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Introduction: Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes., Methods: This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours., Results: Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell's vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference -0.4, 95% CI, -0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred., Conclusion: For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background and Significance: Positron Emission Tomography (PET) using fluorodeoxyglucose (FDG-PET) is a standard imaging modality for detecting areas of hypometabolism associated with the seizure onset zone (SOZ) in temporal lobe epilepsy (TLE). However, FDG-PET is costly and involves the use of a radioactive tracer. Arterial Spin Labeling (ASL) offers an MRI-based quantification of cerebral blood flow (CBF) that could also help localize the SOZ, but its performance in doing so, relative to FDG-PET, is limited. In this study, we seek to improve ASL's diagnostic performance by developing a deep learning framework for synthesizing FDG-PET-like images from ASL and structural MRI inputs., Methods: We included 68 epilepsy patients, out of which 36 had well lateralized TLE. We compared the coupling between FDG-PET and ASL CBF values in different brain regions, as well as the asymmetry of these values across the brain. We additionally assessed each modality's ability to lateralize the SOZ across brain regions. Using our paired PET-ASL data, we developed FlowGAN, a generative adversarial neural network (GAN) that synthesizes PET-like images from ASL and T1-weighted MRI inputs. We tested our synthetic PET images against the actual PET images of subjects to assess their ability to reproduce clinically meaningful hypometabolism and asymmetries in TLE., Results: We found variable coupling between PET and ASL CBF values across brain regions. PET and ASL had high coupling in neocortical temporal and frontal brain regions (Spearman's r > 0.30, p < 0.05) but low coupling in mesial temporal structures (Spearman's r < 0.30, p > 0.05). Both whole brain PET and ASL CBF asymmetry values provided good separability between left and right TLE subjects, but PET (AUC = 0.96, 95% CI: [0.88, 1.00]) outperformed ASL (AUC = 0.81; 95% CI: [0.65, 0.96]). FlowGAN-generated images demonstrated high structural similarity to actual PET images (SSIM = 0.85). Globally, asymmetry values were better correlated between synthetic PET and original PET than between ASL CBF and original PET, with a mean correlation increase of 0.15 (95% CI: [0.07, 0.24], p <0.001, Cohen's d = 0.91). Furthermore, regions that had poor ASL-PET correlation (e.g. mesial temporal structures) showed the greatest improvement with synthetic PET images., Conclusions: FlowGAN improves ASL's diagnostic performance, generating synthetic PET images that closely mimic actual FDG-PET in depicting hypometabolism associated with TLE. This approach could improve non-invasive SOZ localization, offering a promising tool for epilepsy presurgical assessment. It potentially broadens the applicability of ASL in clinical practice and could reduce reliance on FDG-PET for epilepsy and other neurological disorders., Competing Interests: Competing Interests Thomas Campbell Arnold is an employee of Subtle Medical, but this work is unrelated to his work at the company. He contributed to this work during his time at the University of Pennsylvania. The rest of the authors report no competing or financial interests.

Background: Portable low-field-strength magnetic resonance imaging (MRI) systems represent a promising alternative to traditional high-field-strength systems with the potential to make MR technology available at scale in low-resource settings. However, lower image quality and resolution may limit the research and clinical potential of these devices. We tested two super-resolution methods to enhance image quality in a low-field MR system and compared their correspondence with images acquired from a high-field system in a sample of young people., Methods: T1- and T2-weighted structural MR images were obtained from a low-field (64mT) Hyperfine and high-field (3T) Siemens system in N  = 70 individuals (mean age = 20.39 years, range 9-26 years). We tested two super-resolution approaches to improve image correspondence between images acquired at high- and low-field: (1) processing via a convolutional neural network ('SynthSR'), and (2) multi-orientation image averaging. We extracted brain region volumes, cortical thickness, and cortical surface area estimates. We used Pearson correlations to test the correspondence between these measures, and Steiger Z tests to compare the difference in correspondence between standard imaging and super-resolution approaches., Results: Single pairs of T1- and T2-weighted images acquired at low field showed high correspondence to high-field-strength images for estimates of total intracranial volume, surface area cortical volume, subcortical volume, and total brain volume ( r range = 0.60-0.88). Correspondence was lower for cerebral white matter volume ( r  = 0.32, p  = 0.007, q  = 0.009) and non-significant for mean cortical thickness ( r  = -0.05, p  = 0.664, q  = 0.664). Processing images with SynthSR yielded significant improvements in correspondence for total brain volume, white matter volume, total surface area, subcortical volume, cortical volume, and total intracranial volume ( r range = 0.85-0.97), with the exception of global mean cortical thickness ( r  = 0.14). An alternative multi-orientation image averaging approach improved correspondence for cerebral white matter and total brain volume. Processing with SynthSR also significantly improved correspondence across widespread regions for estimates of cortical volume, surface area and subcortical volume, as well as within isolated prefrontal and temporal regions for estimates of cortical thickness., Conclusion: Applying super-resolution approaches to low-field imaging improves regional brain volume and surface area accuracy in young people. Finer-scale brain measurements, such as cortical thickness, remain challenging with the limited resolution of low-field systems., Competing Interests: TA is an employee of Subtle Medical. JS has received support through sponsored-research agreements with Hyperfine Research, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cooper, Hayes, Corcoran, Sheth, Arnold, Stein, Glahn and Jalbrzikowski.)

