Search

Permafrost soils store between 1330 and 1580 Pg carbon (C), which is 3 times the amount of C in global vegetation, almost twice the amount of C in the atmosphere, and half of the global soil organic C pool. Despite the massive amount of C in permafrost, estimates of soil C storage in the high-latitude permafrost region are highly uncertain, primarily due to undersampling at all spatial scales; circumpolar soil C estimates lack sufficient continental spatial diversity, regional intensity, and replication at the field-site level. Siberian forests are particularly undersampled, yet the larch forests that dominate this region may store more than twice as much soil C as all other boreal forest types in the continuous permafrost zone combined. Here we present above- and belowground C stocks from 20 sites representing a gradient of stand age and structure in a larch watershed of the Kolyma River, near Chersky, Sakha Republic, Russia. We found that the majority of C stored in the top 1 m of the watershed was stored belowground (92 %), with 19 % in the top 10 cm of soil and 40 % in the top 30 cm. Carbon was more variable in surface soils (10 cm; coefficient of variation (CV) = 0.35 between stands) than in the top 30 cm (CV = 0.14) or soil profile to 1 m (CV = 0.20). Combined active-layer and deep frozen deposits (surface – 15 m) contained 205 kg C m−2 (yedoma, non-ice wedge) and 331 kg C m−2 (alas), which, even when accounting for landscape-level ice content, is an order of magnitude more C than that stored in the top meter of soil and 2 orders of magnitude more C than in aboveground biomass. Aboveground biomass was composed of primarily larch (53 %) but also included understory vegetation (30 %), woody debris (11 %) and snag (6 %) biomass. While aboveground biomass contained relatively little (8 %) of the C stocks in the watershed, aboveground processes were linked to thaw depth and belowground C storage. Thaw depth was negatively related to stand age, and soil C density (top 10 cm) was positively related to soil moisture and negatively related to moss and lichen cover. These results suggest that, as the climate warms, changes in stand age and structure may be as important as direct climate effects on belowground environmental conditions and permafrost C vulnerability.

Purpose: Guidelines recommend cardiovascular (CV) risk assessment and counseling for cancer survivors. This study evaluated the automated heart-health assessment (AH-HA) clinical decision support tool to promote provider-patient CV health (CVH) discussions in outpatient oncology., Methods: The AH-HA trial (WF-1804CD), coordinated by the Wake Forest National Cancer Institute Community Oncology Research Program Research Base, randomized practices to the AH-HA tool or usual care (UC) and enrolled survivors receiving routine care ≥6 months after curative cancer treatment. The tool displayed American Heart Association Life's Simple 7 CVH factors (BMI, physical activity, diet, smoking status, blood pressure, cholesterol, and glucose), populated from the electronic health record (EHR), alongside cancer treatments received with cardiotoxic potential. The primary end point was survivor-reported discussion of nonideal or missing CVH factors. A mixed-effects logistic regression model assessed the effect of AH-HA on CVH discussions, adjusting for practice., Results: Five UC and four AH-HA practices enrolled 645 survivors (82% breast, 8% endometrial, 5% colorectal, and 5% lymphoma, prostate, or multiple types) from October 1, 2020, to February 28, 2023. Most survivors were female (96%; 84% White/non-Hispanic, 8% Black; 3% Hispanic). Nearly all survivors (98%) in AH-HA practices reported a discussion for ≥1 nonideal or missing CVH factor compared with 55% in UC ( P < .001). The average number of survivor-reported factors discussed was higher in AH-HA compared with UC (mean, 4.06 v 1.27; P < .001), as were EHR-documented discussions (3.83 v 0.77; P = .03). Survivors in AH-HA practices were also significantly more likely to report a recommendation to see a primary care provider (39%) compared with UC practices (25%, P = .02). Reported recommendations to see a cardiologist were low (approximately 6%) and did not differ between groups., Conclusion: The AH-HA tool was effective at promoting CVH discussions during routine follow-up care for survivors and recommendations to consult primary care.

