related) and one additional route of administration (intrathecal) to better describe the cases., Results: A total of 172 cases were evaluated. The majority of the patients were female (52.3%) with a median age of 58.5 years (range: 2 days to 96 years). The most commonly reported medication error was "other incorrect dose" (22.7%) followed by other/unknown error (15.1%). The route of exposure was primarily parenteral (54.9%), followed by ingestion (30.2%), then intrathecal (7.0%). The most common medications were cardiac drugs, chemotherapeutics, opioids, anticoagulants, and sedative-hypnotic/antipsychotics., Conclusions: Iatrogenic and in-hospital medication errors have been studied extensively with goals to reduce their occurrence. Specific controls to prevent incorrect dosing routes, 10-fold overdoses, and incorrect intrathecal administration have been instituted. Despite interventions, all three of these therapeutic errors continued to occur in 2017, suggesting that more preventive controls should be instituted.

Purpose: Evaluate opioid prescribing before and after emergency department (ED) renal colic guideline implementation focused on multi-modal pain management., Methods: Retrospective study of ED patients who received analgesia for urolithiasis before and after guideline implementation. The guideline recommends oral acetaminophen, intravenous (IV) ketorolac, and a fluid bolus as first line, IV lidocaine as second line, and opioids as refractory therapy to control pain. Opioid exposure, adverse effects, length of stay (LOS), and ED representation were evaluated. Comparisons were made with univariate analyses. Backwards stepwise binomial multivariate logistic regression to identify factors related to opioid use was performed., Results: Overall, 962 patients were included (451 pre- and 511 post-implementation). ED and discharge opioid use decreased; 65% vs. 58% and 71% vs. 63% in pre- and post-implementation groups, respectively. More post-implementation patients received non-opioid analgesia (65% vs. 56%) and non-opioid analgesia prior to opioids (50% vs. 38%). A longer ED LOS and higher initial pain score were associated with ED opioid administration. Guideline implementation, receiving non-opioid therapy first, and first renal colic episode were associated with decreased ED opioid administration. Seventeen adverse events (1.8%) were reported. There was no difference in change in ED pain score between groups, but patients in the post-implementation group were admitted more and had a higher 7-day ED representation (11% vs. 7%)., Conclusions: A multimodal analgesia protocol for renal colic was associated with decreased opioid prescribing, higher rates of admission to the hospital, and a higher 7-day ED representation rate., Competing Interests: Declaration of competing interest F. S. Minhaj, M. Hoang-Nguyen, A. Tenney, A. Bragg, W. Zhang, J. Foster, J. Rotoli, N. M. Acquisto have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To date, very little literature describes the outcomes of acute unintentional ingestions of lithium in young children. This study aimed to describe the clinical effects and outcomes reported in these patients reported to the National Poison Data System (NPDS). Methods: This is a retrospective observational study of acute unintentional lithium ingestions in children <6 years of age. The primary intent of the study was to characterize acute unintentional exposures to lithium in children in this age group. As a secondary outcome, we sought to identify a weight-based threshold to empirically refer patients into a healthcare facility for symptoms consistent with moderate effect or worse. The American Association of Poison Control Centers' NPDS was queried for all acute ingestions of lithium salts in children <6 years of age from 2000 to 2018. Inclusion criteria were single substance ingestions, unintentional-general exposure (i.e., exploratory ingestion), and followed to a known outcome or coded as potentially toxic exposure unable to follow and the patient was experiencing symptoms. Results: A total of 3045 single-substance exploratory ingestions of lithium were reported to poison centers that showed a decrease over time, consistent with decreasing use of lithium and decreasing calls to poison centers. Of the 3045 cases, we excluded 1178 leaving 1863 cases for analysis. Median age was 2 years (IQR: 1.5, 2) with 51% male cases. Management site was primarily non-health care facility ( n  = 808; 43.4%) with 569 (30.5%) already in a healthcare facility (HCF) when the Poison Control Center (PCC) was called and 477 (25.6%) referred to a HCF. The route of exposure was most commonly ingestion ( n  = 1853; 99.5%) and site of exposure was primarily home (1743; 93.6%). Medical outcomes were predominantly no effect and minor effect. There were 262 related clinical effects were reported in 184 patients (10%). The most frequently reported were vomiting ( n  = 76), drowsiness/lethargy ( n  = 58), other ( n  = 22), and ataxia ( n  = 20). Clinical effects lasted ≤2 h for 65 (33%), 2-8 h for 57 (28.9%), 8-24 h for 51 (25.9%), 1-3 days for 11 (5.6%), and >3 days to ≤1 week for 1 (0.5%); no cases resulted in clinical effects thought to be permanent and no deaths were reported. There were 1173 treatments provided to 857 patients. The most common treatments were basic and are readily performed at home; dilution ( n  = 492) and food/snack ( n  = 180). A smaller subset of patients received care that could likely only be provided in a healthcare facility including IV fluids ( n  = 173), other ( n  = 120), whole bowel irrigation ( n  = 46), single dose activated charcoal ( n  = 41), syrup of ipecac ( n  = 34), and lavage ( n  = 31). No patients received hemodialysis. A total of 425 of the exposures were referred to a healthcare facility by the PCC which had a dose coded. There was no difference in dose that resulted to referral to a healthcare facility over time ( p  = 0.2747). Due to the small number of moderate/major effect cases with dose information, we were unable to identify a dose-based threshold for referral to HCF. Conclusions: Severe outcomes after unintentional ingestion of lithium in pediatric patients are rare. It is likely that most asymptomatic pediatric patients <6 years do not need to be referred to the hospital after ingestion of lithium.