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Recent material advancements in organic plastic scintillators enable marked increases in material detection efficiency, light yield, and pulse shape discrimination properties. These advances may resolve significant capability gaps for low-cost, portable, and durable dual-particle imaging (DPI) systems for nuclear safety, security, and safeguard purposes. One such material, a 21% bismuth-loaded polyvinyl toluene (BiPVT), is computationally evaluated as a small, pixelated radiographic array using Monte Carlo N-Particle (MCNP) and Zemax OpticStudio, and it is compared to identical evaluations of EJ-200 and EJ-256 arrays. MCNP software enables estimates of particle interaction and energy deposition, while OpticStudio computes optical light transport within each material. Computational estimates of spatial resolution and relative light collection at 370 kVp are found to agree with experimental results for both EJ-200 and EJ-256 arrays, thereby validating predictions of the same for the BiPVT array. As such, for equivalent exposures at 370 kVp, a BiPVT array may provide $\sim 20\times $ the light collection expected from EJ-200 and $\sim 10\times $ that expected from EJ-256. Similar comparisons of estimated light collection are also computed at 150 and 270 kVp, and these results suggest that BiPVT will provide significantly improved performance over EJ-200 and EJ-256 across all energies practical for portable X-ray radiography.

Governments frequently use financial incentives to encourage the creation, expansion, or relocation of businesses within their borders. Previous research on financial incentives have given little clarity as to what impact these incentives may have on the government. While incentives may draw in more economic growth, they also pull resources from the government’s coffers and may commit future funding for public services that benefit the incentivized business. Using a panel of 32 states from 1990 to 2015, we seek to understand how incentives affect a state’s fiscal health. After controlling for the governmental, political, economic, and demographic characteristics of a state, we find that incentives draw resources away from the state. Ultimately, the results show that financial incentives negatively affect the overall fiscal health of a state.

Plastic scintillators utilizing iridium complex fluorophores offer substantial improvements in light yield, and their light yield is not significantly quenched in compositions with bismuth metalorganic loading, at a loading level of 21 wt% bismuth metal. This new bismuth plastic (Ir-Bi-Plastic) offers improved detection efficiency over commercial plastic scintillators. One application for Ir-Bi-Plastic is in low-cost, portable, and durable dual-particle imaging (DPI) systems supporting nuclear safety, security, and safeguards. However, new materials must undergo investigation using industry standards to quantify their capabilities. In this work, an Ir-Bi-Plastic was experimentally evaluated as a small, pixelated radiographic array in a fast neutron environment, with individual pixel dimensions of 2×2×19 mm. For comparison, identical evaluations were conducted for two similarly sized arrays made from EJ-200 and EJ-256. A separate Ir-Bi-Plastic array with 5×5×20 mm pixels was also evaluated. ASTM methods were leveraged to determine the modulation transfer function and spatial resolution for each array. Edge response measurements of a 2-in thick tungsten block were recorded by pressure coupling all four arrays to a commercial a-Si digital radiographic panel. Experimental results were then compared for all four arrays, and the results demonstrated that the Ir-Bi-Plastic outperforms similar arrays made from EJ-200 and EJ-256 (5 wt% Pb). These findings suggest that DPI systems utilizing Ir-Bi-Plastic hold promise for continued development over older, more traditional, alternatives.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (&lt, 50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

Radiation protection factor (RPF) values are relevant to various US defense and civil support organizations. An equation was developed to quantify the angular-dependent protection of a shielding configuration in the presence of a mono-energetic radiation field. Values of ambient dose equivalent, H*(10), were computed with version 6.1 of the Monte Carlo N-Particle Code (MCNP6.1) for more than 70 distinct, mono-energetic, planar photon and neutron fields using both the kerma approximation and energy deposition from primary and secondary radiations. The two computational approaches were compared, and the MCNP6.1 models were then modified to simulate the same radiation fields and compute values of directional dose equivalent, H′(10,α), in a tissue sphere centered inside a surrogate vehicle for 13 angles of incidence. Values of H*(10) and H′(10,α) were recast as energy- and angular-dependent RPF values for the incident field–shielding geometries and tabulated. Examples of implementation are provided, and limitations are discussed.

In our information-driven society, there is increasing use of statistical graphics to convey information in a variety of settings, including industry, mass media, government operations, and health care. Current methods for assessing a reader’s ability to comprehend statistical graphics are custom-written, not widely accepted, usable only once, and/or reliant on subjective interpretations and inferences. We have developed a method for generating queries suitable for evaluating graph comprehension capability. Our method is based on the Sentence Verification Technique (SVT), an empirically validated framework for measuring an individual’s comprehension of prose material. Compared to ad hoc methods for testing graph comprehension, our technique is less subjective, requires less manual effort and subject matter expertise, and addresses the essential features of a given graph: values and relationships depicted, frames of reference, and style attributes. The SVT, and therefore our method, combat superficial comprehension by testing what the reader has encoded, as opposed to testing the reader’s ability at visual recall or ability to look up data without reaching real comprehension. We motivate and describe our query generation method and report on a pilot study using queries generated with it.

