Search

Background: Mammographic breast density is a strong breast cancer risk factor but is not used in the clinical setting, partly because of a lack of standardization and automation. We developed an automated and objective measurement of the grayscale value variation within a mammogram, evaluated its association with breast cancer, and compared its performance with that of percent density (PD).Methods: Three clinic-based studies were included: a case-cohort study of 217 breast cancer case subjects and 2094 non-case subjects and two case-control studies comprising 928 case subjects and 1039 control subjects and 246 case subjects and 516 control subjects, respectively. Percent density was estimated from digitized mammograms using the computer-assisted Cumulus thresholding program, and variation was estimated from an automated algorithm. We estimated hazards ratios (HRs), odds ratios (ORs), the area under the receiver operating characteristic curve (AUC), and 95% confidence intervals (CIs) using Cox proportional hazards models for the cohort and logistic regression for case-control studies, with adjustment for age and body mass index. We performed a meta-analysis using random study effects to obtain pooled estimates of the associations between the two mammographic measures and breast cancer. All statistical tests were two-sided.Results: The variation measure was statistically significantly associated with the risk of breast cancer in all three studies (highest vs lowest quartile: HR = 2.0 [95% CI = 1.3 to 3.1]; OR = 2.7 [95% CI = 2.1 to 3.6]; OR = 2.4 [95% CI = 1.4 to 3.9]; [corrected] all P (trend) < .001). [corrected]. The risk estimates and AUCs for the variation measure were similar to [corrected] those for percent density (AUCs for variation = 0.60-0.62 and [corrected] AUCs for percent density = 0.61-0.65). [corrected]. A meta-analysis of the three studies demonstrated similar associations [corrected] between variation and breast cancer (highest vs lowest quartile: RR = 1.8, 95% CI = 1.4 to 2.3) and [corrected] percent density and breast cancer (highest vs lowest quartile: RR = 2.3, 95% CI = 1.9 to 2.9).Conclusion: The association between the automated variation measure and the risk of breast cancer is at least as strong as that for percent density. Efforts to further evaluate and translate the variation measure to the clinical setting are warranted. [ABSTRACT FROM AUTHOR]

Context: Annual ultrasound screening may detect small, node-negative breast cancers that are not seen on mammography. Magnetic resonance imaging (MRI) may reveal additional breast cancers missed by both mammography and ultrasound screening.Objective: To determine supplemental cancer detection yield of ultrasound and MRI in women at elevated risk for breast cancer.Design, Setting, and Participants: From April 2004-February 2006, 2809 women at 21 sites with elevated cancer risk and dense breasts consented to 3 annual independent screens with mammography and ultrasound in randomized order. After 3 rounds of both screenings, 612 of 703 women who chose to undergo an MRI had complete data. The reference standard was defined as a combination of pathology (biopsy results that showed in situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma in the breast or axillary lymph nodes) and 12-month follow-up.Main Outcome Measures: Cancer detection rate (yield), sensitivity, specificity, positive predictive value (PPV3) of biopsies performed and interval cancer rate.Results: A total of 2662 women underwent 7473 mammogram and ultrasound screenings, 110 of whom had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Among 4814 incidence screens in the second and third years combined, 75 women were diagnosed with cancer. Supplemental incidence-screening ultrasound identified 3.7 cancers per 1000 screens (95% CI, 2.1-5.8; P < .001). Sensitivity for mammography plus ultrasound was 0.76 (95% CI, 0.65-0.85); specificity, 0.84 (95% CI, 0.83-0.85); and PPV3, 0.16 (95% CI, 0.12-0.21). For mammography alone, sensitivity was 0.52 (95% CI, 0.40-0.64); specificity, 0.91 (95% CI, 0.90-0.92); and PPV3, 0.38 (95% CI, 0.28-0.49; P < .001 all comparisons). Of the MRI participants, 16 women (2.6%) had breast cancer diagnosed. The supplemental yield of MRI was 14.7 per 1000 (95% CI, 3.5-25.9; P = .004). Sensitivity for MRI and mammography plus ultrasound was 1.00 (95% CI, 0.79-1.00); specificity, 0.65 (95% CI, 0.61-0.69); and PPV3, 0.19 (95% CI, 0.11-0.29). For mammography and ultrasound, sensitivity was 0.44 (95% CI, 0.20-0.70, P = .004); specificity 0.84 (95% CI, 0.81-0.87; P < .001); and PPV3, 0.18 (95% CI, 0.08 to 0.34; P = .98). The number of screens needed to detect 1 cancer was 127 (95% CI, 99-167) for mammography; 234 (95% CI, 173-345) for supplemental ultrasound; and 68 (95% CI, 39-286) for MRI after negative mammography and ultrasound results.Conclusion: The addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in not only a higher cancer detection yield but also an increase in false-positive findings.Trial Registration: clinicaltrials.gov Identifier: NCT00072501. [ABSTRACT FROM AUTHOR]