Background: In the ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke), treatment with nerinetide was associated with a smaller infarct volume among patients who did not receive intravenous alteplase. We assessed the effect of nerinetide on the surrogate imaging outcome of final infarct volume in patients who did not receive intravenous alteplase and explored predictors of outcome and modifiers of nerinetide's effect on infarct volume., Methods: ESCAPE-NA1 was a multicenter, randomized trial in which patients with acute stroke with a baseline Alberta Stroke Program Early CT Score >4, undergoing endovascular thrombectomy, were randomized to receive intravenous nerinetide or placebo. Patients not receiving intravenous alteplase were included in this post hoc secondary analysis of the trial data. Final infarct volume was manually segmented on 24-hour noncontrast computed tomography or diffusion-weighted magnetic resonance imaging. Predictors of final infarct volume were identified using multivariable linear regression with cubic-root-transformed infarct volume as the dependent variable. Evidence of treatment-by-predictor interaction was tested by including interaction terms in the model., Results: Four hundred forty-six patients (219 who received nerinetide and 227 who received a placebo) out of a total of 1105 enrolled patients were included in this secondary post hoc analysis of the randomized ESCAPE-NA1 trial. Nerinetide was a strong predictor of smaller infarct volume (adjusted β coefficient, -0.35 [95% CI, -0.67 to -0.02]). Other predictors of smaller infarct volume were history of hypertension, good pial collateral filling on multiphase computed tomography angiography, a middle cerebral artery occlusion compared with an internal carotid artery occlusion, lower baseline National Institutes of Health Stroke Scale score, lower baseline systolic blood pressure, lower baseline serum glucose, shorter onset-to-randomization time, and higher Alberta Stroke Program Early CT Score. There was evidence of a treatment-by-systolic blood pressure and treatment-by-anesthesia interaction: nerinetide attenuated the negative effects of elevated baseline ( P interaction =0.02) and postdose ( P interaction =0.04) systolic blood pressure and use of general anesthesia ( P interaction =0.06) on final infarct volume. We observed a marginally significant interaction with reperfusion status, such that nerinetide may attenuate the harmful effect of poor reperfusion status on infarct volume ( P interaction =0.08)., Conclusions: Nerinetide treatment was strongly associated with smaller final infarct volumes among patients not cotreated with alteplase. The reduction in infarct volume was greater among patients with poor prognostic factors., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02930018., Competing Interests: Dr Goyal reports compensation from MicroVention, Inc, for consultant services; grants from Medtronic to others; compensation from Mentice for consultant services; compensation from Philips for consultant services; grants from Johnson & Johnson Health Care Systems, Inc, to others; and compensation from Medtronic for consultant services. Dr Almekhlafi reports compensation from Palmera Medical, Inc, for other services. Dr Nogueira reports compensation from Biogen, Inc, for consultant services; stock holdings in Brain4Care; compensation from Brainomix for consultant services; compensation from Philips for consultant services; stock options in viz-AI; compensation from Biogen, Inc, for consultant services; compensation from Corindus, Inc, for consultant services; compensation from Astrocyte for consultant services; compensation from Imperative Care for consultant services; compensation from Ceretrieve for consultant services; stock options in Cerebrotech; stock options in Brainomix; compensation from Corindus Vascular Robotics for consultant services; compensation from Stryker for consultant services; stock options in Corindus, Inc; stock options in viz-AI; grants from Cerenovus; compensation from Brainomix for consultant services; compensation from Genentech for consultant services; stock options in Vesalio; compensation from Cerenovus for consultant services; compensation from Stryker Corporation for consultant services; compensation from Genentech for consultant services; grants from Stryker; compensation from Vesalio for consultant services; compensation from NeuroVasc Technologies, Inc, for consultant services; compensation from Phenox, Inc, for consultant services; stock holdings in Piraeus Medical; stock options in Perfuze; compensation from Anaconda for consultant services; compensation from Imperative Care, Inc, for consultant services; compensation from Perfuze for consultant services; compensation from Hybernia for consultant services; stock holdings in Quantanosis AI; compensation from Phenox for consultant services; stock options in Viseon, Inc; compensation from Prolong Pharmaceuticals for consultant services; compensation from Prolong Pharmaceuticals for consultant services; compensation from Synchron for data and safety monitoring services; compensation from Ceretrieve for consultant services; stock options in Ceretrieve; compensation from viz-AI for consultant services; compensation from Cerenovus for consultant services; stock options in Perfuze; compensation from RapidPulse for consultant services; compensation from RapidPulse for consultant services; stock options in Reist/Q’Apel Medical; compensation from Perfuze for consultant services; compensation from Cerebrotech for consultant services; compensation from Medtronic USA, Inc, for consultant services; compensation from Vesalio for consultant services; compensation from Shanghai Wallaby for consultant services; compensation from Anaconda Biomed for consultant services; stock options in Truvic; compensation from viz-AI for consultant services; and compensation from Medtronic USA, Inc, for consultant services. Dr Demchuk reports compensation from Philips for data and safety monitoring services; compensation from Medtronic for consultant services; compensation from Lumosa for data and safety monitoring services; compensation from AstraZeneca Canada for other services; compensation from NovaSignal for consultant services; compensation from Hoffmann-La Roche Limited for consultant services; a patent issued for stroke imaging software licensed to Circle NVI; stock holdings in Circle NVI; and compensation from Boehringer Ingelheim for consultant services. Dr Poppe reports compensation from Roche for other services. Dr Rempel reports compensation from Rapid Medical, Ltd, for consultant services; compensation from Vena for consultant services; and compensation from Penumbra, Inc, for consultant services. Dr Joshi reports compensation from Circle Neurovascular Imaging for consultant services; compensation from Eli Lilly for consultant services; compensation from BioClinica for consultant services; compensation from Biogen, Inc, for consultant services; and compensation from EISAI, Inc, for consultant services. K. Heard reports employment by NoNO, Inc; stock holdings in NoNO, Inc; and stock options in NoNO, Inc. Dr Field reports compensation from Novartis for consultant services; compensation from the Canadian Medical Protective Association for expert witness services; service as a board member for Destine Health; compensation from AstraZeneca Canada for consultant services; compensation from Bayer for consultant services; and compensation from HLS Therapeutics for consultant services. Dr Dowlatshahi reports compensation from AstraZeneca Canada for consultant services. Dr van Adel reports employment by McMaster University. Dr Swartz reports compensation from Sunnybrook Research Institute for other services; stock holdings in Follow MD, Inc; and compensation from F. Hoffmann-La Roche for consultant services. Dr Sauvageau reports stock holdings in Penumbra, Inc. Dr Tymianski reports stock options in NoNO, Inc; stock holdings in NoNO, Inc; and employment by NoNO, Inc. Dr Hill reports grants from Canadian Institutes of Health Research; grants from Boehringer Ingelheim; grants from NoNO, Inc; compensation from Brainsgate, Ltd, for consultant services; stock options in Basking Bioscience LLC; employment by the University of Calgary; and grants from Medtronic. The other authors report no conflicts.

Objectives: To describe the operational model, epidemiology and outcomes of COVID-19 cases managed by the first decentralised Victorian Public Health Unit (PHU) in the Barwon South-West (BSW) region in 2020., Methods: The Barwon Health team used a clinician-led, locally-based interprofessional model of care, combining clinical care and monitoring, contact tracing and public health measures., Results: From 7th March to 5th October 2020, 575 confirmed COVID-19 cases (82 in Wave 1; 493 in Wave 2) were identified in residents of the BSW region. Overall, 4.7% were admitted to local hospitals (0.7% to intensive care units) and 1.7% died. COVID-19 incidence in the region was 129 cases/100,000. Wave 2 in the region featured community transmission in high-risk settings and among culturally and linguistically diverse and mobile populations. Within 3 months of the initial local case in Wave 2, SARS-COV-2 was eliminated from the community., Conclusions: A local interprofessional model of care was key to the containment of community transmission and complex outbreaks with the elimination of COVID-19 in the community., Implications for Public Health: Key successes and learnings from the BSW PHU contributed to the improvement of statewide systems and responses and provided an impetus for the implementation of a decentralised public health model for Victoria., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emergency departments (EDs) are the front line in providing suicide care. Expert consensus recommends the delivery of several suicide prevention evidence-based interventions for individuals with acute suicidal ideation in the ED. ED personnel demands and staff shortages compromise delivery and contribute to long wait times and unnecessary hospitalization. Digital technologies can play an important role in helping EDs deliver suicide care without placing further demands on the care team if their use is safe to patients in a routine care context., Objective: This study evaluates the safety and effectiveness of an evidence-based digital technology (Jaspr Health) designed for persons with acute suicidal ideation seeking psychiatric crisis ED services when used as part of routine ED-based suicide care. This study deployed Jaspr Health for real-world use in 2 large health care systems in the United States and aimed to evaluate (1) how and whether Jaspr Health could be safely and effectively used outside the context of a researcher-facilitated clinical trial, and (2) that Jaspr's use would be associated with improved patient agitation and distress., Methods: Under the auspices of a nonsignificant risk device study, ED patients with acute suicidal ideation (N=962) from 2 health care systems representing 10 EDs received access to Jaspr Health as part of their routine suicide care. Primary outcome measures included how many eligible patients were assigned Jaspr Health, which modules were assigned and completed, and finally, the number of adverse events reported by patients or by medical staff. Secondary outcome measures were patient agitation, distress, and satisfaction., Results: The most frequent modules assigned were Comfort and Skills (98% of users; n=942) and lethal means assessment (90% of patient users; n=870). Patient task completion rates for all modules ranged from 51% to 79%. No adverse events were reported, suggesting that digital technologies can be safely used for people seeking ED-based psychiatric services. Statistically significant (P<.001) reductions in agitation and distress were reported after using the app. Average patient satisfaction ratings by site were 7.81 (SD 2.22) and 7.10 (SD 2.65), with 88.8% (n=325) and 84% (n=90) of patients recommending the app to others., Conclusions: Digital technologies such as Jaspr Health may be safely and effectively integrated into existing workflows to help deliver evidence-based suicide care in EDs. These findings hold promise for the use of digital technologies in delivering evidence-based care to other vulnerable populations in complex environments., (©Linda A Dimeff, Kelly Koerner, Kandi Heard, Allison K Ruork, Angela Kelley-Brimer, Suzanne T Witterholt, Mary Beth Lardizabal, Joseph R Clubb, Julie McComish, Arpan Waghray, Roger Dowdy, Sara Asad-Pursley, Maria Ilac, Hannah Lawrence, Frank Zhou, Blair Beadnell. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.09.2024.)