PURPOSE: The ColoCare Study is an international cohort of men and women (>18 years age) newly diagnosed with stage I-IV colorectal cancer from seven centers in the United States and Germany. Study enrollment is currently ongoing. Here, we describe the clinical and demographic characteristics of this large cohort of prospectively followed colorectal cancer patients and describe differences in demographic, lifestyle, and clinical characteristics by age of onset and tumor site. METHODS: Data on demographics (sex, age, race, ethnicity) and lifestyle factors (smoking, body mass index) collected at baseline are included in this analysis, in addition to information on tumor characteristics (tumor stage and site), treatment (neoadjuvant and adjuvant therapy), and clinical outcomes (vital status, recurrence). Patients were categorized into early- ( RESULTS: Data on 1,933 stage I-IV colorectal cancer cases were included in this study, 19% of which were deceased at the time of this analysis. On average, patients were 60 years old, had a BMI of 29 kg/m2, and were predominantly diagnosed with stage II (25%) and stage III (33%) colorectal cancer. Fifty three percent of cases were diagnosed with colon cancer, while 47% were rectal cancer cases. Twenty percent (n=364) of patients were diagnosed before age 50 (i.e. early-onset cases). The early-onset group presented with a higher percentage of rectal cancer (52%) and more advanced disease (64% stage III-IV cancer) compared to late-onset cases (46% and 48%, respectively). Percentages of ever smokers were higher among late-onset compared to early-onset patients (51% vs. 38%), independent of tumor site. Early-onset cancers were more likely to originate in the rectum compared to colon, particularly among women (61% vs. 51%). Early-onset rectal cancer cases were more likely to be female as compared to late-onset rectal cancer cases (61% vs. 36%). Corresponding with national trends, early-onset cases received more aggressive adjuvant therapy after surgical resection compared to late-onset patients (54% vs. 40%). DISCUSSION: Within this large international multi-center cohort, patients with early-onset colorectal cancer were more likely to be diagnosed with rectal cancer and advanced stage disease. The majority of early-onset cases in the ColoCare Study were non-smokers. As expected, more aggressive treatment modalities were used in patients with early-onset disease. Citation Format: Caroline Himbert, Jane Figueiredo, Lyen Huang, Biljana Gigic, Courtney L. Scaife, Bartley Pickron, Laura Lambert, Jessica Cohan, Mary Bronner, Jolanta Jedrzkiewicz, Esther Herpel, Matthias Kloor, Johanna Nattenmueller, Hans-Ulrich Kauczor, Alexis Ulrich, Seth Felder, Julian Sanchez, Sophie Dessureault, Nathan Hinkle, Justin Monroe, Matthew Mutch, Cory Bernadt, Deyali Chatterjee, Mika Sinanan, Stacey Cohen, Ulrik Wallin, Deepti Reddi, Mukta Krane, Afshin E. Gabayan, David M. Hoffman, Yosef Y. Nasseri, Robert W. Decker, Karen Zaghiyan, Zuri A. Murrell, Andrew E. Hendifar, Jun Gong, Eiman Firoozmand, Alexandra Gangi, Beth A. Moore, Kyle G. Cologne, Maryliza El-Masry, William Grady, Martin Schneider, Stephanie L. Schmit, Erin Siegel, David Shibata, Adetunji Toriola, Christopher Li, Cornelia Ulrich, Sheetal Hardikar. Clinical characteristics and outcomes of colorectal cancer in the ColoCare Study: Differences by age of onset [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 2364.

Computational and experimental estimates of radiation protection factor (RPF) values are of significant interest to various defense-related organizations. Values of the operational quantity of ambient dose equivalent were computed, using version 6.1 of the Monte Carlo N-Particle® code (MCNP6.1), for 25 photon energies and 53 neutrons energies. Energy-dependent values for absorbed dose at a 10-mm depth in the 30-cm-diameter ICRU tissue-equivalent sphere, D * ( 10 ) , were estimated using the kerma approximation for photon (MCNP F6:p tally) and neutron (MCNP F6:n tally) radiation fields, and then transformed to fluence-to-ambient dose equivalent conversion coefficients, H * ( 10 ) / ϕ , using appropriate quality factors, Q, and radiation fluences. MCNP6.1-computed values of H * ( 10 ) / ϕ were compared with tabulated values from ICRP Publication 74. The published conversion coefficients for photon radiation fields were within the error bounds of all MCNP6.1-calculated values. For neutron fields, the computed and published conversion coefficients agreed within calculated error bounds for neutron energies of 100 keV and above, while responses to neutron fields below 100 keV exhibited the same shape and were consistent with the kerma approximation applied in the computational model. The MCNP6.1 models were then modified to simulate the same radiation fields, but H * ( 10 ) / ϕ conversion coefficients were calculated in the shielded environment of a surrogate vehicle (steel cube)—in keeping with historical and recent studies—and the ratios of shielded and unshielded vehicle response functions were expressed as energy-dependent RPF values. The MCNP6.1-computed neutron RPF values were compared with two prior experimental studies involving a mono-energetic neutron source and a high-yield, short-duration fission neutron spectrum and found to agree within the uncertainty of the experimentally-measured values. Limitations of the computed RPF values are discussed.

Background ABT-126 is a novel, safe, and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated squirrel monkeys with moderate and more severe nigrostriatal damage. Methods Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT-126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only 1× to 2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. Results With moderate nigrostriatal damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1×-2×), ABT-126 dose-dependently decreased dyskinesias (∼60%), with similar results seen with ABT-894 (∼60%) or nicotine (∼60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. Conclusion The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society

This clinical policy focuses on critical issues in the evaluation and management of patients with acute myocardial infarction or unstable angina. A MEDLINE search for articles published between January 1993 and December 1998 was performed using combinations of the key words chest pain, acute myocardial infarction, unstable angina, thrombolytics, primary angioplasty, 12-lead ECG, ST-segment monitoring, cardiac serum markers, and chest pain centers. Subcommittee members and expert peer reviewers also supplied articles with direct bearing on the policy. This policy focuses on 5 areas of current interest and/or controversy: (1) ECG eligibility criteria for fibrinolytic therapy, (2) role of primary angioplasty in patients with acute myocardial infarction, (3) use of serum markers to diagnose acute myocardial infarction, (4) serial 12-lead ECGs during the initial evaluation, and (5) chest pain evaluation units. Recommendations for patient management are provided for each of these 5 topics based on strength of evidence (Standards, Guidelines, Options). Standards represent patient management principles that reflect a high degree of clinical certainty; Guidelines represent patient management principles that reflect moderate clinical certainty; and Options represent other patient management strategies based on preliminary, inconclusive, or conflicting evidence, or based on panel consensus. This guideline is intended for physicians working in hospital-based emergency departments or chest pain evaluation units. [American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting with suspected acute myocardial infarction or unstable angina. Ann Emerg Med. May 2000;35:521-544.].

Background Anaphylaxis is a potentially life-threatening allergic reaction that may require emergency medical system (EMS) transport. Fatal anaphylaxis is associated with delayed epinephrine administration. Patient outcome data to assess appropriateness of EMS epinephrine administration are sparse. Objectives The objectives of this study are to (1) determine the frequency of epinephrine administration in EMS-transported patients with allergic complaints, (2) identify predictors of epinephrine administration, and (3) determine frequency of emergency department (ED) epinephrine administration after EMS transport. Methods A cohort study was conducted from over 5 years. A total of 59187 EMS transports of an Advanced Life Support (ALS) ambulance service were studied. Results One hundred and three patient transports for allergic complaints were analyzed. Fifteen patients received EMS epinephrine, and epinephrine was recommended for 2 additional patients who refused, for a total of 17 (17%) patients for whom epinephrine was administered or recommended. Emergency medical system epinephrine administration or recommendation was associated with venom as a trigger (29% vs 8%; odds ratio [OR], 4.70; 95% confidence interval [CI], 1.28-17.22; P = .013), respiratory symptoms (88% vs 52%; OR, 6.83; 95% CI, 1.47-31.71; P = .006), and fulfillment of anaphylaxis diagnostic criteria (82% vs 49%; OR, 3.50; 95% CI, 0.94-13.2; P = .0498). Four (4%) patients received epinephrine after ED arrival. Conclusion Low rates of epinephrine administration were observed. The association of EMS administration of epinephrine with respiratory symptoms, fulfillment of anaphylaxis diagnostic criteria, and low rate of additional epinephrine administration in the ED suggest that ALS EMS administered epinephrine based on symptom severity. Additional studies of EMS anaphylaxis management including ED management and outcomes are needed.