We describe a 45-year-old woman who presented with a spontaneous unilateral nipple discharge. With a negative breast examination and screening tests (mammography and ultrasonography) she underwent mammary ductography, which revealed a small 3-4 mm intraluminal filling defect. A core biopsy showed high-grade ductal carcinoma in situ (DCIS). An attempted wide local excision was unsuccessful, and the patient underwent a mastectomy. Pathologic assessment revealed high-grade DCIS and multiple foci of invasive mucinous ductal adenocarcinoma. Rare tumor cells were identified in the subcapsular sinuses in both sentinel lymph nodes. We report this case to point out the importance of the diagnostic examination for patients with a pathologic nipple discharge and review current and possible future diagnostic management. [ABSTRACT FROM AUTHOR]

Childhood muscle-related cancer rhabdomyosarcoma is a rare disease with a 50-year unmet clinical need for the patients presented with advanced disease. The rarity of ∼350 cases per year in North America generally diminishes the viability of large-scale, pharmaceutical industry driven drug development efforts for rhabdomyosarcoma. In this study, we performed a large-scale screen of 640,000 compounds to identify the dihydropyridine (DHP) class of anti-hypertensives as a priority compound hit. A structure-activity relationship was uncovered with increasing cell growth inhibition as side chain length increases at the ortho and para positions of the parent DHP molecule. Growth inhibition was consistent across n = 21 rhabdomyosarcoma cell line models. Anti-tumor activity in vitro was paralleled by studies in vivo. The unexpected finding was that the action of DHPs appears to be other than on the DHP receptor (i.e., L-type voltage-gated calcium channel). These findings provide the basis of a medicinal chemistry program to develop dihydropyridine derivatives that retain anti-rhabdomyosarcoma activity without anti-hypertensive effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Charles Keller reports equipment, drugs, or supplies was provided by Novartis GNF., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A practical, broadband, all-optical linearization concept for a Mach-Zehnder modulator (MZM) is proposed and demonstrated. The unique transmitter design includes an amplitude modulated (AM) standard MZM with two optical outputs, where the alternative (or complimentary) output is combined with the laser carrier to create a linearizing optical local oscillator, which when coherently combined with the AM signal fully cancels 3 rd order intermodulation distortion components. Using this scheme, record linearity is achieved for a non-amplified RF photonic link, with spurious free dynamic range (SFDR) of 118.5 dB.Hz 2/3 and 123 dB.Hz 2/3 for single and dual fiber/photodetector schemes.

The Premarket Tobacco Product Applications (PMTA) guidance issued by the Food and Drug Administration for electronic nicotine delivery systems (ENDSs) recommends that in addition to reporting harmful and potentially harmful constituents (HPHCs), manufacturers should evaluate these products for other chemicals that could form during use and over time. Although e-vapor product aerosols are considerably less complex than mainstream smoke from cigarettes and heated tobacco product (HTP) aerosols, there are challenges with performing a comprehensive chemical characterization. Some of these challenges include the complexity of the e-liquid chemical compositions, the variety of flavors used, and the aerosol collection efficiency of volatile and semi-volatile compounds generated from aerosols. In this study, a non-targeted analysis method was developed using gas chromatography-mass spectrometry (GC-MS) that allows evaluation of volatile and semi-volatile compounds in e-liquids and aerosols of e-vapor products. The method employed an automated data analysis workflow using Agilent MassHunter Unknowns Analysis software for mass spectral deconvolution, peak detection, and library searching and reporting. The automated process ensured data integrity and consistency of compound identification with >99% of known compounds being identified using an in-house custom mass spectral library. The custom library was created to aid in compound identifications and includes over 1,100 unique mass spectral entries, of which 600 have been confirmed from reference standard comparisons. The method validation included accuracy, precision, repeatability, limit of detection (LOD), and selectivity. The validation also demonstrated that this semi-quantitative method provides estimated concentrations with an accuracy ranging between 0.5- and 2.0-fold as compared to the actual values. The LOD threshold of 0.7 ppm was established based on instrument sensitivity and accuracy of the compounds identified. To demonstrate the application of this method, we share results from the comprehensive chemical profile of e-liquids and aerosols collected from a marketed e-vapor product. Applying the data processing workflow developed here, 46 compounds were detected in the e-liquid formulation and 55 compounds in the aerosol sample. More than 50% of compounds reported have been confirmed with reference standards. The profiling approach described in this publication is applicable to evaluating volatile and semi-volatile compounds in e-vapor products., Competing Interests: This study was funded by Altria Client Services LLC. During the execution of this research, all authors were employees of Altria Client Services LLC., (Copyright © 2021 Shah, Noe, Agnew-Heard, Pithawalla, Gardner, Chakraborty, McCutcheon, Grisevich, Hurst, Morton, Melvin and Miller IV.)

