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Objective The purpose of this study was to investigate the efficacy of hyperangulated video laryngoscopy (HAVL) versus standard geometry video laryngoscopy (SGVL) in the simulated prehospital environment using a manikin. There is consensus that video laryngoscopy (VL) can be very useful in the emergency department when difficult intubations are predicted. Emergency medical service (EMS) providers are also often faced with difficult, rapidly deteriorating airway management situations that not only involve patient and operator factors but also include challenging unique environmental factors, such as nonoptimized positions in transport vehicles (eg, helicopters and ambulances) or at ground level or entrapped positions. To our knowledge, there has never been a study purposefully investigating the efficacy of hyperangulated geometry versus standard geometry VL techniques in the prehospital environment. Methods A single-center, randomized controlled crossover trial was performed using attending physician helicopter EMS providers. Physicians were randomized to perform 5 HAVL or SGVL intubations followed by the subsequent technique. Intubations were performed on ground level and then repeated in the helicopter with the first location also randomized. A manikin airway management trainer was used to simulate intubation in each environment. The time to intubation (primary outcome) as well as first-pass success and the Cormack-Lehane view were recorded for each attempt. Qualitative data were also obtained for physician preference and perceived difficulty. Results There was no statistically significant difference in the time to intubation with HAVL versus SGVL (ground: 15.02 vs. 14.88 seconds, P = .86; helicopter: 16.11 vs. 16.14 seconds, P = .93). First-pass success was 100% for both techniques in both scenarios. More Grade 1 views were obtained with HAVL (147/150 vs. 134/150). Moreover, most physicians preferred HAVL overall and felt that HAVL required less force (9/15 grounded manikin and 10/15 helicopter manikin) and led to the best chance for first-pass success (11/15 grounded manikin and 10/15 helicopter manikin). Conclusion The results of this study are limited because of the static and highly favorable anatomy of a manikin versus the variability and often difficult anatomy of individual patients. Our results suggest that both techniques are efficacious when the patient is both on the ground or in the helicopter, although provider preference does seem to vary.

Study objective To describe changes in cardiac function throughout the course of resuscitation of patients with suspected septic shock. Methods Prospective observational cohort study of Point-of-Care Transthoracic Echocardiograms (TTE) obtained in Emergency Department (ED) patients with a presumed infectious cause of hypotension within one hour of initiating IV fluid resuscitation. Findings of this pre-resuscitation TTE were compared to mid-resuscitation TTE (obtained upon disposition from the ED), and post-resuscitation TTE (obtained after admission to hospital). Results 22 enrolled patients had a second TTE available for comparison to the initial, pre-resuscitation TTE. 12 patients had a mid-resuscitation TTE and 16 patients had a post-resuscitation TTE. We observed a high incidence of changes on TTE during the clinical course of resuscitation (14/22 [64%]). Patients who developed LV or RV dysfunction during resuscitation were more likely to require vasopressor infusion and ICU admission (Spearman's coefficients [95% CI] of 0.68 [0.36–0.86] and 0.47 [0.04;0.75] respectively). Development of RV dysfunction alone was associated with increased use of positive pressure ventilation and vasopressor infusion (Spearman's coefficients [95% CI] of 0.43 [0;0.72] and 0.47 [0.05,0.75] respectively). Conclusions Cardiac function changes assessed by TTE are common during the resuscitation of patients with septic shock. These changes likely reflect the underlying physiology of patients with septic shock and correlate with need for interventions and higher level of care. Further work is required to characterize these changes and to elucidate how to use these physiologic data to guide management.