Objective: Epilepsy surgery is an effective treatment for drug-resistant patients. However, how different surgical approaches affect long-term brain structure remains poorly characterized. Here, we present a semiautomated method for quantifying structural changes after epilepsy surgery and compare the remote structural effects of two approaches, anterior temporal lobectomy (ATL), and selective amygdalohippocampectomy (SAH)., Methods: We studied 36 temporal lobe epilepsy patients who underwent resective surgery (ATL = 22, SAH = 14). All patients received same-scanner MR imaging preoperatively and postoperatively (mean 2 years). To analyze postoperative structural changes, we segmented the resection zone and modified the Advanced Normalization Tools (ANTs) longitudinal cortical pipeline to account for resections. We compared global and regional annualized cortical thinning between surgical treatments., Results: Across procedures, there was significant cortical thinning in the ipsilateral insula, fusiform, pericalcarine, and several temporal lobe regions outside the resection zone as well as the contralateral hippocampus. Additionally, increased postoperative cortical thickness was seen in the supramarginal gyrus. Patients treated with ATL exhibited greater annualized cortical thinning compared with SAH cases (ATL: -0.08 ± 0.11 mm per year, SAH: -0.01 ± 0.02 mm per year, t = 2.99, P = 0.006). There were focal postoperative differences between the two treatment groups in the ipsilateral insula (P = 0.039, corrected). Annualized cortical thinning rates correlated with preoperative cortical thickness (r = 0.60, P < 0.001) and had weaker associations with age at surgery (r = -0.33, P = 0.051) and disease duration (r = -0.42, P = 0.058)., Significance: Our evidence suggests that selective procedures are associated with less cortical thinning and that earlier surgical intervention may reduce long-term impacts on brain structure., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Modern MRI scanners have trended toward higher field strengths to maximize signal and resolution while minimizing scan time. However, high-field devices remain expensive to install and operate, making them scarce outside of high-income countries and major population centers. Low-field strength scanners have drawn renewed academic, industry, and philanthropic interest due to advantages that could dramatically increase imaging access, including lower cost and portability. Nevertheless, low-field MRI still faces inherent limitations in image quality that come with decreased signal. In this article, we review advantages and disadvantages of low-field MRI scanners, describe hardware and software innovations that accentuate advantages and mitigate disadvantages, and consider clinical applications for a new generation of low-field devices. In our review, we explore how these devices are being or could be used for high acuity brain imaging, outpatient neuroimaging, MRI-guided procedures, pediatric imaging, and musculoskeletal imaging. Challenges for their successful clinical translation include selecting and validating appropriate use cases, integrating with standards of care in high resource settings, expanding options with actionable information in low resource settings, and facilitating health care providers and clinical practice in new ways. By embracing both the promise and challenges of low-field MRI, clinicians and researchers have an opportunity to transform medical care for patients around the world. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 6., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Assessment of immune-cell subsets within the tumor immune microenvironment is a powerful approach to better understand cancer immunotherapy responses. However, the use of biopsies to assess the tumor immune microenvironment poses challenges, including the potential for sampling error, restricted sampling over time, and inaccessibility of some tissues/organs, as well as the fact that single biopsy analyses do not reflect discordance across multiple intrapatient tumor lesions. Immuno-positron emission tomography (PET) presents a promising translational imaging approach to address the limitations and assess changes in the tumor microenvironment. We have developed 89Zr-DFO-REGN5054, a fully human CD8A-specific antibody conjugate, to assess CD8+ tumor-infiltrating lymphocytes (TIL) pre- and posttherapy. We used multiple assays, including in vitro T-cell activation, proliferation, and cytokine production, and in vivo viral clearance and CD8 receptor occupancy, to demonstrate that REGN5054 has minimal impact on T-cell activity. Preclinical immuno-PET studies demonstrated that 89Zr-DFO-REGN5054 specifically detected CD8+ T cells in lymphoid tissues of CD8-genetically humanized immunocompetent mice (VelociT mice) and discerned therapy-induced changes in CD8+ TILs in two models of response to a CD20xCD3 T-cell activating bispecific antibody (REGN1979, odronextamab). Toxicology studies in cynomolgus monkeys showed no overt toxicity, and immuno-PET imaging in cynomolgus monkeys demonstrated dose-dependent clearance and specific targeting to lymphoid tissues. This work supports the clinical investigation of 89Zr-DFO-REGN5054 to monitor T-cell responses in patients undergoing cancer immunotherapy., (©2022 American Association for Cancer Research.)

Brain maps, or atlases, are essential tools for studying brain function and organization. The abundance of available atlases used across the neuroscience literature, however, creates an implicit challenge that may alter the hypotheses and predictions we make about neurological function and pathophysiology. Here, we demonstrate how parcellation scale, shape, anatomical coverage, and other atlas features may impact our prediction of the brain's function from its underlying structure. We show how network topology, structure-function correlation (SFC), and the power to test specific hypotheses about epilepsy pathophysiology may change as a result of atlas choice and atlas features. Through the lens of our disease system, we propose a general framework and algorithm for atlas selection. This framework aims to maximize the descriptive, explanatory, and predictive validity of an atlas. Broadly, our framework strives to provide empirical guidance to neuroscience research utilizing the various atlases published over the last century., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Planning surgery for patients with medically refractory epilepsy often requires recording seizures using intracranial EEG. Quantitative measures derived from interictal intracranial EEG yield potentially appealing biomarkers to guide these surgical procedures; however, their utility is limited by the sparsity of electrode implantation as well as the normal confounds of spatiotemporally varying neural activity and connectivity. We propose that comparing intracranial EEG recordings to a normative atlas of intracranial EEG activity and connectivity can reliably map abnormal regions, identify targets for invasive treatment and increase our understanding of human epilepsy. Merging data from the Penn Epilepsy Center and a public database from the Montreal Neurological Institute, we aggregated interictal intracranial EEG retrospectively across 166 subjects comprising >5000 channels. For each channel, we calculated the normalized spectral power and coherence in each canonical frequency band. We constructed an intracranial EEG atlas by mapping the distribution of each feature across the brain and tested the atlas against data from novel patients by generating a z-score for each channel. We demonstrate that for seizure onset zones within the mesial temporal lobe, measures of connectivity abnormality provide greater distinguishing value than univariate measures of abnormal neural activity. We also find that patients with a longer diagnosis of epilepsy have greater abnormalities in connectivity. By integrating measures of both single-channel activity and inter-regional functional connectivity, we find a better accuracy in predicting the seizure onset zones versus normal brain (area under the curve = 0.77) compared with either group of features alone. We propose that aggregating normative intracranial EEG data across epilepsy centres into a normative atlas provides a rigorous, quantitative method to map epileptic networks and guide invasive therapy. We publicly share our data, infrastructure and methods, and propose an international framework for leveraging big data in surgical planning for refractory epilepsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The purpose of this study is to demonstrate a method for virtually evaluating novel imaging devices using machine learning and open-access datasets, here applied to a new, low-field strength portable 64mT MRI device. Paired 3 T and 64mT brain images were used to develop and validate a transformation converting standard clinical images to low-field quality images. Separately, 3 T images were aggregated from open-source databases spanning four neuropathologies: low-grade glioma (LGG, N = 76), high-grade glioma (HGG, N = 259), stroke (N = 28), and multiple sclerosis (MS, N = 20). The transformation method was then applied to the open-source data to generate simulated low-field images for each pathology. Convolutional neural networks (DenseNet-121) were trained to detect pathology in axial slices from either 3 T or simulated 64 mT images, and their relative performance was compared to characterize the potential diagnostic capabilities of low-field imaging. Algorithm performance was measured using area under the receiver operating characteristic curve. Across all cohorts, pathology detection was similar between 3 T and simulated 64mT images (LGG: 0.97 vs. 0.98; HGG: 0.96 vs. 0.95; stroke: 0.94 vs. 0.94; MS: 0.90 vs 0.87). Pathology detection was further characterized as a function of lesion size, intensity, and contrast. Simulated images showed decreasing sensitivity for lesions smaller than 4 cm 2 . While simulations cannot replace prospective trials during the evaluation of medical devices, they can provide guidance and justification for prospective studies. Simulated data derived from open-source imaging databases may facilitate testing and validation of new imaging devices., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to declare.