Study Objectives: To quantify the readiness of individual academic emergency departments (EDs) in the United States for an outbreak of pandemic influenza. Methods, design, and setting: Cross-sectional assessment of influenza pandemic preparedness level of EDs in the United States via survey of medical directors and department chairs from the 135 academic emergency medicine departments in the United States. Preparedness assessed using a novel score of 15 critical preparedness indicators. Data analysis consisted of summary statistics, χ 2 , and ANOVA., Participants: ED medical directors and department chairs., Results: One hundred and thirty academic emergency medicine departments contacted; 66 (50.4 percent) responded. Approximately half (56.0 percent) stated their ED had a written plan for pandemic influenza response. Mean preparedness score was 7.2 (SD = 4.0) out of 15 (48.0 percent); only one program (1.5 percent) achieved a perfect score. Respondents from programs with larger EDs (=30 beds) were more likely to have a higher preparedness score (p < 0.035), an ED pandemic preparedness plan (p = 0.004) and a hospital pandemic preparedness plan (p = 0.007). Respondents from programs with larger EDs were more likely to feel that their ED was prepared for a pandemic or other major disease outbreak (p = 0.01). Only one-third (34.0 percent) felt their ED was prepared for a major disease outbreak, and only 27 percent felt their hospital was prepared to respond to a major disease outbreak., Conclusions: Significant deficits in preparedness for pandemic influenza and other disease outbreaks exist in US EDs, relative to HHS guidelines, which appear to be related in part to ED size. Further study should be undertaken to determine the barriers to appropriate pandemic preparedness, as well as to develop and validate preparedness metrics.

Objective: To assess the level of pandemic preparedness at emergency departments (EDs) around the country and to better understand current barriers to preparedness in the United States represented by health professionals in the American College of Emergency Physician (ACEP) Disaster Medicine Section (DMS). Methods, design, and setting: A cross-sectional survey of ACEP DMS members was performed. A total of 300 members were surveyed both via e-mail and with paper surveys during the 2009 ACEP Scientific Assembly DMS Meeting. An optional comments section was included for section members' perspectives on barriers to preparedness. A 15-item pandemic preparedness score was calculated for each respondent based on key preparedness indicators as defined by the authors. Results were analyzed with descriptive statistics, χ 2 analysis, Cochran-Armitage trend test, and analysis of variance. Free text comments were coded and subjected to frequency-based analysis., Results: A total of 92 DMS members completed the survey with a response rate of 31 percent. Although 85 percent of those surveyed indicated that their hospital had a plan for pandemic influenza response and other infectious disease threats, only 68 percent indicated that their ED had a plan, and 52 percent indicated that their hospital or ED had conducted disaster preparedness drills. Only 57 percent indicated that there was a plan to augment ED staff in the event of a staffing shortage, and 63 percent indicated that there were adequate supplies of personal protective equipment. While 63 percent of respondents indicated that their ED had a plan for distribution of vaccines and antivirals, only 32 percent of EDs had a plan for allocation of ventilators. A total of 42 percent of respondents felt that their ED was prepared in the event of a pandemic influenza or other disease outbreak, and only 35 percent felt that their hospital was prepared. The average pandemic preparedness score among respondents was 8.30 of a total of 15. Larger EDs were more likely to have a higher preparedness score (p = 0.03) and more likely to have a pandemic preparedness plan (p = 0.037). Some major barriers to preparedness cited by section members included lack of local administration support, challenges in funding, need for dedicated disaster preparedness personnel, staffing shortages, and a lack of communication among disaster response agencies, particularly at the federal level., Conclusions: There appear to be significant gaps in pandemic influenza and other infectious disease outbreak planning among the hospitals where ACEP DMS members work. This may reflect a broader underlying inadequacy of preparedness measures.

Tobacco-specific nitrosamines (TSNAs) have been of concern to the public health community for decades and their reduction through agricultural practices, plant breeding, and tobacco processing has also been a decades-long industry effort. Despite those efforts, TSNAs, though lower, continue to be constituents of concern in tobacco products. This paper examines the TSNA levels of dark air-cured, dark fire-cured, and burley tobaccos purchased in the United States by U.S. Smokeless Tobacco Company LLC (USSTC) and of nine finished USSTC moist smokeless tobacco products. TSNA values of the incoming purchased tobaccos and the finished products showed considerable variability. For the incoming tobaccos, the coefficient of variation was generally more than 100 % for each tobacco type and for each of the measured TSNAs. The relative TSNA variability of the finished tobacco products was also considerable, averaging approximately 25 %. It was also found that the measured values for the finished products averaged well above the proposed FDA NNN proposed product standard of 1.0 μg/g dry weight. Because of the large variability in NNN values, products would have to average well below FDA's proposed product standard to be consistently compliant., Competing Interests: All authors were employees of Altria Client Services LLC or U.S. Smokeless Tobacco Company at the time the research was done, and those companies funded the work., (© 2020 The Authors. Published by Elsevier B.V.)

Objective: Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH., Methods: We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1-1, 2-1 or 2-2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3-6)., Results: We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume., Conclusion: The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH., Methods: The HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV., Results: The HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin., Conclusion: The HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm., Competing Interests: Competing interests A.I.O. is a former employee and J.M. is a current employee of Bio Products Laboratory Limited, a plasma-derived therapeutics manufacturing company.