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

Introduction: Efficient and complete medical charting is essential for patient care and research purposes. In this study, we sought to determine if Chat Generative Pre-Trained Transformer could generate cogent, suitable charts from recorded, real-world poison center calls and abstract and tabulate data., Methods: De-identified transcripts of real-world hospital-initiated poison center consults were summarized by Chat Generative Pre-Trained Transformer 4.0. Additionally, Chat Generative Pre-Trained Transformer organized tables for data points, including vital signs, test results, therapies, and recommendations. Seven trained reviewers, including certified specialists in poison information and board-certified medical toxicologists, graded summaries using a 1 to 5 scale to determine appropriateness for entry into the medical record. Intra-rater reliability was calculated. Tabulated data was quantitatively evaluated for accuracy. Finally, reviewers selected preferred documentation: original or Chat Generative Pre-Trained Transformer organized., Results: Eighty percent of summaries had a median score high enough to be deemed appropriate for entry into the medical record. In three duplicate cases, reviewers did change scores, leading to moderate intra-rater reliability (kappa = 0.6). Among all cases, 91 percent of data points were correctly abstracted into table format., Discussion: By utilizing a large language model with a unified prompt, charts can be generated directly from conversations in seconds without the need for additional training. Charts generated by Chat Generative Pre-Trained Transformer were preferred over extant charts, even when they were deemed unacceptable for entry into the medical record prior to the correction of errors. However, there were several limitations to our study, including poor intra-rater-reliability and a limited number of cases examined., Conclusions: In this study, we demonstrate that large language models can generate coherent summaries of real-world poison center calls that are often acceptable for entry to the medical record as is. When errors were present, these were often fixed with the addition or deletion of a word or phrase, presenting an enormous opportunity for efficiency gains. Our future work will focus on implementing this process in a prospective fashion.

Background: Phenobarbital has been used in the emergency department (ED) as both a primary and adjunctive medication for alcohol withdrawal, but previous studies evaluating its impact on patient outcomes are limited by heterogenous symptom severity., Objectives: We compared the clinical outcomes of ED patients with moderate alcohol withdrawal who received phenobarbital, with or without benzodiazepines, with patients who received benzodiazepine treatment alone., Methods: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of ED patients with moderate alcohol withdrawal between 2015 and 2020. Patient encounters were classified into two treatment categories based on medication treatment: phenobarbital alone or in combination with benzodiazepines vs. benzodiazepines alone. Chi-square test or Fisher's exact was used to analyze categorical variables and the Student's t-test for continuous data., Results: Among the 287 encounters that met inclusion criteria, 100 received phenobarbital, compared with 187 that received benzodiazepines alone. Patients who received phenobarbital were provided significantly more lorazepam equivalents. There was a significant difference in the percentage of patient encounters that required admission to the hospital in the phenobarbital cohort compared with the benzodiazepine cohort (75% vs. 43.3%, p < 0.001). However, there was no difference in admission level of care to the floor (51.2% vs. 52.0%), stepdown (33.8% vs. 28%), or intensive care unit (15% vs. 20%), respectively., Conclusions: Patients who received phenobarbital for moderate alcohol withdrawal were more likely to be admitted to the hospital, but there was no difference in admission level of care when compared with patients who received benzodiazepines alone. Patients who received phenobarbital were provided greater lorazepam equivalents in the ED., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Study Objective(s): To evaluate the implementation of 3 electronic health record (EHR)-based interventions to increase prescription drug monitoring program (PDMP) use in the emergency department (ED): EHR-PDMP integration, addition of a PDMP risk score, and addition of EHR-based clinical decision support alert to review the PDMP when prescribing an opioid., Methods: Three intervention stages were implemented using a prospective stepped-wedge design at 5 university-affiliated EDs split into 3 practice groups. The PDMP use and prescribing rates during the 3 stages were compared with baseline before EHR integration and a sustainability stage where the clinical decision support alert was removed, but EHR integration and risk score remained. Generalized linear mixed model with logit link function and a random intercept for clinicians was analyzed., Results: The ED provider PDMP review before opioid prescribing was low in all stages. The highest review rate occurred during interruptive clinical decision support alerts, 23.8% (interquartile range 10.6 to 37.5). Overall, opioid prescribing declined, and PDMP review was not associated with a decrease in opioid prescribing. PDMP review was associated with a reduction in the probability of prescribing an opioid as the number of prior opioid prescriptions increased (odds ratio: 0.92 [95% confidence interval: 0.91 to 0.94] for every additional prescription)., Conclusion: The EHR-PDMP integration did not increase PDMP use in the ED, but a PDMP risk score and a clinical decision support alert were associated with modest increases in the probability of PDMP review. When the PDMP is reviewed, ED clinicians are less likely to prescribe opioids to patients with a high number of prior opioid prescriptions., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Acetaminophen overdose is common in the pediatric population. N-acetylcysteine (NAC) is effective at preventing liver injury in most patients when started shortly after the overdose. Delays to therapy increase risk of hepatotoxicity and liver failure that may necessitate organ transplant. Animal studies have demonstrated fomepizole may provide added benefit in acetaminophen overdose because of its ability to block the metabolic pathway that produces the toxic acetaminophen metabolite and downstream inhibition of oxidative stress pathways that lead to cell death. Several adult case reports describe use of fomepizole in patients at higher risk for poor outcomes despite NAC. We describe a case of a 7-month-old female who presented in acute liver failure with persistently elevated acetaminophen concentration secondary to repeated supratherapeutic doses of acetaminophen to manage fever. Fomepizole and NAC antidotes were used in the management of the patient. She fully recovered despite demonstrating multiple markers of poor outcome on initial presentation. Although randomized trials are lacking, this case suggests that fomepizole may safely provide additional benefit in pediatric patients at risk for severe acetaminophen toxicity., (Copyright © 2023 by the American Academy of Pediatrics.)