Fundamental understanding of large-scale dynamic connectivity within a living organism requires volumetric imaging over a large field of view (FOV) at biologically relevant speed and resolution. However, most microscopy methods make trade-offs between FOV and depth resolution, making it challenging to observe highly dynamic processes at cellular resolution in 3D across mesoscopic scales (e.g., whole zebrafish larva). To overcome this limitation, we have developed mesoscopic oblique plane microscopy (Meso-OPM) with a diffractive light sheet. By augmenting the illumination angle of the light sheet with a transmission grating, the axial resolution was improved ~6-fold over existing methods and ~2-fold beyond the diffraction limitation of the primary objective lens. We demonstrated an unprecedented FOV up to 5.4 × 3.3 mm with resolution of 2.5× 3 × 6 μm, allowing volumetric imaging of 3D cellular structures with a single scan. Applying Meso-OPM for in vivo imaging of zebrafish larvae, we report here the first in toto whole body volumetric recordings of neuronal activity at 2 Hz volume rate and the first example of whole body volumetric recordings of blood flow dynamics at 5 Hz with 3D cellular resolution.

Transgenic expression of bacterial nitroreductase (NTR) enzymes sensitizes eukaryotic cells to prodrugs such as metronidazole (MTZ), enabling selective cell-ablation paradigms that have expanded studies of cell function and regeneration in vertebrates. However, first-generation NTRs required confoundingly toxic prodrug treatments to achieve effective cell ablation, and some cell types have proven resistant. Here we used rational engineering and cross-species screening to develop an NTR variant, NTR 2.0, which exhibits ~100-fold improvement in MTZ-mediated cell-specific ablation efficacy, eliminating the need for near-toxic prodrug treatment regimens. NTR 2.0 therefore enables sustained cell-loss paradigms and ablation of previously resistant cell types. These properties permit enhanced interrogations of cell function, extended challenges to the regenerative capacities of discrete stem cell niches, and novel modeling of chronic degenerative diseases. Accordingly, we have created a series of bipartite transgenic reporter/effector resources to facilitate dissemination of NTR 2.0 to the research community.

Fundamental understanding of large-scale dynamic connectivity within a living organism requires volumetric imaging over a large field of view (FOV) at biologically relevant speed and resolution. However, most microscopy methods make trade-offs between FOV and axial resolution, making it challenging to observe highly dynamic processes at cellular resolution in 3D across mesoscopic scales (e.g., whole zebrafish larva). To overcome this limitation, we have developed mesoscopic oblique plane microscopy (Meso-OPM) with a diffractive light sheet. By augmenting the illumination angle of the light sheet with a transmission grating, we improved the axial resolution approximately sixfold over existing methods and approximately twofold beyond the diffraction limitation of the primary objective lens. We demonstrated a FOV up to 5.4 m m × 3.3 m m with resolution of 2.5 µ m × 3 µ m × 6 µ m , allowing volumetric imaging of 3D cellular structures with a single scan. Applying Meso-OPM for in vivo imaging of zebrafish larvae, we report here in toto whole-body volumetric recordings of neuronal activity at 2 Hz volume rate and whole-body volumetric recordings of blood flow dynamics at 5 Hz with 3D cellular resolution.

Müller glia (MG) function as injury-induced retinal stem cells in zebrafish but not mammals. Insights from zebrafish, however, have been used to stimulate limited regenerative responses from mammalian MG. Microglia/macrophages regulate MG stem cell activity in the chick, zebrafish and mouse. We previously showed that dexamethasone can accelerate retinal regeneration in zebrafish. Similarly, microglia ablation enhances regenerative outcomes in the mouse retina. Targeted immunomodulation may therefore enhance the regenerative potential of human MG. Nanoparticle-based immunomodulation is an emerging field with immense therapeutic potential. Here, we investigated how regeneration-enhancing dexamethasone treatments alter microglia behavior and how dendrimer-based targeting of dexamethasone to reactive microglia impact retinal regeneration kinetics. Intravital time-lapse imaging revealed specific dexamethasone-induced changes in microglia reactivity. Dendrimer-conjugated dexamethasone treatments resulted in: 1) decreased toxicity, 2) selective targeting of reactive microglia and, 3) “super-accelerated” retinal regeneration kinetics. These data support the use of dendrimer-based drug formulations for modulating microglia reactivity in degenerative disease contexts, especially as therapeutic strategies for promoting regenerative responses to neuronal cell loss.