Data show that toxicity to the central nervous system (CNS) is the most frequent cause of safety failures during the clinical phase of drug development. CNS endpoints such as seizure pose a safety risk to patients and volunteers and can lead to a loss of competitiveness, delays, and increased costs. Current methods rely on detection in the nonclinical rodent and non-rodent studies required to support clinical trials. There are two main issues with this approach; seizure may be missed in the animal studies and, even if seizure is detected, significant resource has already been invested in the project by this stage. Thus, there is a need to develop improved screening methods that can be used earlier in drug discovery to predict seizure. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. Human derived induced pluripotent stem cells (hiPSCs) representative of almost all cellular subtypes present in the brain can be incorporated into physiologically relevant in vitro models that can be used to determine seizure risk using high-throughput methods. Akin to the success of screening against a panel of ion channels such as hERG to reduce cardiovascular safety liability, the involvement of ion channels in seizure suggests that a similar approach to early seizure detection is valid. Profiling of the ion channels expressed in hiPSC models showing the seizurogenic phenotype coupled with electrophysiological assessment of ion channel function could translate into an ion channel seizure panel for rapid and reliable in vitro detection of seizure. The mechanistic information gathered would support optimal drug design early in development before resources, animals and time have been wasted., (This journal is © The Royal Society of Chemistry 2019.)

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported . A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f ., (This journal is © The Royal Society of Chemistry 2019.)

Haptoglobin (Hp) is a major plasma acute-phase glycoprotein, which binds free haemoglobin to neutralize its toxicity. The HP gene exists as two copy number variants (CNV), Hp1 and HP2, which differ in two ways: serum Hp level and functional differences in Hp protein products. Both mechanisms may underlie the HP CNV's influence on susceptibility and/or outcome in several diseases. A single nucleotide polymorphism rs2000999 has also been associated with serum Hp level. In a meta-analysis of three studies from England, France and Japan, with a combined sample size of 1210 participants, we show that rs2000999's effect on circulating Hp level is independent from that of the HP CNV. The combined use of rs2000999 and the HP CNV can be an important genetic epidemiological tool to discriminate between the two potential mechanisms underlying differences between HP1 and HP2 alleles., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: In 2006, Academic Emergency Medicine (AEM) published a special issue summarizing the proceedings of the AEM consensus conference on the "Science of Surge." One major goal of the conference was to establish research priorities in the field of "disasters" surge. For this review, we wished to determine the progress toward the conference's identified research priorities: 1) defining criteria and methods for allocation of scarce resources, 2) identifying effective triage protocols, 3) determining decision-makers and means to evaluate response efficacy, 4) developing communication and information sharing strategies, and 5) identifying methods for evaluating workforce needs., Methods: Specific criteria were developed in conjunction with library search experts. PubMed, Embase, Web of Science, Scopus, and the Cochrane Library databases were queried for peer-reviewed articles from 2007 to 2015 addressing scientific advances related to the above five research priorities identified by AEM consensus conference. Abstracts and foreign language articles were excluded. Only articles with quantitative data on predefined outcomes were included; consensus panel recommendations on the above priorities were also included for the purposes of this review. Included study designs were randomized controlled trials, prospective, retrospective, qualitative (consensus panel), observational, cohort, case-control, or controlled before-and-after studies. Quality assessment was performed using a standardized tool for quantitative studies., Results: Of the 2,484 unique articles identified by the search strategy, 313 articles appeared to be related to disaster surge. Following detailed text review, 50 articles with quantitative data and 11 concept papers (consensus conference recommendations) addressed at least one AEM consensus conference surge research priority. Outcomes included validation of the benchmark of 500 beds/million of population for disaster surge capacity, effectiveness of simulation- and Internet-based tools for forecasting of hospital and regional demand during disasters, effectiveness of reverse triage approaches, development of new disaster surge metrics, validation of mass critical care approaches (altered standards of care), use of telemedicine, and predictions of optimal hospital staffing levels for disaster surge events. Simulation tools appeared to provide some of the highest quality research., Conclusion: Disaster simulation studies have arguably revolutionized the study of disaster surge in the intervening years since the 2006 AEM Science of Surge conference, helping to validate some previously known disaster surge benchmarks and to generate new surge metrics. Use of reverse triage approaches and altered standards of care, as well as Internet-based tools such as Google Flu Trends, have also proven effective. However, there remains significant work to be done toward standardizing research methodologies and outcomes, as well as validating disaster surge metrics., (© 2015 by the Society for Academic Emergency Medicine.)

Background and Purpose: We aimed to characterize the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded K(+) channel (Kv 11.1)., Experimental Approach: Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology., Key Results: AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 μM respectively. At 100 μM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at -30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv 4.3-hKChIP2.2, hCav 3.2 and hKv 1.5 and activated hCav 1.2/β2/α2δ channels., Conclusion and Implications: The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome., (© 2015 The British Pharmacological Society.)