L-dopa is the gold standard treatment for Parkinson’s disease motor symptoms 1, 2. However, although L-dopa improves the tremor, rigidity and bradykinesia, particularly in the early stages, there is a loss of efficacy with disease progression. Moreover, side effects arise including abnormal involuntary movements or dyskinesias that limit its usefulness 3, 4. New treatment strategies to reduce L-dopa-induced dyskinesias (LIDs) are therefore a key research focus. Extensive studies show that drugs targeting the serotonergic, glutamatergic adrenergic, noradrenergic, cannabinoid and histaminergic systems attenuate LIDs to varying extents in animal models of Parkinson’s disease 4-9. Furthermore, L-dopa treatment modulates expression of numerous molecular and cellular markers linked to these neurotransmitters. Thus drugs targeting these CNS systems have potential as antidyskinetic agents. However, useful clinical candidates have proved elusive because they cause parkinsonism or lead to other adverse side effects 4. Recent pre-clinical studies show that drugs directed to the nicotinic cholinergic system improve LIDs in parkinsonian mice, rats and monkeys 10-14. Nicotine reduced LIDs using several methods of administration including oral application, injection and slow-release minipump with no decline in its effectiveness with time 10-14. Nicotine acts at nAChRs, of which there are multiple subtypes. This includes receptors in both the peripheral and central nervous system, such as α1β1*, α3β4*, α4β2*, α6β2* and α7 as well as other minor receptor subtypes 15, 16. The asterisk denotes the possible presence of other nAChR subunits in the receptor. Notably, the α4β2* and α6β2* nAChR subtypes are expressed only in the brain 15, 17. These subtypes are of relevance to LIDs, as studies in α4, α6, and β2 nAChR null mutant mice show that they regulate LIDs 14. Thus, drugs targeting α4β2* and α6β2* nAChRs may yield a selective therapy to reduce LIDs. Studies have been done to evaluate whether such drugs reduce LIDs in parkinsonian animals. The general nAChR agonist varenicline, as well as several β2* selective agonists including A-85380, sazetidine, TC-2696, TI-10165, TC-8831 and TC-10600 reduced LIDs to varying extents in rats with a unilateral 6-hydroxydopamine lesion 18, 19. Additionally, varenicline and TC-8831 decreased LIDs ~50% in nonhuman primates with no development of tolerance 20, 21. These combined results suggest that nAChR drugs may be useful for the management of LIDs, although a limitation of the drugs tested to date in nonhuman primates was the development of emesis 22. The objective of the present experiments was to investigate the potential of two β2* selective nAChR agonists that had previously been evaluated in phase 2 clinical trials for other indications with minimal side effects. This included ABT-089, a partial nAChR agonist 23-27, as well as the full agonist ABT-894 28-30. The results show that ABT-089 and ABT-894 reduced LIDs in nonhuman primates with no adverse responses, suggesting they may be a useful treatment for LIDs in Parkinson’s disease.

Idiosyncratic drug-induced liver injury (DILI) is a rare form of liver injury that occurs in patients taking therapeutic doses of drugs. While idiosyncratic hepatotoxic drugs are not structurally or chemically related, most drugs that cause DILI have been shown to “stress” mitochondria through inhibition of mitochondrial respiration, increased mitochondrial reactive oxygen species (ROS) generation, and other changes that disrupt mitochondrial homeostasis. In most cases, hepatocytes adapt to drug-induced mitochondrial stress by activating adaptation signaling pathways, including mitochondrial adaptive responses such as autophagy/mitophagy, mitochondrial remodeling, and alterations in mitochondrial fusion-fission. Due to these adaptations, drug intake alone is not sufficient to cause liver injury, with acetaminophen being the notable exception. Idiosyncratic DILI involves other extrinsic factors, including inflammation and the adaptive immune system. Inflammation may promote DILI because mitochondrial stress (i.e., increased mitochondrial ROS generation) induced by hepatotoxic drugs can inhibit adaptation/survival signaling pathways, such as NF-κB, needed to withstand the cytotoxic effects of tumor necrosis factor-α (TNF) released during inflammation. If mitochondrial and hepatocellular injury reach a critical threshold, death signaling pathways involving c-Jun N-terminal kinase (JNK) that target mitochondria become activated. Binding of activated JNK to mitochondria triggers the mitochondrial permeability transition (MPT) that results in hepatocyte death and liver injury. Mitochondria, therefore, play a critical role in all stages of DILI.

Statistical graphs are images that display quantitative information in a visual format that allows for the easy and consistent interpretation of the information. Often, statistical graphs are in the form of line graphs or bar graphs. In fields, such as cybersecurity, sets of statistical graphs are used to present complex information; however, the interpretation of these more complex graphs is often not obvious. Unless the viewer has been trained to understand each graph used, the interpretation of the data may be limited or incomplete [1]. In order to study the perception of statistical graphs, we tracked users’ eyes while studying simple statistical graphs. Participants studied a graph, and later viewed a graph purporting to be a subset of the data. They were asked to look for a substantive change in the meaning of the second graph compared to the first.

A proposed simply structured gated silicon (Si) drift X-ray detector operated using Peltier cooling and only a single high-voltage source is investigated. Because the device structure is much simpler than that of commercial Si drift detectors (SDDs), which require at least two high-voltage sources, the cost of the X-ray detection system can be reduced. The absorption of cadmium X-ray fluorescence photons (energy: 23.1 keV) in 0.3-mm-thick Si is only 19% in commercial SDDs. Toward realizing detectors with thicker Si substrates, we simulate the electric potential distribution in the proposed detector with a Si substrate having thickness of 0.625 mm and resistivity of 10 kΩ·cm, and we perform fundamental experiments on a fabricated prototype. The simulation result is in good agreement with the experimental result that the effective active area of the detector is approximately 18 mm2 by using incident X-rays passed through a 0.1-mm-diameter pinhole. An energy resolution of 145 eV at 5.9 keV is experimentally obtained from an 55Fe source at -38 °C.