Magnetic resonance imaging (MRI) is a fundamental tool in the diagnosis and management of neurological diseases such as multiple sclerosis (MS). New portable, low-field strength, MRI scanners could potentially lower financial and technical barriers to neuroimaging and reach underserved or disabled populations, but the sensitivity of these devices for MS lesions is unknown. We sought to determine if white matter lesions can be detected on a portable 64mT scanner, compare automated lesion segmentations and total lesion volume between paired 3T and 64mT scans, identify features that contribute to lesion detection accuracy, and explore super-resolution imaging at low-field. In this prospective, cross-sectional study, same-day brain MRI (FLAIR, T1w, and T2w) scans were collected from 36 adults (32 women; mean age, 50 ± 14 years) with known or suspected MS using Siemens 3T (FLAIR: 1 mm isotropic, T1w: 1 mm isotropic, and T2w: 0.34-0.5 × 0.34-0.5 × 3-5 mm) and Hyperfine 64mT (FLAIR: 1.6 × 1.6 × 5 mm, T1w: 1.5 × 1.5 × 5 mm, and T2w: 1.5 × 1.5 × 5 mm) scanners at two centers. Images were reviewed by neuroradiologists. MS lesions were measured manually and segmented using an automated algorithm. Statistical analyses assessed accuracy and variability of segmentations across scanners and systematic scanner biases in automated volumetric measurements. Lesions were identified on 64mT scans in 94% (31/33) of patients with confirmed MS. The average smallest lesions manually detected were 5.7 ± 1.3 mm in maximum diameter at 64mT vs 2.1 ± 0.6 mm at 3T, approaching the spatial resolution of the respective scanner sequences (3T: 1 mm, 64mT: 5 mm slice thickness). Automated lesion volume estimates were highly correlated between 3T and 64mT scans (r = 0.89, p < 0.001). Bland-Altman analysis identified bias in 64mT segmentations (mean = 1.6 ml, standard error = 5.2 ml, limits of agreement = -19.0-15.9 ml), which over-estimated low lesion volume and under-estimated high volume (r = 0.74, p < 0.001). Visual inspection revealed over-segmentation was driven venous hyperintensities on 64mT T2-FLAIR. Lesion size drove segmentation accuracy, with 93% of lesions > 1.0 ml and all lesions > 1.5 ml being detected. Using multi-acquisition volume averaging, we were able to generate 1.6 mm isotropic images on the 64mT device. Overall, our results demonstrate that in established MS, a portable 64mT MRI scanner can identify white matter lesions, and that automated estimates of total lesion volume correlate with measurements from 3T scans., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The rise of the platform economy in the past two decades (and neoliberal capitalist expansion and crises more in general), have on the whole negatively affected working conditions, leading to growing concerns about the "human side" of organizations. To address these concerns, the purpose of this paper is to apply Axel Honneth's recognition theory and method of normative reconstruction to working conditions in the platform economy. The paper concludes that the ways in which platform organizations function constitutes a normative paradox, promising flexibility and autonomy while at the same time creating working conditions that undercut these promises. The paper ends with a critical discussion of Honneth's approach, possible supplementing ideas and further lines of future research., Competing Interests: Conflicts of Interest/Competing InterestsNot applicable., (© The Author(s) 2021, corrected publication 2021.)