A total of 20 commercial cigarette and 16 commercial smokeless tobacco products were assayed for 96 compounds listed as harmful and potentially harmful constituents (HPHCs) by the US Food and Drug Administration. For each product, a single lot was used for all testing. Both International Organization for Standardization and Health Canada smoking regimens were used for cigarette testing. For those HPHCs detected, measured levels were consistent with levels reported in the literature, however substantial assay variability (measured as average relative standard deviation) was found for most results. Using an abbreviated list of HPHCs, statistically significant differences for most of these HPHCs occurred when results were obtained 4-6months apart (i.e., temporal variability). The assay variability and temporal variability demonstrate the need for standardized analytical methods with defined repeatability and reproducibility for each HPHC using certified reference standards. Temporal variability also means that simple conventional comparisons, such as two-sample t-tests, are inappropriate for comparing products tested at different points in time from the same laboratory or from different laboratories. Until capable laboratories use standardized assays with established repeatability, reproducibility, and certified reference standards, the resulting HPHC data will be unreliable for product comparisons or other decision making in regulatory science., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies - radioligand-binding or automated electrophysiology - was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cardiomyocytes represent one of the most useful models to conduct cardiac research. A single adult heart yields millions of cardiomyocytes, but these cells do not survive for long after isolation. We aimed to determine whether inhibition of myosin II ATPase that is essential for muscle contraction may preserve fully differentiated adult cardiomyocytes. Using inhibitors of the myosin II ATPase, blebbistatin and N-benzyl-p-toluene sulphonamide (BTS), we preserved freshly isolated fully differentiated adult primary cardiomyocytes that were stored at a refrigerated temperature. Specifically, preserved cardiomyocytes stayed viable for a 2-week period with a stable expression of cardiac genes and retained the expression of key markers characteristic of cardiomyocytes. Furthermore, voltage-clamp, action potential, calcium transient and contractility studies confirmed that the preserved cardiomyocytes are comparable to freshly isolated cells. Long-term exposure of preserved cardiomyocytes to four tyrosine kinase inhibitors, sunitinib malate, dasatinib, sorafenib tosylate and imatinib mesylate, revealed their potential to induce cardiac toxicity that was manifested with a decrease in contractility and induction of cell death, but this toxicity was not observed in acute experiments conducted over the time course amenable to freshly prepared cardiomyocytes. This study introduces the concept that the inhibition of myosin II ATPase safeguards the structure and function of fully differentiated adult cardiomyocytes. The fact that these preserved cardiomyocytes can be used for numerous days after preparation makes them a robust and versatile tool in cardiac research and allows the investigation of long-term exposure to novel drugs on cardiomyocyte function., (© 2013.)

Background: Memorial Sloan Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) have established nomograms to predict sentinel node positivity. We propose the addition of two novel variables-distance of tumor from the nipple and from the skin-can improve their performance., Methods: Ultrasounds of clinical T1/T2 tumors were reviewed. Distances of the tumor from the skin and from the nipple were measured. MSKCC and MDACC nomogram predictions and the AUC-ROC for each model were calculated. The added utility of the two variables was then examined using multiple logistic regression., Results: Of 401 cancers studied, 79 (19.7 %) were node positive. The mean distance of tumors from the nipple in node-positive patients was 4.9 cm compared with 6.0 cm in node-negative patients (p = 0.0007). The mean distance of tumors from the skin was closer in node-positive cases (0.8 cm) versus node-negative cases (1.0 cm, p = 0.0007). The MSKCC and MDACC nomograms AUC-ROC values were 0.71 (95 % CI 0.64-0.77) and 0.74 (95 % CI 0.68-0.81). When adjusted for the MSKCC predicted probability, addition of both distance from nipple (p = 0.008) and distance from skin (p = 0.02) contributed significantly to prediction of nodal positivity and improved the AUC-ROC to 0.75 (95 % CI 0.70-0.81). Similarly, distance from nipple (p = 0.002), but not distance from skin (p = 0.09), added modestly to the MDACC nomogram performance (AUC 0.77; 95 % CI 0.71-0.83)., Conclusions: Distance of tumor from the nipple and from the skin are important variables associated with nodal positivity. Adding these to established nomograms improves prediction of nodal positivity.

Background: Ovarian torsion (OT) is one of the most common gynecologic surgical emergencies. All age groups can be affected, but ovarian stimulation, as found during early pregnancy or infertility treatment, is a major risk factor., Objective: Diagnosing OT in early pregnancy can be challenging. Patients frequently present with abdominal pain and non-specific symptoms. Missed diagnosis of OT could lead not only to ovarian necrosis and sepsis, but also threaten the pregnancy. The objective of this article is to present a case of OT in early pregnancy and to review its epidemiology, diagnosis, and treatment., Case Report: A 30-year-old woman at 10 weeks gestational age presented to the Emergency Department (ED) with 2 h duration of abdominal pain, nausea, and vomiting. The patient was not on ovarian stimulation treatments. A bedside ED ultrasound showed an enlarged edematous right ovary with a large cyst, but without flow on color Doppler. Immediate obstetric consultation was initiated. Eventual radiology ultrasound showed decreased but present flow in the right ovary. The patient underwent emergent laparoscopic surgery, during which the necrotic right ovary was removed. She was placed on progesterone therapy upon hospital discharge and eventually delivered a healthy term infant., Conclusions: Ovarian torsion in pregnancy is increasing in frequency due to the growing prevalence of ovarian stimulation treatment. Although diagnostic ultrasound is a frequently used imaging tool in patients with suspected OT, the mere presence of blood flow on Doppler ultrasonography of the adnexa has a poor negative predictive value. A high clinical suspicion and early laparoscopic management correlate with favorable maternal and fetal outcomes., (Published by Elsevier Inc.)