Syncope, a clinical syndrome, has many potential causes. The prognosis of a patient experiencing syncope varies from benign outcome to increased risk of mortality or sudden death, determined by the etiology of syncope and the presence of underlying disease. Because a definitive diagnosis often cannot be established immediately, hospital admission is frequently recommended as the "default" approach to ensure patient's safety and an expedited evaluation. Hospital care is costly while no studies have shown that clinical outcomes are improved by the in-patient practice approach. The syncope unit is an evolving practice model based on the hypothesis that a multidisciplinary team of physicians and allied staff with expertise in syncope management, working together and equipped with standard clinical tools could improve clinical outcomes. Preliminary data have demonstrated that a specialized syncope unit can improve diagnosis in a timely manner, reduce hospital admission and decrease the use of unnecessary diagnostic tests. In this review, models of syncope units in the emergency department, hospital and outpatient clinics from different practices in different countries are discussed. Similarities and differences of these syncope units are compared. Outcomes and endpoints from these studies are summarized. Developing a syncope unit with a standardized protocol applicable to most practice settings would be an ultimate goal for clinicians and investigators who have interest, expertise, and commitment to improve care for this large patient population.

Background Diagnostic criteria were proposed at the Second Symposium on the Definition and Management of Anaphylaxis convened by the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN). Validation is needed before these criteria can be widely adapted into clinical practice. Objective Our aim was to retrospectively assess the diagnostic accuracy of the NIAID/FAAN criteria for the diagnosis of anaphylaxis in emergency department (ED) patients. Methods A retrospective cohort study of ED patients presenting from April to October 2008 was conducted. Patients given a diagnosis of an allergic reaction or anaphylaxis and a subset of patients with related diagnoses were included. Electronic medical records were reviewed and data were abstracted to determine whether the NIAID/FAAN criteria were met. Records were also independently reviewed in a blinded fashion by 2 experienced attending allergists. Final diagnosis by allergists was considered the reference standard. Results Of 214 patients, 86 (40.2%) met the NIAID/FAAN criteria for anaphylaxis. Allergists gave 61 (28.5%) patients diagnoses of anaphylaxis, 59 (96.7%) of whom satisfied the NIAID/FAAN criteria. The interrater agreement between allergists was substantial (κ = 0.77). The test characteristics of the NIAID/FAAN criteria were as follows: sensitivity, 96.7% (95% CI, 88.8% to 99.1%); specificity, 82.4% (95% CI, 75.5% to 87.6%); positive predictive value, 68.6% (95% CI, 58.2% to 77.4%); negative predictive value, 98.4% (95% CI, 94.5% to 99.6%); positive likelihood ratio, 5.48; and negative likelihood ratio, 0.04. Conclusions These results suggest that the NIAID/FAAN criteria are highly sensitive but less specific and are likely to be useful in the ED for the diagnosis of anaphylaxis.

We have proposed two types of simple-structure silicon (Si) X-ray detectors with 1.5-mm-thick high-resistivity Si substrates, which are able to be operated at reasonably low negative bias and cooled by Peltier cooling. Since the device structures are simple and the detectors require only one high voltage, the cost of the X-ray detection system can be reduced very much. Moreover, the absorption of cadmium X-ray fluorescence (energy: 23.1 keV) in 1.5-mm-thick Si is approximately 65%, whereas in commercial silicon drift detectors (Si thickness: approximately 0.3 mm), it is approximately 19%. We have simulated the electric potential distribution within the proposed detectors and carried out fundamental experiments towards the realization of the detectors.

This review highlights some of the many contributions of the late Dr. Jerry J. Buccafusco to the neurobiology of nicotinic acetylcholine receptors (nAChRs) and cognition over a 25 year period. The article is written by two of Dr. Buccafusco's professional colleagues, one from academia and one from the pharmaceutical industry. While Dr. Buccafusco's expertise in the cholinergic field was extensive, his insights into the practical relevance of his work (with a long-term goal of formulating new drug development strategies) were unique, and a great asset to both the basic science community and pharmaceutical companies. In 1988, Dr. Buccafusco's laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he studied a large number of novel pro-cognitive agents from several pharmacological classes in rodents as well as monkeys. Based on years of observing paradoxical effects of nicotinic ligands in vitro and in vivo, Dr. Buccafusco made the provocative argument that it might be possible to develop new chemical entities (with pro-cognitive actions) that have the ability to desensitize nAChRs without producing an antecedent agonist action. Some of his more recent work focused on development of single molecular entities that act on multiple CNS targets (including nAChRs) to enhance cognition, provide neuroprotection, and/or provide additional therapeutic actions (e.g., antipsychotic effects). Dr. Buccafusco's influence will live on in the work of the numerous graduate students, postdoctoral fellows, and junior faculty that he mentored over the years who now serve in prestigious positions throughout the world.

We have previously reported the association of hyperglycemia and mortality after ischemic stroke. This study attempts to answer the hypothesis, if hyperglycemia at arrival, is associated with early mortality and functional outcome in patients with acute non-traumatic intracerebral hemorrhage (ICH). The study cohort consisted of 237 patients who presented to the ED with ICH and had blood glucose measured on ED presentation. The presence of hyperglycemia on presentation was correlated with outcome measures including volume of hematoma, intraventricular extension of hematoma (IVE), stroke severity, functional outcome at discharge, and date of death. Of the cohort of 237 patients, a total of 47 patients had prior history of Diabetes Mellitus (DM). Median blood glucose at presentation was 140 mg/dl (Inter-quartile range 112–181 mg/dl). DM patients had higher glucose levels on arrival (median 202 mg/dl for DM vs. 132.5 mg/dl for non-DM, P

We sought to examine the relationship of the QTc interval with mortality and functional outcome after acute ischemic stroke, and determine whether a threshold cutoff is present beyond which risk of death increases.The QTc interval was measured for all patients presenting to the emergency department. The outcomes were mortality at 90 days and functional outcome at hospital discharge. The cutoffs were determined plotting martingale residuals.Patients with a prolonged QTc interval were more likely to die within 90 days compared with patients without a prolonged interval (relative risk [RR] 2.5; 95% confidence interval [CI] 1.5-4.1; P.001). The estimated survival at 90 days was 70.5% and 87.1%, respectively. This association retained statistical significance after adjusting for age and National Institutes of Health Stroke Scale score (RR 1.7; 95% CI 1.0-2.9; P = .043). Patients with a prolonged QTc interval were also more likely to have poor functional status compared with patients without a prolonged interval (odds ratio 1.8; 95% CI 1.2-3.0; P = .006). This association was not statistically significant after adjusting for age and National Institutes of Health Stroke Scale score (odds ratio 1.2; 95% CI 0.7-2.4). The identified threshold cutoffs for increased risk of death at 90 days were 440 milliseconds for women and 438 milliseconds for men.There appears to be an increased risk of early death in patients with acute ischemic stroke and a prolonged QTc interval at the time of emergency department presentation. Prognosis appears to be worse with QTc intervals longer than 440 milliseconds in women and longer than 438 milliseconds in men.

