A proof-of-concept multi-tiered Bayesian approach for the integration of physiochemical properties and toxicokinetic time-course data for Daphnia magna.

The use of in silico and in vitro methods, commonly referred to as New Approach Methodologies (NAMs), has been proposed to support environmental (and human) chemical safety decisions, ensuring enhanced environmental protection. Toxicokinetic models developed for environmentally relevant species are fundamental to the deployment of a NAMs-based safety strategy, enabling the conversion between external and internal chemical concentrations, although they require historical toxicokinetic data and robust physical models to be considered a viable solution. Daphnia magna is a key model organism in ecotoxicology albeit with limited and scattered quantitative toxicokinetic data, as for most invertebrates, resulting in a lack of robust toxicokinetic models. Moreover, current D. magna models are chemical specific, which restricts their applicability domain. One aim of this study was to address the current data availability limitations by collecting toxicokinetic time-course data for D. magna covering a broad chemical space and assessing the dataset's uniqueness. The collated toxicokinetic dataset included 48 time-courses for 30 chemicals from 17 studies, which was developed into an R package named AquaTK, with 11 studies unique to our work when compared to existing databases. Subsequently, a proof-of-concept Bayesian analysis was developed to estimate the steady-state concentration ratio (internal concentration / external concentration) from the data at three different levels of precision given three different data availability scenarios for environmental risk assessment. Specifically, an atrazine case study illustrates the multi-level modelling approach providing improvements (uncertainty reductions) in predictions of ratios for increasing amounts of data availability. Our work provides a consistent and self-contained Bayesian framework that irrespective of the hierarchy or resolution of individual experiments, can utilise the available information to generate optimal predictions of steady-state concentration ratios in D. magna. This approach is paramount to supporting the implementation of a NAMs based environmental safety paradigm shift in environmental risk assessment.

Comparing Intubation Rates in Patients Receiving Parenteral Olanzapine With and Without a Parenteral Benzodiazepine in the Emergency Department.

STUDY OBJECTIVE: United States prescribing information recommends against coadministration of injectable olanzapine with injectable benzodiazepines due to a risk of cardiorespiratory depression, whereas European prescribing information recommends the 2 drugs not be administered within 60 minutes of each other. In contrast, a recently published American College of Emergency Physicians clinical policy recommends injectable olanzapine and benzodiazepines be coadministered for treating severe agitation. We sought to compare injectable olanzapine with and without injectable benzodiazepines for evidence of cardiorespiratory depression. METHODS: We performed a retrospective study of patients in an urban emergency department from January 2017 through November 2019 who received parenteral olanzapine with or without parenteral benzodiazepines. We included patients receiving 2 total medication doses, either olanzapine+benzodiazepine or 2 doses of olanzapine, coadministered within 60 minutes. The primary outcome was tracheal intubation in the emergency department. Secondary outcomes included hypotension (systolic blood pressure less than 90 mmHg) and hypoxemia (SpO2 less than 90%). RESULTS: We identified 693 patients (median [alcohol]=210 mg/dL, median age=37 years [IQR 29 to 49]). In total, 549 received 2 doses of olanzapine, and 144 patients received olanzapine and a benzodiazepine. We found no difference in intubation rates between the olanzapine-only group (21/549, 3.8%) and the olanzapine+benzodiazepine group (5/144, 3.5%; difference=0.3%, 95% confidence interval -3.0% to 3.7%). Rates of hypoxemia (2% olanzapine-only and 3% olanzapine+benzodiazepine) and hypotension (9% both groups) also were not different between groups. CONCLUSION: We found no difference in cardiorespiratory depression between patients receiving only olanzapine versus olanzapine plus a benzodiazepine.

Can the global marine aquarium trade (MAT) be a model for sustainable coral reef fisheries?

Globally, 6 million coral reef fishers provide ~25% of emergent countries' catch, but species have low value. The marine aquarium trade (MAT) targets high-value biodiversity, but missing data amplify draconian governance and demand for international prohibition. To stimulate sustainability and reef conservation investment, we generate a fiscal baseline using the first global analysis of numbers, diversity, and biomass of MAT-traded organisms. Each year, ~55 million organisms worth US$2.15 billion at retail are traded comparable with major fisheries, e.g., tuna. A sustainable MAT also requires overexploitation assessments. We identify 25 species/genera with "Extremely High" risk ratios and place the Indonesian and Sulu-Celebes Seas in the highest exploitation category. Despite predicted hobbyist number increases, unabated reef degradation and low governance will transform the MAT into an aquaculture-dominated industry decoupled from communities (i.e., culture located in importing countries). A "MAT-positive" future requires evidence-based management/governance, consumer education, and sustainable practice incentivization but can address the biodiversity and social and economic inequality crises.

Verification of In Vivo Estrogenic Activity for Four Per- and Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists via New Approach Methodologies.

Given concerns about potential toxicological hazards of the thousands of data-poor per- and polyfluorinated alkyl substances (PFAS) currently in commerce and detected in the environment, tiered testing strategies that employ high-throughput in vitro screening as an initial testing tier have been implemented. The present study evaluated the effectiveness of previous in vitro screening for identifying PFAS capable, or incapable, of inducing estrogenic responses in fish exposed in vivo. Fathead minnows (Pimephales promelas) were exposed for 96 h to five PFAS (perfluorooctanoic acid [PFOA]; 1H,1H,8H,8H-perfluorooctane-1,8-diol [FC8-diol]; 1H,1H,10H,10H-perfluorodecane-1,10-diol [FC10-diol]; 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol [FC8-DOD]; and perfluoro-2-methyl-3-oxahexanoic acid [HFPO-DA]) that showed varying levels of in vitro estrogenic potency. In agreement with in vitro screening results, exposure to FC8-diol, FC10-diol, and FC8-DOD caused concentration-dependent increases in the expression of transcript coding for vitellogenin and estrogen receptor alpha and reduced expression of insulin-like growth factor and apolipoprotein eb. Once differences in bioconcentration were accounted for, the rank order of potency in vivo matched that determined in vitro. These results provide a screening level benchmark for worst-case estimates of potential estrogenic hazards of PFAS and a basis for identifying structurally similar PFAS to scrutinize for putative estrogenic activity.