Introduction: Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine., Methods: This was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry., Results: There were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively., Discussion: The clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures., Conclusions: Hydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.

Importance: Goal-concordant care is an ongoing challenge in hospital settings. Identification of high mortality risk within 30 days may call attention to the need to have serious illness conversations, including the documentation of patient goals of care., Objective: To examine goals of care discussions (GOCDs) in a community hospital setting with patients identified as having a high risk of mortality by a machine learning mortality prediction algorithm., Design, Setting, and Participants: This cohort study took place at community hospitals within 1 health care system. Participants included adult patients with a high risk of 30-day mortality who were admitted to 1 of 4 hospitals between January 2 and July 15, 2021. Patient encounters of inpatients in the intervention hospital where physicians were notified of the computed high risk mortality score were compared with patient encounters of inpatients in 3 community hospitals without the intervention (ie, matched control)., Intervention: Physicians of patients with a high risk of mortality within 30 days received notification and were encouraged to arrange for GOCDs., Main Outcomes and Measures: The primary outcome was the percentage change of documented GOCDs prior to discharge. Propensity-score matching was completed on a preintervention and postintervention period using age, sex, race, COVID-19 status, and machine learning-predicted mortality risk scores. A difference-in-difference analysis validated the results., Results: Overall, 537 patients were included in this study with 201 in the preintervention period (94 in the intervention group; 104 in the control group) and 336 patients in the postintervention period. The intervention and control groups included 168 patients per group and were well-balanced in age (mean [SD], 79.3 [9.60] vs 79.6 [9.21] years; standardized mean difference [SMD], 0.03), sex (female, 85 [51%] vs 85 [51%]; SMD, 0), race (White patients, 145 [86%] vs 144 [86%]; SMD 0.006), and Charlson comorbidities (median [range], 8.00 [2.00-15.0] vs 9.00 [2.00 to 19.0]; SMD, 0.34). Patients in the intervention group from preintervention to postintervention period were associated with being 5 times more likely to have documented GOCDs (OR, 5.11 [95% CI, 1.93 to 13.42]; P = .001) by discharge compared with matched controls, and GOCD occurred significantly earlier in the hospitalization in the intervention patients as compared with matched controls (median, 4 [95% CI, 3 to 6] days vs 16 [95% CI, 15 to not applicable] days; P < .001). Similar findings were observed for Black patient and White patient subgroups., Conclusions and Relevance: In this cohort study, patients whose physicians had knowledge of high-risk predictions from machine learning mortality algorithms were associated with being 5 times more likely to have documented GOCDs than matched controls. Additional external validation is needed to determine if similar interventions would be helpful at other institutions.

Background: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing., Hypothesis: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses., Methods: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses., Results: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001)., Conclusion: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production., (© 2022. American College of Medical Toxicology.)

Introduction: Oral antimicrobials, including ciprofloxacin, levofloxacin and doxycycline, are susceptible to binding with enteral therapies such as calcium and iron therapies. Administered together, the bioavailability of these antimicrobials is expected to be reduced., Methods: A retrospective case series of patients receiving oral antimicrobials (ciprofloxacin, levofloxacin and doxycycline) was analysed at a single-centre NHS acute hospital (April 2016-September 2019). Patient demographics, including concurrent enteral therapies, were recorded using medical records. Clinically important interactions were defined as doses administered within 2 hours of antimicrobial therapy., Results: A total of 4067 prescriptions for the study antimicrobials (ciprofloxacin, n=1905; levofloxacin, n=538; and doxycycline, n=1624) were prescribed for 3584 patients. 1918/3583 (53.5%) of the patients were female, and the median age was 67 years (range 0.5-105.0 years). 810/4067 (19.3%) prescriptions reviewed had an interacting enteral therapy (calcium or iron salt) administered within 2 hours of the study medication., Conclusion: The concomitant administration of enteral calcium and iron with oral antimicrobials is common within the acute care hospital setting. Approximately one in five patients has a clinically important interaction which may impair oral bioavailability and limit treatment efficacy. As antimicrobial stewardship teams strive for increased intravenous-to-oral de-escalation, it is important that optimum dosing administration is followed to optimise patient outcomes., Competing Interests: Competing interests: LSPM has consulted for DNAelectronics (2015), Dairy Crest (2017–2018) and bioMerieux (2013–2020); has received speaker fees from Profile Pharma (2018) and Pfizer (2018-2020); has received research grants from the National Institute for Health Research (2013–2019), Leo Pharma (2016) and CW+ Charity (2017–2020); and has received educational support from Eumedica (2016–2017). NM has consulted for Pfizer (2019) and has received educational support from Eumedica (2015) and Baxter (2017). SH has consulted for Shionogi (2020) and has received educational support from Baxter (2017). All other authors have no conflicts of interest to declare., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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

Background: The coronavirus disease 2019 (COVID-19) pandemic has challenged the accuracy and racial biases present in traditional mortality scores. An accurate prognostic model that can be applied to hospitalized patients irrespective of race or COVID-19 status may benefit patient care., Research Design: This cohort study utilized historical and ongoing electronic health record features to develop and validate a deep-learning model applied on the second day of admission predicting a composite outcome of in-hospital mortality, discharge to hospice, or death within 30 days of admission. Model features included patient demographics, diagnoses, procedures, inpatient medications, laboratory values, vital signs, and substance use history. Conventional performance metrics were assessed, and subgroup analysis was performed based on race, COVID-19 status, and intensive care unit admission., Subjects: A total of 35,521 patients hospitalized between April 2020 and October 2020 at a single health care system including a tertiary academic referral center and 9 community hospitals., Results: Of 35,521 patients, including 9831 non-White patients and 2020 COVID-19 patients, 2838 (8.0%) met the composite outcome. Patients who experienced the composite outcome were older (73 vs. 61 y old) with similar sex and race distributions between groups. The model achieved an area under the receiver operating characteristic curve of 0.89 (95% confidence interval: 0.88, 0.91) and an average positive predictive value of 0.46 (0.40, 0.52). Model performance did not differ significantly in White (0.89) and non-White (0.90) subgroups or when grouping by COVID-19 status and intensive care unit admission., Conclusion: A deep-learning model using large-volume, structured electronic health record data can effectively predict short-term mortality or hospice outcomes on the second day of admission in the general inpatient population without significant racial bias., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFβ/BMP signaling pathway that included increased canonical TGFβ and noncanonical BMP signaling. In this study, the role of FLNB in the TGFβ/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFβ/BMP signaling and that loss of FLNB produces increased TGFβ receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFβ/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFβ/BMP pathway activity restored Flnb -/- IVD morphology. These most effective improvements resulted from specific inhibition of TGFβ and p38 signaling activation. FLNB acts as a bridge for TGFβ/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFβ/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders., (© 2022. The Author(s).)