Background— American College of Cardiology/American Heart Association guidelines recommend a door-to-balloon time (DTB) Methods and Results— The Mayo Clinic STEMI protocol was implemented in April 2004 and included activation of the cardiac catheterization laboratory by the emergency medicine physician; a single call system to activate the catheterization laboratory; catheterization laboratory staff arrival within 20 to 30 minutes of activation; and real-time performance feedback within 24 to 48 hours. Data were collected on nontransferred STEMI patients. The preimplementation group (June 2002 to March 2004) comprised 96 patients with a median DTB of 97 (interquartile range, 82, 130) minutes, and 40% had a DTB P P =0.41). Conclusions— The Mayo Clinic STEMI protocol implemented strategies to reduce DTB for nontransferred patients with STEMI. DTB was significantly reduced, and the results were sustained over the 4-year follow-up period. Our experience demonstrates the effectiveness and durability of process changes targeting timeliness of primary percutaneous coronary intervention.

Background and purpose: Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain. Experimental approach: WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB1 and CB2 receptor antagonists. Key results: WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB1 versus CB2 receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB1 receptor antagonist, but not with a CB2 receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB1 and CB2 antagonists blocked systemic WIN-induced analgesic activity. Conclusions and implications: Both CB1 and CB2 receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB1 but not CB2 receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB1 receptors in the brain. British Journal of Pharmacology (2009) 157, 645–655; doi:10.1111/j.1476-5381.2009.00184.x; published online 3 April 2009

Background Statins have been shown to improve the functional outcome of patients after an ischemic stroke. We hypothesized that daily statin intake improves functional outcome after an acute ischemic stroke in patients with low-density lipoprotein (LDL) less than or equal to 100 mg/dL. Methods This was a prospective cohort study during a 22-month period of patients presenting with an acute ischemic stroke and lipid profiles measured. The functional disability was determined using modified Rankin scale score (0-2 good outcome, 3-6 bad outcome) at discharge. Chi-square test for binary data and nonparametric tests for nonnormally distributed variables were used for analysis. Results Of 508 patients, 207 presented with an LDL of 100 mg/dL or less and were included in the analysis. There was no significant difference in admission stroke severity (National Institutes of Health Stroke Scale [NIHSS]; P = .18), age ( P = .31), and sex ( P = .06) between those taking statins and not taking statins. Patients with LDL less than or equal to 100 mg/dL and taking statins (n = 100) were significantly more likely to have a good functional outcome (odds ratio 1.91; 95% confidence interval 1.05-3.47) when compared with those not on the medication. After adjusting for age, sex, and NIHSS, statin intake still predicted a better functional outcome ( P Conclusion Daily statin intake appears to result in a better functional outcome after an ischemic stroke in patients with ideal LDL levels (≤100 mg/dL) before and after adjusting for age and stroke severity. Pleiotropic effects of statins may play a role in this.

Objective: To assess stroke awareness among patients presenting to the emergency department with an acute ischaemic stroke or transient ischaemic attack (TIA). Methods: A consecutive cohort of patients presenting with a cerebrovascular event was prospectively enrolled over a 15-month period and questionnaires were administered. If the patient was unable to respond to the questions or answer the questionnaire, it was administered to the primary caregiver. Comprehension of having a cerebrovascular event, reason for delay in presentation, mode of arrival and knowledge of treatment modalities were determined. Results: Only 42% of 400 patients thought they were having a stroke or TIA. The median time to presentation was 3.4 h. Delayed presentation was almost equal in men and women. When asked about onset, 19.4% thought that a stroke came on gradually and only 51.9% thought immediate presentation was crucial. 20.8% of patients had heard of thrombolysis. Conclusion: Community knowledge of ischaemic stroke needs to be enhanced so that individuals present earlier, leading to timely management.

The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti-inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic beta-cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic beta-cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10 years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of beta-cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving beta-cell function in type 2 diabetes as well as the ability of these agents to exert anti-inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed.

Background Exercise treadmill testing (ETT) has been standard for evaluating outpatients at risk for cardiovascular events. Few studies have demonstrated its prognostic usefulness in emergency department chest pain units or have used the Duke score [(exercise duration in minutes) − (5 × ST-segment deviation in millimeters) − (4 × treadmill angina index)] to grade its performance. Aims Our objective was to assess the usefulness of this score in a chest pain unit to predict cardiovascular events. Methods From November 2000 to October 2001, we retrospectively studied consecutive patients in the chest pain unit. Those undergoing ETT were stratified into “low” (Duke score ≥ 5) and “moderate/high” risk groups ( 24 h after presentation, revascularization, acute congestive heart failure, stroke or arrhythmia were identified within 1 year after presentation. Differences in risk of having a cardiovascular event among low-risk and moderate/high-risk groups are presented. Results During the study period, 1,048 patients entered the chest pain unit; 800 met inclusion criteria. Of these, 599 received ETT and 201 had contraindications or a positive finding in the chest pain unit protocol before ETT. Cardiovascular event rates were 0.7% (3/454), 15.2% (22/145) and 14.9% (30/201) after 1 month of follow-up for low-risk, moderate/high-risk and no-ETT groups, respectively. Conclusions According to the Duke score, the low-risk group developed minimal cardiovascular events compared with the moderate/high-risk group. The Duke score appears effective for risk stratification of chest pain patients in chest pain units.