Objectives: Emergency department (ED) computed tomography (CT) use has increased significantly during the past decade. It has been suggested that adherence to clinical decision support (CDS) may result in a safe decrease in CT ordering. In this study, the authors quantified the percentage agreement between routine and CDS-recommended care and the anticipated consequence of strict adherence to CDS on CT use in mild traumatic brain injury (mTBI)., Methods: This was a prospective observational study of patients with mTBI who presented to an urban academic ED of a tertiary care hospital. Patients 18 years or older, presenting within 24 hours of nonpenetrating trauma to the head, from August 2010 to July 2011, were eligible for enrollment. Structured data forms were completed by trained research assistants (RAs). The primary outcome was the percentage agreement between routine head CT use and CDS-recommended head CT use. CDS examined were: the 2008 American College of Emergency Physicians [ACEP] neuroimaging, the New Orleans rule, and the Canadian head CT rule. Differences between outcome groups were assessed using the chi-square test for categorical variables and the Kruskal-Wallis rank test for continuous variables. The percentage agreement between routine practice and CDS-recommended practice was calculated., Results: Of the 169 patients enrolled, 130 (76.9%) received head CT scans, and five of the 130 (3.8%) had acute traumatic intracranial findings. For all subjects, agreement between routine practice and CDS-recommended practice was 77.5, 65.7, and 78.1%, for the ACEP, Canadian, and New Orleans CDS, respectively. Strict adherence to the 2008 ACEP neuroimaging CDS would result in no statistically significant difference in head CT use (routine care, 76.9%; CDS-recommended, 82.8%; p = 0.17). Strict adherence to the New Orleans CDS would result in an increase in head CT use (routine care, 76.9%; CDS-recommended, 94.1%; p < 0.01). Strict adherence to the Canadian CDS would result in a decrease in head CT use (routine care, 76.9%; CDS-recommended, 56.8%; p < 0.01)., Conclusions: There is a 60% to 80% agreement between routine and CDS-recommended head CT use. Of the three CDS systems examined, the only one that may result in a reduction in head CT use if strictly followed was the Canadian head CT CDS. Further studies are needed to examine reasons for the less than optimal agreement between routine care and care recommended by the Canadian head CT CDS., (© 2013 by the Society for Academic Emergency Medicine.)

The automated electrophysiology platform IonWorks has facilitated the medium-throughput study of ion channel biology and pharmacology. Electrical and chemical access to the cell is by perforated patch, afforded by amphotericin. Permeation of the amphotericin pore is limited to monovalent cations. We describe here the use of the saponin escin as an alternative perforating agent. With respect to the number and robustness of seals formed across a variety of cell and ion channel types, the performance of escin is equal to that of amphotericin. Escin also permits the permeation of larger molecules through its pore. These include nucleotides, important intracellular modulators of ion channel activity that can be used to prevent ion channel rundown of, for instance, Ca(V)1.2. Furthermore, pharmacologic agents such as QX314 can also permeate and be used for mechanistic studies. Escin, in combination with IonWorks, increases the scope of ion channel screening and can facilitate the assay of previously difficult-to-assay targets.

Introduction: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association., Methods: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding., Results: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer., Conclusions: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique.

Background: The use of breast magnetic resonance imaging (MRI) for screening high-risk patients is well established. However, the role of MRI as a diagnostic problem-solving tool is less well studied. With the increasing availability of MRI, its use for problem solving has increased. This small retrospective study examines the use and utility of breast MRI in evaluating palpable breast masses with negative diagnostic mammogram and ultrasound studies., Methods: We reviewed our breast MRI database, selecting breast MRI studies performed to assess palpable abnormalities with negative mammogram and ultrasound findings. Evidence of cancer was determined by biopsy., Results: Seventy-seven studies were included, comprising 1.3% of all breast MRI studies performed at our institution during the study period (2005-2011). Twenty-two patients underwent biopsy, and 55 were followed clinically without biopsy. Approximately half (27 of 55) of the patients without biopsy were lost to follow-up after negative MRI, and the rest had no evidence of cancer on imaging or clinical examination at 1 year. Of the 22 patients who underwent biopsy, 2 were diagnosed with cancer, both with positive MRI studies. Sensitivity of MRI when compared to tissue diagnosis was 100%, and specificity was 70%. Positive and negative predictive values were 25% and 100%, respectively., Conclusions: When used for evaluation of a palpable breast mass with negative traditional imaging, breast MRI likely offers low yield of cancer diagnosis and low specificity. Negative MRI results may cause a low compliance rate for recommended follow-up. Because a biopsy is indicated for persistent palpable masses, the addition of diagnostic MRI only adds another step, with associated costs and burdens.