Background and Aims: To estimate during pregnancy correlations between frequency of self-reported use of marijuana and quantified marijuana metabolite in biospecimens including urine, sera and umbilical cord homogenate., Design: Prospective cohort., Setting: Two urban hospitals in Colorado with legal recreational and medicinal marijuana., Participants: Pregnant women (<16 weeks gestation) self-reporting marijuana use., Measurements: Participants completed a written self-report survey and provided biospecimens at <16 weeks gestation (n = 46), 18 to 22 weeks gestation (n = 43), 32 to 36 weeks gestation (n = 39), and delivery (n = 37). Self-reported marijuana use frequency was calculated based on past-month days of use multiplied by number of daily uses. Maternal urine and sera were tested for presence (>5 ng/mL) of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH). Liquid chromatography tandem mass spectrometry quantified THC-COOH in umbilical cord homogenate (ng/g). Last marijuana use by any measure was recorded to evaluate the time frame over which THC-COOH remains detectable (>0.10 ng/g) in cord., Findings: From December 2017 through May 2019, 51 pregnant women enrolled, and 46 were included in analyses (2 withdrew and 3 had a spontaneous abortion). The majority were normal weight, White or Black race, and insured by Medicaid. At the time of enrollment between 7 to 15 weeks' gestation, 87% had ongoing use by self-report, or positive urine or serum. The majority (33 [66%]) stopped using before delivery. Sera and urine results were strongly correlated with self-reported use frequency (Spearman correlation coefficient [r] range 0.70-0.87 across visits, P < 0.001), and with each other. There was only one positive cord result when use stopped before 22 weeks. Frequency of self-reported marijuana use at delivery had strong correlation with quantified cord THC-COOH (r = 0.80, 95% CI = 0.62-0.89)., Conclusions: Quantified umbilical cord THC-COOH appears to strongly correlate with frequency of maternal marijuana use in the last month of pregnancy. Earlier use can be measured by either quantitative urine or serum assay., (© 2021 Society for the Study of Addiction.)

Vaccine-induced thrombotic thrombocytopenia is a newly described disease process in the setting of expanding access to COVID-19 vaccination. The United States Centers for Disease Control and Prevention recommends treatment with an alternative to heparin in patients suspected of having vaccine-induced thrombotic thrombocytopenia. At this time there have been no reported outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. We describe the early outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. A 40-year-old Caucasian woman was found to have thrombocytopenia, cerebral venous sinus thrombosis, and pulmonary embolism following vaccination for COVID-19 with Ad26.COV2.S. She exhibited a steady rise in platelet count: 20×10 9 /L at hospital day 0, 115×10 9 /L at discharge on hospital day 6, and 182×10 9 /L on outpatient follow-up on day 9. While the patient exhibited a transient drop in hemoglobin, there was no clinical evidence of bleeding. This patient did not demonstrate any clinical sequelae of thrombosis, and she reported resolution of her headache. Vaccination with Ad26.COV2.S appears to be associated with a small but significant risk for thrombotic thrombocytopenia within 13 days of receipt. The Centers for Disease Control and Prevention guidance to consider an alternative to heparin was not accompanied by specifically recommended alternatives. A single patient treated with bivalirudin for suspected vaccine-induced thrombotic thrombocytopenia subsequently experienced symptom improvement and a rise in platelet count and did not demonstrate any immediate negative outcomes. A provider may consider bivalirudin as an alternative to heparin in patients with suspected vaccine-induced thrombotic thrombocytopenia following Ad26.COV2.S vaccination, pending more definitive research., (Copyright © 2021 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation., Methods: This was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-<18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion., Results: Ten (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%, p  = 0.01) and at the 4th hour of infusion (22% vs 100%, p  < 0.001) compared to patients who received lorazepam. There was a significant decrease in agitation scores in the physostigmine arm compared to the lorazepam arm after the initial bolus (89% vs 30%, p  = 0.02), but no difference at the 4th hour of infusion ( p  > 0.99). There were no seizures, bradycardia, bronchorrhea, bronchospasm, intubation, or cardiac dysrhythmias., Conclusion: Physostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.

Study Objective: Emergency Departments (ED) are rapidly becoming an important location for initiation of buprenorphine (EDBUP) for the treatment of opioid use disorder (OUD). Previous investigations of emergency medicine physicians' perceived barriers and attitudes toward EDBUP exclusively sampled from urban, academic-affiliated physicians. We administered a multistate survey to an institutionally and geographically diverse collection of emergency medicine physicians to better understand the professional opinions of EDBUP implementation across a variety of practice settings., Methods: This cross-sectional survey study used an online survey instrument to convenience sample emergency medicine physicians. In order to sample from various practice environments, participants were identified from (1) statewide ACEP chapters and (2) Facebook groups exclusive to emergency medicine physicians. The survey explored physicians' attitudes of EDBUP adoption and the perceived barriers to doing so., Results: 162 emergency medicine physicians completed the survey. 76% of respondents agreed that emergency medicine physicians should offer EDBUP in the treatment of OUD. When stratified by practice setting and X-waiver status, 96% of X-waivered physicians, 73% of academic physicians, 49% of non-academic physicians, and 34% of non-X-waivered physicians felt comfortable initiating EDBUP. Lack of access to outpatient MOUD referral was the most frequently cited barrier to EDBUP across all practice settings., Conclusions: An institutionally and geographically diverse group of emergency medicine physicians endorsed substantial support for EDBUP. Emergency medicine physicians practicing in different clinical environments endorsed similar barriers to EDBUP implementation.