To determine if differences in outcome exist between diabetic and non-diabetic patients who present to the Emergency Department (ED) with acute ischemic stoke (AIS) and elevated blood glucose. The study population consisted of 447 consecutive patients who presented to the ED with AIS within 24 h of symptom onset and had blood glucose measured on presentation. Hyperglycemia was defined as >130 mg/dl. Outcomes studied included infarct volume, stroke severity (NIH Stroke Scale), functional impairment (modified Rankin Score), and 90-day mortality. Patients with hyperglycemia were then stratified into those with and without a prior history of diabetes mellitus (DM) for the purposes of analysis. Patients with hyperglycemia exhibited significantly greater stroke severity (P = 0.002) and greater functional impairment (P = 0.004) than those with normoglycemia. Patients with hyperglycemia were 2.3 times more likely to be dead at 90 days compared to those with normal glucose (P

The problem of automatically recognizing a user’s operational context, the implications of its shifting properties, and reacting in a dynamic manner are at the core of mission intelligence and decision making. Environments such as the OZONE Widget Framework (http://www.owfgoss.org) (OWF) provide the foundation for capturing the objectives, actions, and activities of both the mission analyst and the decision maker. By utilizing a “context container” that envelops an OZONE Application, we hypothesize that both user action and intent can be used to characterize user context with respect to operational modality (strategic, tactical, opportunistic, or random). As the analyst moves from one operational modality to another, we propose that information visualization techniques should adapt and present data and analysis pertinent to the new modality and to the trend of the shift. As a system captures the analyst’s actions and decisions in response to the new visualizations, the context container has the opportunity to assess the analyst’s perception of the information value, risk, uncertainty, prioritization, projection, and insight with respect to the current context stage. This paper will describe a conceptual architecture for an adaptive work environment for inferring user behavior and interaction within the OZONE framework, in order to provide the decision maker with context relevant information. We then bridge from our more conceptual OWF discussion to specific examples describing the role of context in decision making. Our first concrete example demonstrates how the Web analytics of a user’s browsing behavior can be used to authenticate users. The second example briefly examines the role of context in cyber security. Our third example illustrates how to capture the behavior of expert analysts in exploratory data analysis, which coupled with a recommender system, advises domain experts of “standard” analytical operations in order to suggest operations novel to the domain, but consistent with analytical goals. Finally, our fourth example discusses the role of context in a supervisory control problem when managing multiple autonomous systems.

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach.

Background Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Allergists and emergency department (ED) physicians recognize the need for multidisciplinary efforts to increase public awareness of anaphylaxis, improve patient education, and enhance emergency and long-term management for the millions of Americans at risk for anaphylactic reactions. Objectives To provide an overview of the scientific literature documenting inconsistencies and limitations in the management of anaphylaxis in the ED, to highlight the need to enhance ED discharge instructions and patient education materials, and to introduce the SAFE system, an aid to improve the ongoing management and avoidance of factors that contribute to anaphylaxis. Methods An expert panel of allergists and ED physicians was convened by the American College of Allergy, Asthma and Immunology and the American College of Emergency Physicians to develop recommendations for educational materials on anaphylaxis for ED personnel and patients. Results The panel developed the acronym SAFE, a mnemonic device to remind physicians of the 4 basic action steps suggested for the care of a patient with anaphylaxis: (1) Seek support, (2) Allergen identification and avoidance, (3) Follow-up for specialty care, and (4) Epinephrine for emergencies. Conclusion The SAFE system is designed as a tool to raise awareness of anaphylaxis and its treatments among individuals at risk and the ED personnel charged with their care. Future studies need to examine the impact of the SAFE system in decreasing the morbidity and mortality rates associated with anaphylaxis and other severe allergic reactions.

This study examined whether suppression of mammary gland carcinogenesis elicited by low doses of tamoxifen (TAM) can be enhanced by concomitant treatment of rats with indole-3-carbinol (I3C), a component of cruciferous vegetables and a dietary supplement used for its putative antiestrogenicity. Two weeks after one oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 65 mg/kg body weight, female Sprague-Dawley rats started treatment with TAM (10 microg/rat) by subcutaneous injection, I3C (250 mg/kg body weight) by oral gavage, TAM+I3C or their respective vehicles three times per week, for up to 20 weeks. Significant increases in the median latency of malignant mammary tumors and decreases in the mean tumor mass per rat were due to TAM. Significant decreases in the mean tumor number per rat in TAM, I3C and TAM+I3C-treated rats indicated a cooperative effect of the two compounds. In both DMBA-initiated and uninitiated rats, significant increases in the ratios of liver to body weight in I3C and TAM+I3C-treated groups coincided with I3C-dependent increases of hepatic cytochrome P450 levels and activities (1A1, 1A2 and 2B1/2). The ratios of uterus to body weight decreased with the number of treatments and the decreases effected by TAM were greater than those by I3C. The levels of circulating estrone were increased in response to I3C treatment and were greater in DMBA-initiated rats than in uninitiated rats, which may contribute to the preventive effect of I3C. Chemoprevention may be accomplished through up-regulation of apoptotic enzyme (caspase) activities in the mammary gland or mammary tumors. Treatment with TAM, I3C or TAM+I3C had no effect on caspase-3&7, caspase-6, caspase-8 and caspase-9 activities in the mammary tumors or mammary gland of tumor-bearing rats or that of uninitiated rats. In the mammary gland of DMBA-initiated tumor-free rats, however, I3C treatment increased the levels of caspase-3&7 and caspase-9 activities, suggesting an I3C-mediated protective effect. Even though I3C alone is a much less effective suppressing agent of mammary carcinogenesis than TAM, I3C in combination with TAM does not weaken but may foster the benefits of chemoprevention with TAM.

Purpose of review In the absence of an established critical pathway to evaluate patients with syncope presenting to the emergency department, this review is timely because of new clinical evidences supporting a specialized syncope management unit in the emergency department, and it is relevant because of the potential impact on a very large and heterogeneous population. Recent findings Three observational syncope studies from Italy showed a high degree of variability in practice patterns, diagnostic yields, and lengths of hospital stay. An appropriate and efficacious syncope management pathway in the emergency department remains far from established. In a randomized trial from a tertiary care hospital in the US, the SEEDS study demonstrated that a designated 'syncope unit' in the emergency department, with a multidisciplinary effort and appropriate resources, significantly improved diagnostic yield, reduced hospital admission and total length of hospital stay in intermediate-risk patients. Long-term follow-up showed that reduced hospital stay did not negatively affect survival and recurrent syncope. Summary Limited randomized trial data suggest a designated syncope unit in the emergency department holds promise to provide specialized and efficient care for patients with syncope. Additional data are needed to assess the general applicability of this critical pathway in community-based hospitals.

We revisited past user study data on multivariate visualizations, looking at whether image processing measures offer any insight into user performance. While we find statistically significant correlations, some of the greatest insights into user performance came from variables that have strong ties to two key properties of mul-tivariate representations. We discuss our analysis and propose a taxonomy of multivariate visualizations that arises.

We present a framework for recommender systems (RS) to support exploratory data analysis (EDA) in analytical decision making. EDA helps the domain expert, often not a statistical expert, discover interesting relationships between variables and thus be motivated to explain the data. By capturing the behavior of expert analysts in EDA, RS could advise domain experts of “standard” analytical operations and suggest operations novel to the domain but consistent in analytical goals with requested operations. We enhance our framework with rules that encapsulate standard analytical practice and by incorporating user preferences. We present a scalable framework architecture, which we implemented in a prototype system, and discuss two use cases where the prototype was exercised, analyzing data from image analysis and analyzing eye tracking data.