Accurate segmentation of surgical resection sites is critical for clinical assessments and neuroimaging research applications, including resection extent determination, predictive modeling of surgery outcome, and masking image processing near resection sites. In this study, an automated resection cavity segmentation algorithm is developed for analyzing postoperative MRI of epilepsy patients and deployed in an easy-to-use graphical user interface (GUI) that estimates remnant brain volumes, including postsurgical hippocampal remnant tissue. This retrospective study included postoperative T1-weighted MRI from 62 temporal lobe epilepsy (TLE) patients who underwent resective surgery. The resection site was manually segmented and reviewed by a neuroradiologist (JMS). A majority vote ensemble algorithm was used to segment surgical resections, using 3 U-Net convolutional neural networks trained on axial, coronal, and sagittal slices, respectively. The algorithm was trained using 5-fold cross validation, with data partitioned into training (N = 27) testing (N = 9), and validation (N = 9) sets, and evaluated on a separate held-out test set (N = 17). Algorithm performance was assessed using Dice-Sørensen coefficient (DSC), Hausdorff distance, and volume estimates. Additionally, we deploy a fully-automated, GUI-based pipeline that compares resection segmentations with preoperative imaging and reports estimates of resected brain structures. The cross-validation and held-out test median DSCs were 0.84 ± 0.08 and 0.74 ± 0.22 (median ± interquartile range) respectively, which approach inter-rater reliability between radiologists (0.84-0.86) as reported in the literature. Median 95 % Hausdorff distances were 3.6 mm and 4.0 mm respectively, indicating high segmentation boundary confidence. Automated and manual resection volume estimates were highly correlated for both cross-validation (r = 0.94, p < 0.0001) and held-out test subjects (r = 0.87, p < 0.0001). Automated and manual segmentations overlapped in all 62 subjects, indicating a low false negative rate. In control subjects (N = 40), the classifier segmented no voxels (N = 33), <50 voxels (N = 5), or a small volumes<0.5 cm 3 (N = 2), indicating a low false positive rate that can be controlled via thresholding. There was strong agreement between postoperative hippocampal remnant volumes determined using automated and manual resection segmentations (r = 0.90, p < 0.0001, mean absolute error = 6.3 %), indicating that automated resection segmentations can permit quantification of postoperative brain volumes after epilepsy surgery. Applications include quantification of postoperative remnant brain volumes, correction of deformable registration, and localization of removed brain regions for network modeling., Competing Interests: Declaration of Competing 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain network models derived from graph theory have the potential to guide functional neurosurgery, and to improve rates of post-operative seizure freedom for patients with epilepsy. A barrier to applying these models clinically is that intracranial EEG electrode implantation strategies vary by centre, region and country, from cortical grid & strip electrodes (Electrocorticography), to purely stereotactic depth electrodes (Stereo EEG), to a mixture of both. To determine whether models derived from one type of study are broadly applicable to others, we investigate the differences in brain networks mapped by electrocorticography and stereo EEG in a cohort of patients who underwent surgery for temporal lobe epilepsy and achieved a favourable outcome. We show that networks derived from electrocorticography and stereo EEG define distinct relationships between resected and spared tissue, which may be driven by sampling bias of temporal depth electrodes in patients with predominantly cortical grids. We propose a method of correcting for the effect of internodal distance that is specific to electrode type and explore how additional methods for spatially correcting for sampling bias affect network models. Ultimately, we find that smaller surgical targets tend to have lower connectivity with respect to the surrounding network, challenging notions that abnormal connectivity in the epileptogenic zone is typically high. Our findings suggest that effectively applying computational models to localize epileptic networks requires accounting for the effects of spatial sampling, particularly when analysing both electrocorticography and stereo EEG recordings in the same cohort, and that future network studies of epilepsy surgery should also account for differences in focality between resection and ablation. We propose that these findings are broadly relevant to intracranial EEG network modelling in epilepsy and an important step in translating them clinically into patient care., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies including cemiplimab have generated profound clinical activity across diverse cancer types. Tumorous PD-L1 expression, as assessed by immunohistochemistry (IHC), is an accepted predictive marker of response to therapy in some cancers. However, expression is often dynamic and heterogeneous, and therefore not reliably captured by IHC from tumor biopsies or archival samples. Thus, there is significant need for accurate whole-body quantification of PD-L1 levels., Methods: We radiolabeled the novel human anti-PD-L1 antibody REGN3504 with zirconium-89 ( 89 Zr) using the chelator p-SCN-Bn-Deferoxamine to enable non-invasive immuno-positron emission tomography (immuno-PET) of PD-L1 expression. PET imaging assessed the localization of 89 Zr-REGN3504 to multiple human tumor xenografts. Mice genetically humanized for PD-1 and PD-L1 were used to assess the biodistribution of 89 Zr-REGN3504 to normal tissues and the estimated human radiation dosimetry of 89 Zr-REGN3504 was also determined. Pharmacokinetics of REGN3504 was assessed in monkeys., Results: Clear localization of 89 Zr-REGN3504 to human tumor xenografts was observed via PET imaging and ex vivo biodistribution studies demonstrated high (fourfold to sixfold) tumor:blood ratios. 89 Zr-REGN3504 specifically localized to spleen and lymph nodes in the PD-1/PD-L1 humanized mice. 89 Zr-REGN3504 immuno-PET accurately detected a significant reduction in splenic PD-L1 positive cells following systemic treatment with clodronate liposomes. Radiation dosimetry suggested absorbed doses would be within guidelines for other 89 Zr radiolabeled, clinically used antibodies. Pharmacokinetics of REGN3504 was linear., Conclusion: This work supports the clinical translation of 89 Zr-REGN3504 immuno-PET for the assessment of PD-L1 expression. Future clinical studies will aim to investigate the utility of 89 Zr-REGN3504 immuno-PET for predicting and monitoring response to anti-PD-1 therapy., Competing Interests: Competing interests: We have no conflicts of interests to disclose, other than our employment at Regeneron Pharmaceuticals., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The olfactory system is uniquely heterogeneous, performing multifaceted functions (beyond basic sensory processing) across diverse, widely distributed neural substrates. While knowledge of human olfaction continues to grow, it remains unclear how the olfactory network is organized to serve this unique set of functions. Leveraging a large and high-quality resting-state functional magnetic resonance imaging (rs-fMRI) dataset of nearly 900 participants from the Human Connectome Project (HCP), we identified a human olfactory network encompassing cortical and subcortical regions across the temporal and frontal lobes. Highlighting its reliability and generalizability, the connectivity matrix of this olfactory network mapped closely onto that extracted from an independent rs-fMRI dataset. Graph theoretical analysis further explicated the organizational principles of the network. The olfactory network exhibits a modular composition of three (i.e., the sensory, limbic, and frontal) subnetworks and demonstrates strong small-world properties, high in both global integration and local segregation (i.e., circuit specialization). This network organization thus ensures the segregation of local circuits, which are nonetheless integrated via connecting hubs [i.e., amygdala (AMY) and anterior insula (INSa)], thereby enabling the specialized, yet integrative, functions of olfaction. In particular, the degree of local segregation positively predicted olfactory discrimination performance in the independent sample, which we infer as a functional advantage of the network organization. In sum, an olfactory functional network has been identified through the large HCP dataset, affording a representative template of the human olfactory functional neuroanatomy. Importantly, the topological analysis of the olfactory network provides network-level insights into the remarkable functional specialization and spatial segregation of the olfactory system., (Copyright © 2020 Arnold et al.)