Background: We evaluated the usefulness of axillary ultrasound (US) in patients with core biopsy-proven ductal carcinoma in situ (DCIS)., Methods: Preoperative axillary US, fine-needle aspiration (FNA), and sentinel lymph node (SLN) data from women with DCIS were reviewed., Results: Eighty-two women with DCIS underwent axillary US. In 16 women (19.5%) US was abnormal; however, FNA was negative in all cases. Sixty-one women (74%) underwent SLN surgery; 2 were positive for macrometastasis (3%) and 1 had isolated tumor cells. None of them had an abnormal US. Axillary US did not change the management in any of the cases., Conclusions: Axillary US and FNA did not change the management in any of the 82 cases. In women with a core biopsy diagnosis of DCIS, positive nodes are uncommon and unlikely to be detected by axillary US. Routine preoperative axillary US is not recommended for pure DCIS on core biopsy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Measurement of cardiac contractility is a logical part of pre-clinical safety assessment in a drug discovery project, particularly if a risk has been identified or is suspected based on the primary- or non-target pharmacology. However, there are limited validated assays available that can be used to screen several compounds in order to identify and eliminate inotropic liability from a chemical series. We have therefore sought to develop an in vitro model with sufficient throughput for this purpose. Dog ventricular myocytes were isolated using a collagenase perfusion technique and placed in a perfused recording chamber on the stage of a microscope at ~36 °C. Myocytes were stimulated to contract at a pacing frequency of 1 Hz and a digital, cell geometry measurement system (IonOptix™) was used to measure sarcomere shortening in single myocytes. After perfusion with vehicle (0.1% DMSO), concentration-effect curves were constructed for each compound in 4-30 myocytes taken from 1 or 2 dog hearts. The validation test-set was 22 negative and 8 positive inotropes, and 21 inactive compounds, as defined by their effect in dog, cynolomolgous monkey or humans. By comparing the outcome of the assay to the known in vivo contractility effects, the assay sensitivity was 81%, specificity was 75%, and accuracy was 78%. With a throughput of 6-8 compounds/week from 1 cell isolation, this assay may be of value to drug discovery projects to screen for direct contractility effects and, if a hazard is identified, help identify inactive compounds., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A tiered approach for testing ingredients in a cigarette matrix was developed and includes chemical-analytical testing and a standard battery of biological toxicity assays. These assays were adapted for comparative evaluation of mainstream smoke from experimental cigarettes with or without ingredients at various inclusion levels. This adaptation to test cigarette mainstream smoke may impact assay response. Since it is difficult to a priori determine discriminatory power, it was evaluated using a large experimental dataset from a multi-year program of cigarette ingredient testing performed at two separate laboratories. A statistical method, minimum detectable difference (MDD), was used as a measure of assay discriminatory power. MDD of cigarette smoke constituents ranged from 6% to 29% of the average. Salmonella mutagenicity and cytotoxicity test MDDs ranged from 20% to 81% and 18% to 49%, respectively. Body weight gain in 90-day nose-only inhalation studies yielded an MDD of 30-40%. Histopathological findings with severity scores between 0.5 and 1.5 had the lowest MDDs of 23% and higher. In general, discriminatory power decreased with increasing biological complexity and toxicological relevance of the assay. Beyond statistical analysis, however, a weight-of-the-evidence analysis by experienced researchers is required for toxicological assessment of a cigarette ingredient., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Lymphatic drainage of the breast is via subareolar and dermal lymphatics. The aim of this study was to determine whether distance of breast cancers from the skin and/or distance from the nipple impacts the likelihood of axillary nodal metastases., Methods: A retrospective review was performed of sonographically visible T1 and T2 breast cancers with breast and axillary surgery performed at Mayo Clinic, Rochester, MN. Distance of tumor from the nipple was reviewed. Ultrasounds were reviewed to measure the distance of tumor from the skin., Results: Data were collected on 233 eligible T1 or T2 breast cancers, of which 177 (76%) were node negative and 56 (24%) were node positive. On multivariable analysis, tumor stage and lymphovascular invasion, as well as decreasing distance of the tumor from the nipple and decreasing distance of the tumor from the skin, were significantly associated with axillary lymph node positivity. Each 1-cm decrease in the distance of the tumor from the nipple was associated with a 23% increased likelihood of positive lymph nodes (odds ratio 1.23; P = .003). Each 1-mm decrease in the distance of the tumor from the skin was associated with a 15% increased likelihood of positive lymph nodes (odds ratio 1.15; P = .003)., Conclusion: T1 and T2 breast cancers located closer to the skin and those located closer to the nipple have a higher incidence of metastases to axillary lymph nodes. Distance from the skin and distance from the nipple should be considered when estimating a patient's likelihood of axillary nodal positivity.

Context: Cigarette tobacco ingredients may alter the distribution of chemical constituents present in smoke. When considering the toxicological relevance of potential ingredient-related effects on chemical and biological measurements assessing cigarette smoke toxicity, it is critical to understand the intrinsic variability of tobacco and cigarette smoke that is influenced by the environmental conditions during growing, agricultural practices during preparation, cigarette manufacturing tolerances, and stability of the assay methods., Objective: To understand possible effects of ingredients on cigarette smoke toxicity, various chemical and biological endpoints were measured in smoke from experimental cigarettes (added ingredient) to the intrinsic variability of control cigarettes (no added ingredient)., Materials and Methods: Data were collected during a multi-year program testing a variety of cigarette ingredients from several chemical classes. Chemical analysis of mainstream cigarette smoke,and biological procedures (Salmonella mutagenicity, cytotoxicity, and smoke inhalation) were performed using validated and controlled laboratory methods. The within-study and temporal variation of control cigarettes manufactured in parallel with experimental cigarettes was calculated and used to measure intrinsic variability., Results: The overwhelming majority of data generated from experimental cigarettes fell within the experiment variability represented by the pooled standard error of the entire multi-year dataset for the control cigarettes., Conclusion: The results of this evaluation add to a growing body of the literature regarding a weight of evidence assessment of cigarette ingredient toxicity. When assessed against the variability of assay methodology, natural agricultural change, and manufacturing control, the ingredients studied here demonstrated little relevant influence on the mainstream cigarette smoke toxicity endpoints measured.