Audience: This video lecture is appropriate for emergency medical providers who are not comfortable with initial assessment of poisoned patients. Ideal learners include medical students and residents., Introduction: Poisoning is the leading cause of injury-related mortality in the United States, with more than 40,000 deaths annually.1 Of all ED injury-related visits, 2.4% are related to poisoning.2 While providers may have access to support services (poison control center, medical toxicology consulting service), they are often responsible for the initial evaluation of poisoned patients. While a large portion of poisoned patients have good outcomes regardless of the care they receive, inappropriate risk assessment and lack of knowledge about basic interventions can put patients at risk. A standardized approach as outlined in the video will help evaluate and treat the vast majority of poisoned patients., Educational Objectives: By the end of the lecture, learners should be able to: 1) initiate the evaluation of a poisoned patient, 2) identify key interventions to support airway, breathing, and circulation, 3) identify the three components of risk assessment in the poisoned patient, 4) list the four options for gastric decontamination, and 5) select standard diagnostic labs and tests commonly used in evaluating poisoned patients., Educational Methods: This is an enhanced live action greenscreen recording with video animation., Research Methods: This video has been made available for a variety of learners on social medial (Facebook and YouTube) and written feedback has been collected on YouTube., Results: The video has been seen over three thousand times and has received positive comments on social media (Facebook, YouTube). Comments include "dropping some tox knowledge bombs, proving yet again that #ToxRocks," and "This is an excellent talk, thank you very much, but I think it would be worth mentioning antidotes.", Discussion: The goal is to expose learners to basic concepts in approaching poisoned patients and focusses on cognitive knowledge and diagnostic frameworks. The learner may watch the on-demand video as part of a flipped classroom experience with clinical cases, or as a just-in-time resource before seeing a patient who has been poisoned., Topics: Poisoning, resuscitation, risk assessment, gastric decontamination, occult ingestion, supportive care., (© 2021 Heard, et al.)

Objectives: Opioids are commonly administered in the emergency department (ED) and prescribed for the treatment of back pain. It is important to understand the unintended consequences of this approach to inform treatment decisions and the consideration of alternative treatments. Recent evidence has shown that ED opioid prescriptions are associated with future opioid use. The objective of this study was to measure the association of opioid administration in the ED to patients treated for back pain with future opioid use., Methods: This is a retrospective study of opioid-naïve adults discharged from the ED with a diagnosis of back pain. Patients were stratified by opioid therapy (none, ED administration only, prescription only, or ED administration + prescription). Relative risks of ongoing opioid use (filling >90-day supply in 180 days following ED visit as documented in the prescription drug monitoring program) were calculated for each opioid-therapy group and compared to the no-opioid group., Results: We identified 24,487 opioid naïve back pain patients. The median age was 38 years, 55% were female, and 56% were non-Hispanic white. A total of 41% received no opioid, 10% were only administered an opioid in the ED, 18% only received a prescription, and 31% received an opioid in the ED + prescription. The adjusted relative risks of ongoing use compared to the no opioid group were as follows: ED only 1.9, prescription only 2.1, and ED + prescription 2.3. The increased risk persisted for other definitions of ongoing use and after adjustment for baseline pain scores., Conclusions: For opioid-naïve patients with back pain, both administration of an opioid in the ED and opioid prescriptions are associated with a doubling of the risk of ongoing opioid use compared to patients not treated with opioids. This supports the consideration of minimizing exposure to opioids while treating back pain in the ED., (© 2020 by the Society for Academic Emergency Medicine.)

The emergence of carbapenemase-producing Enterobacterales (CPE) as a major cause of invasive infection both within the UK and internationally poses a very real concern for all providers of healthcare. The burden of morbidity and mortality associated with CPE infections is well described. The need for early, targeted, effective and safe antimicrobial therapy remains key for the management of these infected patients yet reliable antimicrobial treatment options remain scarce. In the absence of a universal treatment for these CPE invasive infections, individual treatment options tailored to susceptibilities and severity of infection are required. This working group from within the UK Clinical Pharmacy Association (UKCPA) Pharmacy Infection Network has developed evidence-based treatment recommendations to support infection specialists in managing these complex infections. A systematic review of peer-reviewed research was performed and analysed. We report consensus recommendations for the management of CPE-associated infections. The national expert panel makes therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, dosing, dosage adjustment and monitoring of parameters for novel and established antimicrobial therapies with CPE activity. This manuscript provides the infection specialist with pragmatic and evidence-based options for the management of CPE infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background and Objectives: Despite limited evidence, cannabidiol-rich cannabis extracts have been popularly used in pediatrics. With increased use, it is critical to determine basic pharmacokinetic parameters of cannabidiol in these extracts in the pediatric population. The objective of this study was to determine the disposition of oral cannabidiol cannabis extracts and drug interactions in children with pediatric epilepsy., Methods: We conducted a prospective observational study evaluating the disposition of oral cannabidiol in children (< 18 years of age) receiving cannabidiol extracts for epilepsy. Subjects underwent serial blood draws after oral cannabidiol administration. Cannabidiol and metabolites, along with anticonvulsant concentrations were determined., Results: Twenty-nine patients had sufficient pharmacokinetic data and were included in the analysis. Mean age was 9.7 years (standard deviation 4.3) and 17 patients (59%) were male. Median peak plasma cannabidiol concentrations was 13.1 ng/mL (interquartile range 6.8-39.3 ng mL); median time to peak of 2.0 h (interquartile range 2.0-4.0 h). Mean acute elimination half-life of oral cannabidiol was 6.2 h (standard deviation 1.8 h). There was an observed half-life of degradation of 533 days noted for cannabidiol concentrations when stored for 0.6-3.1 years. There was some impact on cannabidiol pharmacokinetic parameters when cannabidiol was co-administered with zonisamide (elimination rate constant and V1) and levetiracetam (elimination rate constant)., Conclusions: In pediatric patients using oral cannabidiol-rich cannabis extract for epilepsy, the time to peak concentration of plasma cannabidiol and average acute elimination half-life were shorter than those reported for adults. Co-administration of zonisamide and levetiracetam had some impact on cannabidiol pharmacokinetic parameters. There was an observed degradation of plasma cannabidiol in long-term storage., Clinical Registration: ClinicalTrials.gov Identifer no. NCT02447198.

Introduction: Acetaminophen protein adducts in the circulation are a specific biomarker of acetaminophen oxidation, and may be a more sensitive measure of impending hepatic injury following overdose than alanine transaminase (ALT). We performed an exploratory analytical substudy of adducts during a clinical trial (NACSTOP) of abbreviated (12-hour) versus control (20-hour) acetylcysteine to identify any signal of diminished antidotal effectiveness with shortened therapy., Methods: We measured adducts at 0, 12, and 20 hours from a convenience sample of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-hour ("abbreviated"; 200 mg/kg over 4 hours, 50 mg/kg over 8 hours) vs 20-hour acetylcysteine regimen ("control"; 200 mg/kg over 4 hours, 100 mg/kg over 16 hours). Adducts were assayed using high-performance liquid chromatography/mass spectrometry., Results: Median ALT 20 hours after the initiation of acetylcysteine was 12 U/L (IQR 8,14) in the abbreviated 12-hour regimen group (N = 8), compared with the control group 16 U/L (IQR 11,21; N = 21) (p = 0.46). Adduct concentrations were similarly low in both groups: abbreviated [(0.005 μmol/L, IQR (0,0.14)] and control [(0.005 μmol/L, IQR (0,0.05)] (p = 0.61)., Conclusions: There were minimal to no acetaminophen protein adducts detected. These findings further support discontinuing acetylcysteine when acetaminophen concentrations are low and liver function tests normal after 12 hours of treatment.

Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke., Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018., Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups., Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo., Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Haloperidol and ketorolac have been recommended as therapies that may decrease opioid use for treatment of pain in emergency department patients. The objective of our study is to determine if administration of haloperidol or ketorolac is associated with lower use of i.v. opioids for patients with non-specific abdominal pain., Methods: A retrospective cohort study of adults (Age 18-60) with non-specific abdominal pain presenting to an emergency department in a large healthcare system. Cases were identified using ICD-10 codes and variables were abstracted from electronic health records. The association between administration of haloperidol or ketorolac with 1) any i.v. opioid administration and 2) receiving >1 dose of i.v. opioids were measured using adjusted odds ratios (AOR) from nominal logistic regression. The model included potential confounders related to both opioid and ketorolac or haloperidol administration., Results: Of 11,688 patients 4091 received one or more doses of an i.v. opioid, 240 received haloperidol and 1788 received ketorolac. The majority of patients were women (67%) and the median age was 32 years. Odds ratios were adjusted for variables associated with opioids, ketorolac or haloperidol use. Haloperidol was not associated with decreased i.v. opioid use (AOR for receiving iv opioids 2.0, 95% CI 1.5 to 2.6) or a lower odds of reciving >1 dose of (AOR 2.0, 95% CI 1.3 to 3.1). Ketorolac was associated with a modest decrease in i.v. opioid use (AOR 0.84 95% CI.0.76 to 0.94 for receiving iv opioids) and a modest decrease for receiving multiple dose of iv opioids (AOR 0.79 95% CI 0.63 to 0.99)., Conclusions: Haloperidol was not associated with decreased i.v. opioid use. Ketorolac was associated with a modest decrease in i.v. opioid use. Providers should consider the use of haloperidol and ketorolac as potentially beneficial in some cases, but there is a need for high quality studies before they can be recommended as standard therapy., Competing Interests: Declaration of Competing Interest No authors have a conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Although over half of US states have legalized marijuana for medical indications, there is limited research in use in the pediatric population. The objective was to evaluate the disposition of oral tetrahydrocannabinol (THC) in children receiving cannabis extracts for pediatric epilepsy. Methods: Prospective, observational study, evaluating the disposition of oral THC in children receiving cannabis extracts. Subjects were less than 18 years of age, receiving oral cannabis for pediatric epilepsy. Subjects included in the study had at least 2 detectable THC and related metabolite plasma concentrations during serial blood draw over a 10-12 h study period. Results: Nine subjects with a median age of 11 years (IQR 4.75) were included in the study, with oral doses ranging from 0.02 mg/kg to 1.59 mg/kg. Peak plasma concentrations (0.8 to 3.6 ng/ml) in most patients were achieved within 2 hours, while acute phase elimination half-life ranged from 1 to 5 hours. THC-COOH and glucuronide remained elevated through the study period. There was significant variation between the dose ingested and peak concentrations (R 2  = 0.05). Conclusion: In pediatric patients receiving oral THC cannabis extracts, mean time to peak plasma concentrations was 2-7 hours, while mean acute phase elimination half-life was 4.0 hours. THC-COOH and THC-COOH glucuronide metabolites persisted throughout the 10-12 hour study period. Large variation and no correlation was noted between dose of THC by weight and peak concentrations, suggesting variation of bioavailability amongst pediatric population or inaccurate reporting of THC contents.

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., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species., Competing Interests: MM, BH, BK, DY, KV, SL, IN, RS, AD, AM, RO, JC, LM, JG, KH, CF, LR, RK, RX, GC, NH, KP, KS No competing interests declared, AM is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and cellular models focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. FG Reviewing editor, eLife, (© 2019, Marchetto et al.)

Objective: To compare self-reported maternal marijuana use with quantitative biological sampling for a marijuana metabolite, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, in umbilical cord homogenate in a state with legalized marijuana., Methods: We conducted a cross-sectional study of women approached at the time of admission for delivery with live, singleton pregnancies at 24 weeks of gestation or greater at two urban medical centers in Colorado. Maternal marijuana use was estimated by 1) report to a health care provider on admission history and physical, 2) survey of self-reported use, and 3) liquid chromatography-tandem mass spectrometry analysis of umbilical cord homogenate for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid. Women were categorized by survey-reported last use (30 days ago or less, 30 days to 1 year, more than 1 year, never) and proportion of women with cord results above the limit of detection and limit of quantification for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid was reported for each group. Comparisons between groups were made using contingency tables. Correlation between survey-reported frequency of use and quantitative 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid cord homogenate results was evaluated., Results: We included 116 women with self-report surveys linked to cord assay results. Six percent (95% CI 2.5-12.0%) of participants reported use in the past 30 days on survey and 2.6% (95% CI 0.5-7.4%) of participants reported marijuana use to health care providers. On umbilical cord assay, 22.4% (95% CI 15.2-31.1%) had detectable 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid. The proportion of women with detectable 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid increased with more recent self-reported use. Survey-reported frequency of use in the past 30 days had moderate correlation with quantified umbilical cord 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (correlation coefficient 0.44, 95% CI 0.28-0.58, P<.001)., Conclusion: Umbilical cord sampling results in higher estimates of prenatal marijuana use than self-report even in the setting of legalization. Umbilical cord assays for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid demonstrate promise for quantifying use. Future studies should examine how the use of biological sampling informs the association between marijuana use and perinatal outcomes.

Purpose: Accurate capture of medication use is important for high quality research. For epidemiologic studies, medication histories are the most common measure of exposure when trying to identify associations between medications and outcomes. Concomitant medications can alter the efficacy or safety of study drugs in clinical trials. However, there are few studies evaluating the accuracy and efficiency of methods to collect these histories. The objective of this study is to compare the accuracy of medication histories collected by structured interview to histories captured using a tablet-based application., Methods: This was a randomized controlled trial. Subjects were instructed to record all prescription medications, non-prescription medications, vitamins, and dietary supplements in a diary for 30 days. At the end of the diary collection, subjects were randomized to providing a medication history during a structured interview by a trained research assistant (MedHAT) or using a tablet-based application (eMedHAT). The accuracy of these histories was compared using an adjusted analysis. We also measured the duration of the history collection and data entry., Results: A total of 111 subjects were in the MedHAT group and 109 subjects were in the eMedHAT group. Recall of medications for the 30-day period was similar for MedHAT and eMedHAT (76.9% versus 75.2%, respectively). The total time required for researchers and subjects for history collection and data entry was 16 minutes shorter for the tablet-based method., Conclusions: Tablet-based medication histories were as accurate as histories obtained by research assistants and required less time for the researcher., (© 2018 John Wiley & Sons, Ltd.)