Background: Moral distress has detrimental effects on nurses which impacts the entire healthcare cycle. Described as a crescendo effect, resolved situations of moral distress leave residue on the nurse with three potential outcomes: moral numbing, conscious objection to the situation, and burnout., Objective: This metaethnography strives to achieve a fuller understanding of moral distress by interpreting the body of qualitative work of moral distress in emergency and critical care nurses., Method: This study used the Noblit and Hare's approach of interpretative synthesis. Ten studies met the criteria and were used in this synthesis., Ethical Considerations: Ethical issues were minimal since no human subjects were involved. Ethical requirements were respected in all study phases., Results: The synthesis of qualitative research on moral distress resulted in one central theme, "the battle within," and five subthemes., Conclusions: The unique nature of this nursing specialty resulted in a lasting inner conflict for nurses that is consistent with the previously described crescendo effect. The effects are complex and long lasting and may potentially affect the nurses' future patient care.

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.)

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

Background: Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation., Methods: We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm(3), fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8., Results: 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness., Conclusions: In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

Background: Few studies have evaluated the effect of Emergency Department (ED) overcrowding on resident education., Objectives: To determine the impact of ED overcrowding on Emergency Medicine (EM) resident education., Materials and Methods: A prospective cross-sectional study was performed from March to May 2009. Second- and third-year EM residents, blinded to the research objective, completed a questionnaire at the end of each shift. Residents were asked to evaluate the educational quality of each shift using a 10-point Likert scale. Number of patients seen and procedures completed were recorded. Responses were divided into ED overcrowding (group O) and non-ED overcrowding (group N) groups. ED overcrowding was defined as >2 h of ambulance diversion per shift. Questionnaire responses were compared using Mann-Whitney U tests. Number of patients and procedures were compared using unpaired T-tests., Results: During the study period, 125 questionnaires were completed; 54 in group O and 71 in group N. For group O, the median educational value score was 8 (interquartile range [IQR] 7-10), compared to 8 (IQR 8-10) for group N (p = 0.24). Mean number of patients seen in group O was 12.3 (95% confidence interval [CI] 11.4-13.2), compared to 13.9 (95% CI 12.7-15) in group N (p = 0.034). In group O, mean number of procedures was 0.9 (95% CI 0.6-1.2), compared to 1.3 (95% CI 1-1.6) in group N (p = 0.047)., Conclusions: During overcrowding, EM residents saw fewer patients and performed fewer procedures. However, there was no significant difference in resident perception of educational value during times of overcrowding vs. non-overcrowding., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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

Objective: The objective of the study was to determine if the short-axis approach and long-axis approach to ultrasound-guided peripheral intravenous access (USGPIV) differ in success rate, catheter insertion time, and number of needle sticks., Methods: A convenience sample of emergency department patients aged 18 to 65 years with difficult IV access (2 or more failed landmark attempts) was prospectively randomized to short-axis or long-axis USGPIV. Time from skin puncture to catheter insertion (insertion time) and number of needle sticks were recorded. Number of needle sticks and insertion time were compared using Mann-Whitney U tests., Results: Forty subjects were enrolled; 20 were randomized to the short-axis and 20 to the long-axis approach. Success rate was 95% (19/20; 95% confidence interval, 85%-100%) in the short-axis group compared with 85% (17/20; 95% confidence interval, 69%-100%) in the long-axis group. All 3 subjects with failed IV placement in the long-axis group had successful rescue USGPIV placement in short axis. Median insertion time was 34 seconds (interquartile range, 35 seconds) for the short-axis group compared with 91 seconds (interquartile range, 59 seconds) for the long-axis group (P = .02). Mean number of needle sticks was 1.5 (±SD 0.7) in the short-axis group compared with 1.4 (±SD 0.7) in the long-axis group (P = .82)., Conclusions: Short-axis USGPIV technique required less insertion time than the long-axis technique. Success rate was higher in the short-axis group, but this difference was not statistically significant. However, all of the failed IVs in the long axis were rescued successfully in short axis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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

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

Context: Teaching 12-lead electrocardiogram (ECG) interpretation to students and residents is a challenge for medical educators. To date, few studies have compared the effectiveness of different techniques used for ECG teaching., Objectives: This study aimed to determine if common teaching techniques, such as those involving workshops, lectures and self-directed learning (SDL), increase medical students' ability to correctly interpret ECGs. It also aimed to compare the effectiveness of these formats., Methods:   This was a prospective randomised study conducted over a 28-month period. Year 4 medical students were randomised to receive teaching in ECG interpretation using one of three teaching formats: workshop, lecture or SDL. All three formats covered the same content. Students were administered three tests: a pre-test (before teaching); a post-test (immediately after teaching), and a retention test (1 week after teaching). Each tested the same content using 25 questions worth 1 point each. A mixed-model repeated-measures analysis of variance (anova) with least squares post hoc analysis was conducted to determine if differences in test scores between the formats were statistically significant., Results: Of the 223 students for whom data were analysed, 79 were randomised to a workshop, 82 to a lecture-based format and 62 to SDL. All three teaching formats resulted in a statistically significant improvement in individual test scores (p < 0.001). Comparison of the lecture- and workshop-based formats demonstrated no difference in test scores (marginal mean [MM] for both formats = 12.4, 95% confidence interval [95% CI] 11.7-13.2]; p = 0.99). Test scores of students using SDL (MM = 10.7, 95% CI 9.8-11.5) were lower than those of students in the workshop (p = 0.003) and lecture (p = 0.002) groups., Conclusions: Compared with those taught using workshop- and lecture-based formats, medical students learning ECG interpretation by SDL had lower test scores., (© Blackwell Publishing Ltd 2011.)