Background: Dysgerminoma, the ovarian counterpart of seminoma, is the most common type of malignant ovarian germ cell tumor. The role of KIT mutation and amplification in the development of dysgerminoma is not currently established. The purpose of this study was to analyze alterations of the KIT gene in a large series of dysgerminomas and correlate the findings with clinicopathological parameters., Methods: Dysgerminoma cells from 22 patients were analyzed for KIT mutations at exon 17 codon 816. KIT amplification and chromosome 12p anomalies were investigated by way of dual color fluorescence in situ hybridization. KIT protein expression was also examined by way of immunohistochemistry., Results: KIT exon 17 codon 816 mutations and KIT amplification were each detected in 6 cases of dysgerminoma (27%); however, there was no correlation between these 2 factors. KIT expression was detected in 87% of dysgerminomas. The KIT mutation was associated with advanced pathological stage (P < .05), and KIT amplification was associated with elevated KIT protein expression (P < .05). Chromosome 12p anomalies were found in 82% of the dysgerminomas and did not correlate with KIT abnormalities., Conclusions: KIT mutations occur in approximately one-third of cases of dysgerminomas and are associated with advanced stage at presentation. KIT is a potential therapeutic target for those dysgerminomas that have the mutation., (2010 American Cancer Society.)

Objective: To assess the level of pandemic preparedness at emergency departments (EDs) around the country and to better understand current barriers to preparedness in the United States represented by health professionals in the American College of Emergency Physician (ACEP) Disaster Medicine Section (DMS). METHODS, DESIGN, and, Setting: A cross-sectional survey of ACEP DMS members was performed. A total of 300 members were surveyed both via e-mail and with paper surveys during the 2009 ACEP Scientific Assembly DMS Meeting. An optional comments section was included for section members'perspectives on barriers to preparedness. A 15-item pandemic preparedness score was calculated for each respondent based on key preparedness indicators as defined by the authors. Results were analyzed with descriptive statistics, Chi2 analysis, Cochran-Armitage trend test, and analysis of variance. Free text comments were coded and subjected to frequency-based analysis., Results: A total of 92 DMS members completed the survey with a response rate of31 percent. Although 85 percent of those surveyed indicated that their hospital had a plan for pandemic influenza response and other infectious disease threats, only 68 percent indicated that their ED had a plan, and 52 percent indicated that their hospital or ED had conducted disaster preparedness drills. Only 57 percent indicated that there was a plan to augment ED staff in the event of a staffing shortage, and 63 percent indicated that there were adequate supplies of personal protective equipment. While 63 percent of respondents indicated that their ED had a plan for distribution of vaccines and antivirals, only 32 percent ofEDs had a plan for allocation of ventilators. A total of 42 percent of respondents felt that their ED was prepared in the event of a pandemic influenza or other disease outbreak, and only 35 percent felt that their hospital was prepared. The average pandemic preparedness score among respondents was 8.30 of a total of 15. Larger EDs were more likely to have a higher preparedness score (p=0.03) and more likely to have a pandemic preparedness plan (p=0.037). Some major barriers to preparedness cited by section members included lack of local administration support, challenges in funding, need for dedicated disaster preparedness personnel, staffing shortages, and a lack of communication among disaster response agencies, particularly at the federal level., Conclusions: There appear to be significant gaps in pandemic influenza and other infectious disease outbreak planning among the hospitals where ACEP DMS members work. This may reflect a broader underlying inadequacy of preparedness measures.

Introduction: Terrorist use of a radiological dispersal device (RDD, or "dirty bomb"), which combines a conventional explosive device with radiological materials, is among the National Planning Scenarios of the United States government. Understanding employee willingness to respond is critical for planning experts. Previous research has demonstrated that perception of threat and efficacy is key in the assessing willingness to respond to a RDD event., Methods: An anonymous online survey was used to evaluate the willingness of hospital employees to respond to a RDD event. Agreement with a series of belief statements was assessed, following a methodology validated in previous work. The survey was available online to all 18,612 employees of the Johns Hopkins Hospital from January to March 2009., Results: Surveys were completed by 3426 employees (18.4%), whose demographic distribution was similar to overall hospital staff. 39% of hospital workers were not willing to respond to a RDD scenario if asked but not required to do so. Only 11% more were willing if required. Workers who were hesitant to agree to work additional hours when required were 20 times less likely to report during a RDD emergency. Respondents who perceived their peers as likely to report to work in a RDD emergency were 17 times more likely to respond during a RDD event if asked. Only 27.9% of the hospital employees with a perception of low efficacy declared willingness to respond to a severe RDD event. Perception of threat had little impact on willingness to respond among hospital workers., Conclusions: Radiological scenarios such as RDDs are among the most dreaded emergency events yet studied. Several attitudinal indicators can help to identify hospital employees unlikely to respond. These risk-perception modifiers must then be addressed through training to enable effective hospital response to a RDD event.