Diffuse intrinsic pontine glioma (DIPG) and atypical teratoid/rhabdoid tumors (AT/RT) are deadly pediatric brain tumors. There is an urgent need of better therapeutics for improving survival and quality of life for these patients. Additionally, we need improved animal models to accelerate identification of novel therapeutics and improve through-put. In line with our long-term interests of validating therapies and developing model systems for pediatric brain tumors, we tested a repurposed drug quinacrine as a potential therapy using a new and faster model system in zebrafish. Quinacrine is a safe and widely used treatment for pediatric malaria and parasitic infections. We hypothesized that quinacrine will increase tumor cell death and decrease tumorigenicity of DIPG and ATRT. We used quinacrine in six patient-derived cell lines: three AT/RT (BT37, CHLA-05, CHLA-266) and three DIPG (JHHDIPG1, SUDIPGXIII, SF7761). In all tumor cell lines, quinacrine caused a dose-dependent reduction in proliferation (BrdU) and increase in apoptosis (cleaved caspase-3 and cleaved PARP) compared to vehicle-treated cells (P Citation Format: Harpreet Kaur, Huizi Guo, Kevin Emmerich, David White, Peter Green, Alara Michelle Hector, Sepehr Akhtarkhavari, Anukriti Bhargava, Allison Martin, Smit Shah, Charles G. Eberhart, Jeffrey Mumm, Eric H. Raabe. A novel rapid zebrafish model for validation of potential therapies for fatal pediatric brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3449.

Scientific progress depends on evidence-based research, and reliance on accurate scholarship is essential when making management decisions for imperiled species. However, erroneous claims are sometimes perpetuated in the scientific and technical literature, which can complicate policy and regulatory judgments. The literature associated with two enigmatic California desert vertebrates, the Panamint alligator lizardElgaria panamintinaand the Inyo Mountains salamanderBatrachoseps campi, exemplifies this problem. We produced a comprehensive threat analysis and status assessment for these species, which are both under review for possible listing under the US Endangered Species Act (ESA). Despite uncertainties and limited data, we find that many sources contain factual errors about the status of these two species, particularly the original petition that advocated for ESA listing. Although localized declines may have gone undetected, no evidence exists of population declines, population extirpation, or population-scale habitat conversion forE. panamintina. However, there is evidence of recent flash flood damage to some occupiedB. campihabitat, which has possibly led to population declines at those localities. Contrary to inaccurate statements by some authors, all known populations of both species occur exclusively on federal lands, and numerous populations have likely benefited from recent federal management targeted at reducing known threats. Of the 12 threats that we identified for one or both species, only three currently appear to be serious: water diversions, climate change, and flash floods. The remaining threats are neither widespread nor severe, despite numerous contrary yet poorly supported statements in the literature. We thus evaluate the contemporary conservation status of both species as relatively secure, althoughB. campiis more at-risk compared toE. panamintina. This conclusion is independently supported by a recent review. Nonetheless, ongoing stewardship of these species in a multi-use context by federal agencies remains vital, and we identify several priority management actions and research needs for both species. We also recommend updated determinations on the IUCN Red List, and the Species of Conservation Concern list of the Inyo National Forest. To maximize the quality and effectiveness of conservation planning, we urge government agencies, non-governmental organizations, and individual scientists to maintain high standards of scholarship and decision-making.