Background: Alcohol use increases injury risk and severity. However, few studies have evaluated the ability of emergency physicians (EPs) to accurately determine sobriety., Objectives: To determine the predictive value of clinical sobriety assessment by EPs in blunt trauma patients with acute alcohol use., Materials and Methods: Blunt trauma patients, aged 18-65 years with suspected acute alcohol use, were prospectively enrolled in the study. EPs assessed study subjects before sample collection for blood alcohol level (BAL) and urine drug screen measurement. Alcohol exposure was considered significant if BAL was ≥ 80 mg/dL. Sobriety (non-significant alcohol exposure) was defined as a BAL < 80 mg/dL. EP sobriety assessment was compared to measured BAL and predictive values were calculated. Agreement on significance of alcohol exposure occurred if EP-estimated BAL > 80 mg/dL agreed with measured BAL > 80 mg/dL, or estimated BAL < 80 mg/dL agreed with measured BAL < 80 mg/dL. Chi-squared analysis was used to compare the proportion of correct physician assessments among patients with sobriety and those with significant alcohol exposure., Results: Of 158 enrolled subjects, 153 completed clinical assessment. EP assessment had a predictive value of 83% (95% confidence interval [CI] 77-90%) for significant alcohol exposure and 69% (95% CI 60-78%) for sobriety. Agreement on the significance of alcohol exposure was 82% (125/153; 95% CI 76-88%). EPs identified 32% (11/34; 95% CI 17-48%) of sober patients, but identified 96% (114/119; 95% CI 92-99%) of patients with significant alcohol exposure. EP assessment was significantly less accurate in identifying sober patients (p < 0.01)., Conclusions: Emergency physicians identified significant recent alcohol exposure in blunt trauma patients 96% of the time. However, clinical assessment by EPs in blunt trauma patients with recent alcohol use had only moderate predictive value for significant alcohol exposure. Sober patients were frequently misidentified as having significant alcohol exposure., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Emergency physicians (EP) frequently encounter angioedema involving the lips and tongue. However, angioedema from Angiotensin Converting Enzyme inhibitors or hereditary angioedema (HAE) can present with gastrointestinal symptoms due to bowel wall involvement. EPs should begin to consider this clinical entity as a potential cause for abdominal pain and associated gastrointestinal symptoms given the common use of medications that can precipitate angioedema. We report a case of a 34-year-old woman who presented with abdominal cramping, vomiting and diarrhea due to an acute exacerbation of HAE.

Objective: To determine whether ventilator-associated lung hyperinflation injury can be attenuated by a reduction in respiratory frequency., Design: Prospective comparative laboratory investigation., Setting: University medical center research laboratory., Subjects: Male Sprague-Dawley rats., Interventions: Eight groups of isolated, perfused rat lungs were exposed to cyclic ventilation at different respiratory frequencies and tidal volumes. Each group of six to eight lung preparations was assigned to one of four respiratory frequencies (10, 20, 40, or 80 breaths/min) and one of two tidal volumes (5 or 20 mL.kg). Measurement of capillary filtration coefficient (Kf,c), a sensitive index of lung microvascular permeability and injury, was made at baseline and at 30, 60, and 90 mins of the experimental conditions., Measurements and Main Results: Lungs exposed to 5 mL.kg tidal volume had no elevation in Kf,c at any time point regardless of respiratory frequency. Lungs exposed to 20 mL. kg tidal volume and a respiratory frequency of 80 had significant elevations in Kf,c at all times after baseline compared with lungs exposed to respiratory frequencies of 10, 20, or 40 (0.14 +/- 0.03, 0.16 +/- 0.02, 0.31 +/- 0.05 vs. 0.76 +/- 0.16). Furthermore, the Kf,c at 90 mins was significantly higher than permeability at baseline in this group (1.53 +/- 0.45 vs. 0.12 +/- 0.02 mL.min.cm H2O.100 g of lung tissue)., Conclusions: Reduction in respiratory frequency to values much lower than normal ameliorated experimental ventilator-induced hyperinflation lung injury as determined by pulmonary capillary filtration coefficient.

Objectives: Ifenprodil, a NMDA receptor polyamine site antagonist, reduces experimental cardiac arrest (CA)-elicited brain edema, which is associated with an up-regulation of aquaporin 4 (AQP4), a brain water-selective channel. However, the interacting roles of NMDA receptors and AQP4 in CA-elicited brain edema are unknown. The objective of this study was to test our hypothesis that ifenprodil treatment is associated with a down-regulation of brain AQP4., Methods: Twenty-five rats were assigned to normal controls (group 1, n = 6) or subjected to eight minutes of asphyxial CA treated with placebo (group 2, n = 9) or ifenprodil (group 3, n = 10). Ifenprodil at 10 mg/kg or normal saline of equal volume was given intraperitoneally, 5 minutes before CA. The density of AQP4 protein and actin bands was scanned and expressed as the ratios of the optical density of AQP4 relative to that of actin. The ANOVA analysis was used to compare the group differences., Results: The ratios of the optical density of AQP4 to that of actin were 0.88 +/- 0.06 in group 1, 1.11 +/- 0.08 in group 2 (p < 0.05 vs. group 1), and 0.78 +/- 0.04 in group 3 (p < 0.01 vs. group 2; NS vs. group 1)., Conclusion: Ifenprodil given before CA is associated with a downregulation of brain AQP4 in rats.