Multivariate visualization techniques have attracted great interest as the dimensionality of data sets grows. One premise of such techniques is that simultaneous visual representation of multiple variables will enable the data analyst to detect patterns amongst multiple variables. Such insights could lead to development of new techniques for rigorous (numerical) analysis of complex relationships hidden within the data. Two natural questions arise from this premise: Which multivariate visualization techniques are the most effective for high-dimensional data sets? How does the analysis task change this utility ranking? We present a user study with a new task to answer the first question. We provide some insights to the second question based on the results of our study and results available in the literature. Our task led to significant differences in error, response time, and subjective workload ratings amongst four visualization techniques. We implemented three integrated techniques (Data-driven Spots, Oriented Slivers, and Attribute Blocks), as well as a baseline case of separate grayscale images. The baseline case fared poorly on all three measures, whereas Datadriven Spots yielded the best accuracy and was among the best in response time. These results differ from comparisons of similar techniques with other tasks, and we review all the techniques, tasks, and results (from our work and previous work) to understand the reasons for this discrepancy.

Intradermal capsaicin injection produces immediate spontaneous pain behaviors, and a secondary mechanical hypersensitivity (SMH) that is employed in the clinic as a model potentially predictive of human neuropathic pain. Presently, we have characterized capsaicin-induced SMH in rats, and compared pharmacological actions of standard analgesics in this and two nerve injury models, the L5/L6 spinal nerve ligation (SNL) and sciatic nerve chronic constriction injury (CCI) models. Intraplantar capsaicin produced dose-related SMH (enhanced paw withdrawal response to von Frey monofilament stimulation at an area away from injection site) that lasted for over 4 h. While pretreatment with a potent selective transient receptor potential vanilloid receptor-1 (TRPV1) antagonist A-425619 (1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea) prevented development of acute nocifensive (flinching) behavior immediately following capsaicin injection (ED(50)=4.9 mg/kg), the compound failed to attenuate the SMH when administered 2 h following capsaicin (10 microg/10 microl). Additional standard analgesics were also tested 3 h following intraplantar capsaicin in the SMH model. Comparison of their potencies in attenuating mechanical hypersensitivity in capsaicin, SNL and CCI models revealed similar ED(50)s for morphine (2.3 mg/kg, 1.6 mg/kg and 3.2 mg/kg, respectively), gabapentin (33.1 mg/kg, 33.9 mg/kg and 26.3 mg/kg, respectively) and lamotrigine (9.1 mg/kg, 8.9 mg/kg and 15.5 mg/kg, respectively). Duloxetine produced 50-65% effect at the highest tested dose (50 mg/kg), whereas the highest tested doses of morphine (10 mg/kg), gabapentin (85.5 mg/kg) and lamotrigine (30 mg/kg) all produced >70% efficacy in capsaicin SMH, SNL and CCI models. In contrast, celecoxib and ibuprofen showed weak effects in all three models. All standard analgesics generally had weak efficacy in attenuating capsaicin-induced immediate acute flinching behavior when administered before capsaicin. These results provide further support to the suggestions that distinct pharmacological mechanisms underlie capsaicin-induced acute nocifensive and SMH behaviors, and certain neuronal mechanisms underlying neuropathic pain states are also contributory to capsaicin-induced SMH.

From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Reperfusion Therapy in Emergency Department Patients with Suspected Acute Myocardial Infarction: Francis M. Fesmire, MD (Subcommittee Chair) William J. Brady, MD Sigrid Hahn, MD Wyatt W. Decker, MD Deborah B. Diercks, MD Chris A. Ghaemmaghami, MD Devorah Nazarian, MD Andy S. Jagoda, MD (Clinical Policies Committee Chair)

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse effects such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.

The last decade has seen extraordinary advances in the cardiovascular arena, particularly in the evaluation and management of the patient who has acute coronary syndromes. From bedside markers of myocardial damage to drug-eluting stents, technical advances are proliferating. Efforts in developing an international registry for acute aortic dissection have helped elucidate the acute presentation, management, and prognosis of this uncommon but lethal disease. Finally, the multiple research efforts in coordinating clinical decision-making with serologic markers and advanced imaging for the diagnosis of pulmonary embolism is changing the approach to the patient at risk for thromboembolic disease.

Previous studies have demonstrated that Fos-like immunoreactivity is increased in spinal dorsal horn neurons in several pain models, and have suggested that Fos-like immunoreactivity could be used as a marker of neurons activated by painful stimulation. In the present study, we evaluated nociceptive behaviors and spinal Fos-like immunoreactivity in a rat skin incision model of post-operative pain. In this model, evoked and non-evoked pain behaviors were observed at least for 2 days after paw surgery, an increased number of Fos-like immunoreactive neurons was observed in the spinal dorsal horn at lumbar levels 4–5 two-hour post-surgery. The number of Fos-like immunoreactive neurons was significantly greater in animals with skin–muscle incision compared to animals with skin-alone incision. Interestingly, spinal Fos-like immunoreactivity was quickly normalized in rats with paw surgery at later time points (8 and 24 h post-surgery), whereas nociceptive behaviors were still observed. Furthermore, at 24 h post-surgery, spinal Fos-like immunoreactivity induced by thermal stimulation (42, 44, 46, 48, 52 °C for 15 s) was not significantly different between sham animals and animals with surgery. In both groups, an increase in spinal Fos-like immunoreactive neurons was observed with increasing temperatures, with similar laminar distribution. Finally, systemic morphine reduced post-operative pain and Fos-like immunoreactivity in a naloxone reversible manner, with greater potency and efficacy on behavioral endpoints than on Fos-like immunoreactivity. These results demonstrate a different profile of nociceptive behaviors and spinal Fos-like immunoreactivity in the rat skin incision model, suggesting a limited potential of spinal Fos-like immunoreactivity to study post-surgical pain and its pharmacology.

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D(3) and D(2) receptors in these effects is unknown since all antipsychotics are D(2)/D(3) antagonists with limited binding preference at D(2) receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D(3) vs D(2) receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D(2)/D(3) antagonists, haloperidol at 0.3-3 mg/kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D(3)/D(2) antagonist, BP 897 at 8 mg/kg, and the selective D(3) antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D(3) antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D(3) antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D(3) receptors.