Objective To investigate the efficacy of hyper-angulated video laryngoscopy (HAVL) versus standard-geometry video laryngoscopy (SGVL) during a simulated mid-flight helicopter intubation. Introduction Prehospital intubation is often complicated by poor conditions including bad lighting, poor patient positioning, excessive noise, and restricted cervical spine mobility – some of which are known predictors of a difficult airway. These factors are magnified in the setting of a mid-flight helicopter intubation. The specific aim of our investigation was to evaluate if use of a specific video laryngoscopy technique offers advantage in this situation. The SGVL technique requires the creation of nearly a direct line between the oropharynx and glottis in order for endotracheal tube placement. The line must be created by manipulation of the patient's airway by the operator with a laryngoscope. Due to poor operator and patient positioning in a helicopter, this process was hypothesized to be more difficult than HAVL, which allows the operator to pass an endotracheal tube around the natural curvature of the patient's upper airway. There are no studies to date comparing these two distinct techniques by board-certified emergency medicine physicians in a simulated mid-flight environment. Methods A single center, randomized crossover trial was performed using attending physician helicopter EMS providers in a simulated environment. After IRB approval and informed consent, physicians were randomized to perform five HAVL or SGVL intubations, followed by the subsequent technique. Intubations were performed in a grounded EC-135 helicopter with an AirsimTM airway management trainer restrained on the cot. Time to intubation (primary outcome) as well as first pass success (FPS) and Cormack-Lehane views were recorded for each attempt. Qualitative data was also obtained for physician preference and perceived difficulty. Results Fifteen physicians participated in the study. There was no statistically significant difference in time to intubation with HAVL versus SGVL (16.14 seconds vs. 16.12 seconds; p-value 0.97). FPS was 100% for both techniques. Ninety-seven percent of Cormack-Lehane views were grade one for HAVL versus 88% for SGVL. Despite no statistical significance in time to intubation, participants subjectively reported that SGVL required more physical force to perform intubation. The majority also qualitatively prefer HAVL over SGVL after performing the study for future flight intubations. Conclusions/Limitations Our results suggest that both SAVL and HAVL are efficacious techniques to perform intubations in an EC-135 helicopter, should this somewhat rare, but likely difficult procedure, be necessary. Providers did, however, prefer HAVL over SGVL in our group. The discordant quantitative and qualitative results in this study may be due to the static nature and highly favorable anatomy of a manikin, versus the varying anatomy of individual patients.

This chapter will discuss the auscultatory manifestations of pulmonary regurgitation (PR). PR can be caused by a variety of conditions (e.g. pulmonary hypertension, pulmonary valve trauma, and pulmonary artery dilatation), and may be difficult to differentiate from aortic regurgitation. The chapter will also discuss the prognostic implications of pulmonary regurgitation.

BACKGROUND: The relationship of pain, function, and treatment in lateral epicondylitis is not fully understood. Improved understanding of this interrelationship may be required to optimize treatment strategies, particularly with regard to bracing and activity modification. METHODS: A cohort of 36 patients diagnosed by a fellowship-trained hand surgeon over a 25-month period that received treatment in the form of a cock-up wrist splint (CUWS) and recommendations of activity modification was identified. The patients’ function was defined by the QuickDash Outcome measure and pain by the Numeric Pain Rating. Retrospective analysis of prospectively collected pre-treatment data were compared to those obtained following treatment using Wilcoxon signed-rank test. Changes in QuickDash Outcome measures and Numeric Pain Rating following treatment were compared between those individuals that stated the treatment helped and those that stated it did not. RESULTS: Following treatment with a CUWS and activity modification, the median QuickDash score was 8 compared to 40 prior to treatment (95% CI: -32 ~ -20, p-value < 0.0001) indicating statistically significant functional improvement. All 36 of 36 (100%) patients stated that they were able to return to a normal activity level at the time of follow-up. Numeric Pain Rating values improved from 6 to 1 following treatment (95% CI: -6 ~ -4, p-value < 0.0001) The Kendall’s Tau-b correlation coefficient between Numeric Pain Ratings and QuickDash Outcome measure was 0.296 (p-value = 0.018) and 0.473 (p-value = 0.001) before and after treatment, respectively, suggesting a weak to moderate correlation. Patients who stated that the treatment was effective experienced a median change in their QuickDash outcome score of -23 compared to -37 for those whom did not think it was an effective treatment; the estimated difference between the two groups was 14 (CI: 2, 30, p-value 0.019) indicating that patients who thought treatment was not effective actually experienced greater functional improvement. CONCLUSIONS: These results indicate that use of a CUWS and recommendations of activity modification is an effective strategy to help improve patient function and pain levels. However, low to moderate correlation between pain and disability both before and after treatment indicate that other factors such as coping skills and psychosocial influences may effect the disease and treatment course. Furthermore, patients may still make gains in function while questioning the effectiveness of their treatment, which may make assessment of therapeutic response difficult. Future research should be directed at identifying which factors other than pain may influence disability and devising strategies to address them.