Objective: The roles of individual types of cerebral cells in contributing to brain edema are undefined. The objective of this study was to determine the role of cerebral cell-column chromatography in quantifying cell volumes of individual cerebral cell lines, under chemically-induced anoxia/re-oxygenation (A/R)., Methods: Cerebral endothelial cells (4 experiments) or type II astrocytes (4 experiments) were cultured to confluence on microcarrier beads. A chromatographic cell-column of 1.5 cm height was filled with non-treated cell-covered beads. The column was perfused at 1 ml/min with a balanced perfusate for one hour (Baseline). The perfusate was then switched to that containing 5 mM thioglycolic acid for one hour (Anoxia). Then the column was perfused with the normal perfusate for another two hours (Re-oxygenation). The total free space in the column, reversely reflecting cell volumes, was determined by averaged transit time (TTa) of a non-permeable flow tracer blue dextran. Decreased TTa means that cells swell, and vice versa., Results: TTa in endothelial cell columns increased with a peak at 60 minutes of re-oxygenation. TTa in astrocyte columns decreased with a nadir at 30 minutes of re-oxygenation., Conclusion: Cell column chromatography can be used to determine the cerebral cell volume changes following chemically-induced anoxia/re-oxygenation.

Introduction: Cardiac arrest (CA) is associated with poor neurological outcome and is associated with a poor understanding of the cerebral hemodynamic and metabolic changes. The objective of this study was to determine the applicability of near-infrared spectroscopy (NIRS), to observe the changes in cerebral total hemoglobin (T-Hb) reflecting cerebral blood volume, oxygenation state of Hb, oxidized cytochrome oxidase (Cyto-C), and brain water content following CA., Methods: Fourteen rats were subjected to normothermic (37.5 degrees C) or hypothermic (34 degrees C) CA induced by 8 min of asphyxiation. Animals were resuscitated with ventilation, cardiopulmonary resuscitation (CPR), and epinephrine (adrenaline). Hypothermia was induced before CA. NIRS was applied to the animal head to measure T-Hb with a wavelength of 808 nm (n = 10) and oxygenated/deoxygenated Hb, Cyto-C, and brain water content with wavelengths of 620-1120 nm (n = 4)., Results: There were no technical difficulties in applying NIRS to the animal, and the signals were strong and consistent. Normothermic CA caused post-resuscitation hyperemia followed by hypoperfusion determined by the level of T-Hb. Hypothermic CA blunted post-resuscitation hyperemia and resulted in more prominent post-resuscitation hypoperfusion. Both, normothermic and hypothermic CA resulted in a sharp decrease in oxygenated Hb and Cyto-C, and the level of oxygenated Hb was higher in hypothermic CA after resuscitation. There was a rapid increase in brain water signals following CA. Hypothermic CA attenuated increased water signals in normothermic CA following resuscitation., Conclusion: NIRS can be applied to monitor cerebral blood volume, oxygenation state of Hb, Cyto-C, and water content following CA in rats.

Study Objective: Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) effectively treats patients bitten by rattlesnakes. The copperhead snake (Agkistrodon contortrix) caused 37% of venomous snakebites reported to US poison centers in 2001 and is the major envenomating reptile in the southeastern United States. FabAV has not been tested in human beings envenomated by copperhead snakes., Methods: In this preliminary study, we performed a retrospective chart review of all copperhead snake envenomations reported to the Carolinas Poison Center that were treated with FabAV. Progression of limb swelling, coagulopathy, and hemodynamic status before and after FabAV administration, adverse effects of FabAV therapy, and recurrence phenomena were recorded., Results: Of approximately 400 copperhead envenomation cases reported to the poison center during the study period, 32 received FabAV and were included. Most patients had moderate envenomation. The median time to FabAV administration was 4.0 hours. The median time to achieve initial control was 1.0 hour, with a median dose of 4 vials of FabAV. A rapid initial response, defined as cessation of the progression of local tissue injury within 4 hours of FabAV administration, occurred in 28 cases (88%; 95% confidence interval [CI] 76% to 99%). Four cases (13%; 95% CI 1% to 24%) were considered treatment failures. Recurrent swelling occurred in 6 cases (19%; 95% CI 5% to 32%). The incidence of recurrent swelling was not reduced by administration of repeated doses of antivenom on a planned schedule. One patient developed late-onset coagulopathy. One minor allergic reaction was observed., Conclusion: In this select group of patients bitten by copperhead snakes, local tissue effects of envenomation halted promptly after FabAV treatment in most cases. Treatment failures occurred, and recurrence of swelling and defibrination syndrome was sometimes problematic. Time to return to work and long-term limb function were not assessed. A controlled trial with long-term follow-up is needed to define the role of FabAV treatment for copperhead envenomation.

Background: A pilot study was designed to determine if serum procalcitonin levels would assist in the diagnosis of severe bacterial infections in patients presenting to an emergency department (ED) with acute sickle cell pain crisis and evidence of acute inflammatory response., Material/methods: Prospective single cohort study evaluating measured procalcitonin levels in patients with sickle cell pain crisis and evidence of acute inflammation. Acute inflammation was defined as fever (>38 degrees C) and/or elevation in the white blood cell count (>4000 above baseline) and tachycardia (heart rate >100). Procalcitonin was measured using a semi-quantitative monoclonal antibody test. Patients were followed clinically to determine if procalcitonin has predictive value in excluding severe bacterial infections., Results: Twenty four subjects were enrolled and completed the study. Sixteen had levels 0.5 ng/ml or less, two had levels 0.5 to 2 ng/ml, one had a level of 2 but less than 10 ng/ml, and four had levels 10 ng/ml or greater. All subjects with documented infections at presentation had procalcitonin levels > or =2.0 ng/ml. The sensitivity of the test in this study sample was 1, and the specificity was 0.95 (95% CI, 0.75-0.99)., Conclusions: A serum procalcitonin less than 2 ng/ml appears to have good negative predictive value in excluding serious bacterial infections in patients that present with acute sickle cell pain crisis and evidence of acute inflammatory response. Further study is needed to investigate if procalcitonin has positive predictive value in identifying patients with serious bacterial infections in this patient population.