Emergency and critical care physicians commonly evaluate and treat patients poisoned by acetaminophen. While the basics of management were established in the 1970s, over the past 20 years we have recognized subtleties and variations in presentations that alter the approach to evaluation and treatment. In this paper I will present several cases that illustrate some of the most common variations in presentations of acetaminophen poisoning and offer recommendations for modifi cations of testing and treatment based on several recent studies., (Copyright © 2018 by Taiwan Society of Emergency Medicine & Ainosco Press. All Rights Reserved.)

Context: Serum paracetamol-protein adducts (PPAs) are a novel potential biomarker of paracetamol exposure. The relationship between serum PPA concentrations and reported paracetamol use in ambulatory adults has not been previously described., Materials and Methods: This was a cross-sectional study of ambulatory adults. A detailed medication history was obtained from all subjects and subjects were stratified by reported paracetamol use in the 2 weeks prior to enrolment. Serum PPAs were measured in all subjects and correlated with reported dose, time of last ingestion and demographics., Results: We enrolled 230 in the paracetamol exposure arm and 74 in the no exposure arm. 98/230 (42.6%)of subjects who reported paracetamol exposure had PPA detected and 68/74 (91.9%) of subjects who denied paracetamol exposure had no PPA detected. PPA concentrations were positively correlated with total paracetamol dose and with more recent ingestion., Discussion: Detection of serum PPA generally reflects paracetamol exposure histories in ambulatory adults. Concentrations are well correlated with reported dose and time from last dose., Conclusions: Serum PPA can be detected with reported therapeutic use of paracetamol but may not be detected in all patients who report taking paracetamol.

Background: Pharmacology and toxicology are core content knowledge for physicians. Medical students should demonstrate understanding of general pharmacology and basic treatment of poisoning. The objective of this study was to measure the knowledge of the 4th-year medical students (MS4) on these topics over 3 years., Methods: A multiple-choice exam (15 questions) was administered to MS4 students in spring of 2010, 2011, and 2012. Questions were developed by medical toxicologists to evaluate basic knowledge in three areas: pharmacologic effects (PE), treatment of poisoning (TOP), and pharmacokinetics (PK). The students were grouped by intended specialties into pharmacologic intense (anesthesia, emergency medicine, internal medicine, pediatrics, and psychiatry), less pharmacologic intense specialties (dermatology, OB/GYN, ophthalmology, pathology, physical medicine and rehabilitation, radiology, and surgery) and by completion of a pharmacology or toxicology elective. Mean group scores were compared using ANOVA., Results: Totally 332 of 401 (83%) students completed the survey. Mean scores were stable over the three years, higher for students completing a toxicology rotation and for students entering a pharmacologically intense specialty., Conclusion: The external validity is limited to a single medical school with incomplete participation and content was limited by the survey length. Consistent results over the three-year period and correlation of performance with completing a toxicology rotation and intent to enter a pharmacology intensive specialty suggest this survey may correlate with toxicology knowledge. Implementation of required core courses focused on toxicology may improve core content knowledge in fourth year medical students., Competing Interests: Conflicts of interest: The authors state they have no competing interests.

Background: Mantle-cell lymphoma (MCL) and indolent non-Hodgkin lymphoma (iNHL) are incurable heterogeneous diseases characterized by relapse. There is a need for newer treatments in MCL and iNHL, especially in the relapsed/refractory (R/R) setting. We therefore investigated the novel combination of bortezomib (Velcade), cladribine, and rituximab (VCR) in front-line and R/R settings in MCL and iNHL (NCT00980395)., Patients and Methods: Eligible patients included adults with biopsy-proven CD20-positive MCL and iNHL who met the criteria for treatment. Rituximab 375 mg/m 2 intravenous (IV) day 1, cladribine 4 mg/m 2 IV days 1 to 5, and bortezomib 1.3 mg/m 2 IV days 1 and 4 were administered every 28 days for 6 cycles., Results: Twenty-four patients were enrolled onto the study with a median follow-up of 38.5 months. Median age was 66.5 years, and 46% had MCL. The most common adverse events were hematologic, with febrile neutropenia in 3 patients. Neuropathy was noted in 17% of patients, of which 8% was grade 3 or above. The overall response rate was 92%. For the entire cohort, and for MCL patients, the median progression-free survival and the median overall survival were not reached. The 2-year progression-free survival was 82% for the MCL group and 54% for the iNHL group; it was 80% for treatment-naive patients and 57% for R/R patients., Conclusion: VCR is effective in MCL and iNHL. Although hematologic toxicity can be an issue, this study demonstrates a high response rate to a novel combination and provides an alternative option in transplant-ineligible R/R MCL and iNHL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Radioimmunotherapy (RIT) is effective in treating relapsed/refractory follicular lymphoma (FL), with durable remissions in first-line consolidation. We hypothesized that RIT with ibritumomab tiuxetan (Zevalin®) would result in durable remissions by eliminating minimal residual disease after cytoreduction., Methods: Patients with FL received 2 cycles of ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) every 28 days, followed by Zevalin 4-6 weeks later if there was no disease progression and bone marrow biopsy showed < 25% involvement., Results: Twenty-eight patients were treated, with a median age of 61 years, median of 3 prior therapies, 49% high-risk disease (Follicular Lymphoma International Prognostic Index, FLIPI), and 39% progressive disease. Three patients did not receive Zevalin due to residual bone marrow involvement. The main toxicities were cytopenias, with 11% febrile neutropenia. The overall response rate (ORR) was 72%, with 45% achieving complete response. With a median follow-up of 73 months, 1-year progression-free survival (PFS) was 38%, and median PFS was 10 months, but median overall survival (OS) was not reached., Conclusion: The study did not reach its primary endpoint of a 1-year PFS of 67.3%. Reasons for this could include low accrual, high-risk disease, and inadequate debulking provided by 2 cycles of ESHAP. However, this protocol was associated with tolerable toxicity, high ORR, and high OS. Further studies would optimize debulking and focus on high-risk FL patients., (© 2018 S. Karger AG, Basel.)