First attempt success with continued versus paused chest compressions during cardiac arrest in the emergency department.

AIM: Tracheal intubation is associated with interruption in cardiopulmonary resuscitation (CPR). Current knowledge of tracheal intubation during active CPR focuses on the out-of-hospital environment. We aim to describe characteristics of tracheal intubation during active CPR in the emergency department (ED) and determine whether first attempt success was associated with CPR being continued vs paused. MEASUREMENTS: We reviewed overhead video from adult ED patients receiving chest compressions at the start of the orotracheal intubation attempt. We recorded procedural detail including method of CPR, whether CPR was continued vs paused, and first attempt intubation success (primary outcome). We performed logistic regression to determine whether continuing CPR was associated with first attempt success. RESULTS: We reviewed 169 instances of tracheal intubation, including 143 patients with continued CPR and 26 patients with paused CPR. Those with paused CPR were more likely to be receiving manual rather than mechanical chest compressions. Video laryngoscopy and bougie use were common. First attempt success was higher in the continued CPR group (87%, 95% CI 81% to 92%) than the interrupted CPR group (65%, 95% CI 44% to 83%, difference 22% [95% CI 3% to 41%]). The multivariable model demonstrated an adjusted odds ratio of 0.67 (95% CI 0.17 to 2.60) for first attempt intubation success when CPR was interrupted vs continued. CONCLUSIONS: It was common to continue CPR during tracheal intubation, with success comparable to that achieved in patients without cardiac arrest. It is reasonable to attempt tracheal intubation without interrupting CPR, pausing only if necessary.

Intramuscular Midazolam, Olanzapine, Ziprasidone, or Haloperidol for Treating Acute Agitation in the Emergency Department.

STUDY OBJECTIVE: Agitation in the emergency department (ED) can pose a threat to patient and provider safety; therefore, treatment is indicated. The purpose of this study is to compare haloperidol, olanzapine, midazolam, and ziprasidone to treat agitation. METHODS: This was a prospective observational study of consecutive patients receiving intramuscular medication to treat agitation in the ED. Medications were administered according to an a priori protocol in which the initial medication given was predetermined in the following 3-week blocks: haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, and haloperidol 10 mg. The primary outcome was the proportion of patients adequately sedated at 15 minutes, assessed with the Altered Mental Status Scale. RESULTS: Seven hundred thirty-seven patients were enrolled (median age 40 years; 72% men). At 15 minutes, midazolam resulted in a greater proportion of patients adequately sedated (Altered Mental Status Scale <1) compared with ziprasidone (difference 18%; 95% confidence interval [CI] 6% to 29%), haloperidol 5 mg (difference 30%; 95% CI 19% to 41%), haloperidol 10 mg (difference 28%; 95% CI 17% to 39%), and olanzapine (difference 9%; 95% CI -1% to 20%). Olanzapine resulted in a greater proportion of patients adequately sedated at 15 minutes compared with haloperidol 5 mg (difference 20%; 95% CI 10% to 31%), haloperidol 10 mg (difference 18%; 95% CI 7% to 29%), and ziprasidone (difference 8%; 95% CI -3% to 19%). Adverse events were uncommon: cardiac arrest (0), extrapyramidal adverse effects (2; 0.3%), hypotension (5; 0.5%), hypoxemia (10; 1%), and intubation (4; 0.5%), and occurred at similar rates in each group. CONCLUSION: Intramuscular midazolam achieved more effective sedation in agitated ED patients at 15 minutes than haloperidol, ziprasidone, and perhaps olanzapine. Olanzapine provided more effective sedation than haloperidol. No differences in adverse events were identified.

Multicolored Asian lady beetle hypersensitivity: a case series and allergist survey.

BACKGROUND: Multicolored Asian lady beetles (Harmonia axyridis) have been used as a biological control agent against crop-destroying aphids in the United States. Outside their natural habitat, H. axyridis seeks refuge in homes during fall and winter, leading to patient complaints and symptoms of rhinitis, wheezing, and urticaria on exposure to the beetles. OBJECTIVE: To gain a better understanding of the character and spectrum of allergic disease provoked by exposure to home-infesting lady beetles. METHODS: Eight patients with allergic symptoms suspected of being caused by H. axyridis and consistent with an IgE-mediated process were identified and interviewed. A whole-body extract from H. axyridis was prepared. Western blots using the patients' serum identified specific IgE antibodies in the extract. Through a novel technique, immunohistochemical analysis using beetle sections overlayed with patient serum was performed. A random survey of allergists from across the United States was also performed to evaluate experience with cases of lady beetle allergy. RESULTS: Western blots revealed IgE binding to 5 proteins with molecular weights of approximately 8.6, 21, 28, 31, and 75 kDa. Specific IgE bound to proteins localized in the beetle's mouth and leg areas. The allergist survey revealed positive responses in North Central, Mid-Atlantic and New England states. CONCLUSION: In 8 patients with allergic symptoms on exposure to high levels of lady beetles, specific IgE bound to proteins from H. axyridis. There was also an increased frequency of suspected cases of lady beetle allergy in endemic areas.