Background: Previous animal data suggest that aspiration of activated charcoal is associated with pulmonary microvascular injury that may be related to excessive ventilator-induced airway pressures. The purpose of this study was to test the hypothesis that ventilator-induced airway trauma contributes to the lung vascular injury observed following activated charcoal aspiration., Methods: Capillary filtration coefficient (Kf,c), a sensitive measure of lung microvascular permeability, was determined isogravimetrically prior to and after intratracheal instillation of 0.4 ml/kg (12% weight/vol. solution, pH 7.4) activated charcoal oran equal volume of sterile water in isolated, perfused rat lungs in which ventilation was either pressure-controlled at 10cm H2O or volume-controlled at 5 ml/kg., Results: There was significant lung injury in both activated charcoal groups regardless of ventilation method compared to control lungs or lungs administered sterile water (p < 0.05 ANOVA). However, injury to pressure-controlled ventilated lungs was significantly less than lungs ventilated with traditional, volume-controlled ventilation., Conclusion: The results of this investigation demonstrate that pressure-controlled ventilation reduces the lung microvascular injury observed following aspiration of activated charcoal as compared to traditional volume-controlled ventilation methods.

Objectives: The mechanisms by which hypothermia improves cardiac arrest (CA)-induced brain damage are unclear. The authors hypothesized that mild hypothermia induced before CA attenuates brain edema formation by preventing neutrophil-mediated dysfunction of the endothelial cell junction proteins., Methods: Eighteen rats were randomized to normal control surgery (group 1, n = 6), normothermic (37.5 degrees C) CA (group 2, n = 6), or hypothermic (34 degrees C) CA (group 3, n = 6). Hypothermia was induced with external cooling before CA in group 3. Cardiac arrest was induced by 8 minutes of asphyxiation. Brain edema was determined by wet-to-dry weight ratio and cerebral spinal fluid pressure (CSFP). Brain neutrophil content was determined by myeloperoxidase (MPO) activity, and occludin degradation was assessed by western blotting., Results: Normothermic CA significantly increased brain wet-to-dry weight ratio from 4.52 +/- 0.04 in group 1 to 4.80 +/- 0.04 in group 2 (p = 0.0003) and CSFP from 3.6 +/- 0.9 in group 1 to 8.9 +/- 0.9 mm Hg in group 2 (p = 0.004). Mild hypothermia before CA in group 3 significantly reduced brain wet-to-dry weight ratio (4.68 +/- 0.03, p = 0.008 vs. group 2) and CSFP (3.8 +/- 0.5 mm Hg, p = 0.004 vs. group 2). Cardiac arrest increased brain MPO from 0.07 +/- 0.025 in group 1 to 0.16 +/- 0.02 units/gram brain weight in group 2 (p = 0.006) that was not decreased by hypothermia before CA (0.12 +/- 0.02 in group 3 (p = 0.07 vs. group 2). There was no occludin proteolysis in any group., Conclusions: Mild hypothermia before CA decreases CA-induced brain edema. The hypothermia-elicited reduction in brain edema does not appear to be neutrophil-dependent and the early brain edema formation may not involve the proteolysis of occludin.

Background: Two workers from a headlight subassembly plant developed severe peripheral neuropathy. These workers had extensive, but brief (1-2 months) dermal and inhalational exposure to nitromethane, a solvent., Methods: Environmental sampling was performed for nitromethane and ethyl cyanoacrylate. Medical records, including electrodiagnostic studies, were reviewed. Literature on nitromethane, ethyl cyanoacrylate, and other exposures in the workplace was reviewed., Results: Electromyography and nerve conduction studies performed on these patients were consistent with a severe, axonal neuropathy. No etiology was discovered despite an extensive medical evaluation. Environmental sampling revealed exposure to nitromethane at the threshold limit value., Conclusions: The history of acute onset of severe peripheral neuropathy temporally associated with exposure to nitromethane is suggestive of a toxic neuropathy. While it cannot be definitively concluded that these two workers developed peripheral neuropathy secondary to exposures at work, occupational exposure to nitromethane appears to be the most likely etiology., (Copyright 2001 Wiley-Liss, Inc.)

Background: Gastric decontamination with orally administered activated charcoal is the recommended treatment for many poisonings. However, ingestion of central nervous system depressants resulting in loss of protective airway reflexes may result in pulmonary aspiration of activated charcoal. Although activated charcoal has been reported to be an inert substance, evidence suggests that pulmonary aspiration of charcoal is associated with lung edema formation and pulmonary compromise. This study tested the hypothesis that intratracheal instillation of activated charcoal disrupts the integrity of the lung microvascular barrier., Methods: The capillary filtration coefficient (Kf,c), a sensitive measure of lung microvascular permeability, was determined isogravimetrically prior to and after intratracheal instillation of activated charcoal 0.04 g/kg (12% weight/vol solution, pH 7.4) or an equal volume of sterile water in isolated, perfused rat lungs. Arterial blood gas analysis was determined prior to and after tracheal instillation of activated charcoal or sterile water in a separate group of animals., Results: Intratracheal instillation of activated charcoal resulted in a significant increase in pulmonary microvascular permeability compared to lungs treated with sterile water or control lungs (delta Kf,c = +0.21 +/- 0.076; -0.014 +/- 0.04; and -0.041 +/- 0.02 mL/min/cm H2O/100 g lung tissue, respectively, p < 0.05 ANOVA). There was no significant difference in baseline blood gases in the 3 experimental groups. There was a significant decrease in arterial Po2, bicarbonate, and pH in animals administered activated charcoal compared to time-matched controls and animals administered sterile water., Conclusions: Intratracheal instillation of activated charcoal is associated with a significant increase in lung microvascular permeability and arterial blood gas derangements. The effects of activated charcoal on pulmonary microvascular barrier integrity may contribute to the lung edema formation and pulmonary compromise observed following clinical aspiration of activated charcoal.

Two cases of overdose with sustained-release lithium preparations are presented. Initial serum lithium levels were in the therapeutic or subtherapeutic range. Subsequent levels were in the toxic range. These cases illustrate the potential danger of delayed toxicity with ingestion of these agents.