INTRODUCTION: Our ability to predict a positive electrophysiologic (EP) study in the evaluation of unexplained syncope is suboptimal. AIMS: In patients with unexplained syncope, we defined clinical predictors of bradyarrhythmia and ventricular tachycardia (VT) diagnosed during EP study, constructed diagnostic score indices for bradyarrhythmia and VT, and evaluated the predictive power of each score index. METHODS: All patients evaluated in the Arrhythmia Clinic for unexplained syncope from January 1, 1996, through December 31, 1998, were identified and enrolled in the study. Five hundred eight patients (325 [64%] men; mean+/-SD age, 64+/-17 years) underwent EP testing. We analyzed elements from historical data and noninvasive laboratory findings as predictors of bradyarrhythmia and VT diagnosed on EP study. RESULTS: Fifty-eight patients (11%) had sinus node dysfunction, 94 (19%) had atrioventricular (AV) node disease, 92 (18%) had His-Purkinje system disease, and 101 (20%) had VT. Models were fit using logistic regression analysis. Predictors were assigned weighted scores, and a score index was formulated. The area under the curve associated with sinus node dysfunction, AV node disease, His-Purkinje system disease, and VT models was 0.64, 0.60, 0.84, and 0.60, respectively. CONCLUSIONS: We have constructed diagnostic score indices for EP outcomes of bradyarrhythmia and VT in syncope. Of all the score indices, the model for His-Purkinje system disease has the highest predictive power

To evaluate the association of diastolic blood pressure (dBP), systolic blood pressure (sBP), and mean arterial pressure (MAP) in the emergency department (ED) with mortality within 90 days in patients with acute ischemic stroke (AIS).This observational study was conducted at an ED with an annual census of 70,000 visits, with approximately 500 for AIS. The cohort consisted of 357 patients who presented to the ED within 24 hours of stroke symptom onset. sBP and dBP were measured at triage by a nurse blinded to the study. The duration of follow-up was limited to the first 90 days following ED presentation. BP levels were categorized as low, normotensive, and high after examining scatter plots of a patient's risk of death adjusted for duration of follow-up vs dBP, sBP, and MAP. These BP categories were evaluated using indicator variables in Cox proportional hazards models, after adjusting for age, sex, and the National Institute of Health Stroke Scale (NIHSS) score.Patients with low BP (dBP70, sBP155, or MAP100 mm Hg) were significantly more likely to die within 90 days than those with BP in the normotensive range (dBP 70 to 105, sBP 155 to 220, MAP 100 to 140 mm Hg). These associations were significant even after adjusting for age, gender, and NIHSS score.There appears to be an optimal acute BP range below which early mortality is greater following AIS, suggesting avoidance of hypotension in the first 24 hours.

Background The goal of our study was to determine the accuracy of the American College of Emergency Physicians (ACEP) clinical policy in identifying patients with a cardiac cause for their syncope and its potential effect on syncope management. Methods Adult patients with syncope presenting to the emergency department (ED) from January 1996 to December 1998 were identified. Diagnosis was established retrospectively by reviewing medical records. The ACEP guidelines were applied to this population. Results Of the 200 patients identified, 115 (57.5%, 95% CI 60-64) were admitted from the ED and 24 (12%) were found to have cardiogenic syncope. Of the 24 patients with cardiac syncope, 23 were admitted. By applying ACEP level B recommendations to our population, all patients who on further workup were found to have cardiac syncope would have been admitted from the ED (100% sensitivity, 95% CI 86-100) and 81% of patients with no cardiac syncope would have been discharged from the ED (81% specificity, 95% CI 75-87). The admission rate would have been 28.5% (95% CI 22-35). By extending admission to patients satisfying level C in addition to level B recommendations, the sensitivity, specificity, and admission rate would have been 100% (95% CI 86-100), 33% (95% CI 26-40), and 71.0% (95% CI 64-77), respectively. Conclusion High sensitivity and specificity in identifying patients with cardiogenic syncope and significant reduction in the hospital admission rate were observed by applying ACEP level B recommendations to patients presenting to our ED. Application of level C recommendations did not offer any advantage.

As the marketplace for academic positions in emergency medicine grows more competitive, it becomes increasingly important for residents who desire academic careers to distinguish themselves during their residency. This report attempts to outline a road map for department and residency program leaders to help their houseofficers become successful candidates for an academic emergency medicine position. Specific ways a resident can enhance his or her "academic marketability" include 1) involvement in research, 2) establishment of a track record of productivity via scholarly writing, 3) awareness of the literature in the specialty, 4) involvement in specialty organizations and hospital committees, 5) competition for national awards, 6) gaining education skills, 7) developing an academic niche, and 8) fellowship training.

Hugh A. Sampson, MD, Anne Munoz-Furlong, BA, S. Allan Bock, MD, Cara Schmitt, MS, Robert Bass, MD, Badrul A. Chowdhury, MD, Wyatt W. Decker, MD, Terence J. Furlong, MS, Stephen J. Galli, MD, David B. Golden, MD, Rebecca S. Gruchalla, MD, Allen D. Harlor, Jr, MD, David L. Hepner, MD, Marilyn Howarth, MD, Allen P. Kaplan, MD, Jerrold H. Levy, MD, Lawrence M. Lewis, MD, Phillip L. Lieberman, MD, Dean D. Metcalfe, MD, Ramon Murphy, MD, Susan M. Pollart, MD, Richard S. Pumphrey, MD, Lanny J. Rosenwasser, MD, F. Estelle Simons, MD, Joseph P. Wood, MD, and Carlos A. Camargo, Jr, MD New York, NY, Fairfax and Charlottesville, Va, Boulder and Denver, Colo, Baltimore, Rockville, and Bethesda, Md, Rochester, Minn, Stanford, Calif, Dallas, Tex, Eugene, Ore, Boston, Mass, Philadelphia, Pa, Charleston, SC, Atlanta, Ga, St Louis, Mo, Cordova, Tenn, Scottsdale, Ariz, Manchester, United Kingdom, and Winnipeg, Manitoba, Canada

Metabotropic glutamate receptors (mGluRs) have previously been shown to play a role in pain transmission during inflammatory or neuropathic pain states. However, the role of mGluR5 in post-operative pain remains to be fully investigated. The present study was conducted to characterize analgesic activity of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in the skin-incision-induced post-operative pain model in rats. MPEP is a potent and selective mGluR5 antagonist with high affinity ( K i =6.3±0.9 nM) in rat cortex using [ 3 H]-MPEP as a radioligand, while not competing with the mGluR1-selective radioligand [ 3 H]-R214127 ( K i >10,000 nM) in rat cerebellum. Post-operative pain was examined 2 h following surgery using weight-bearing (WB) difference between injured and uninjured paws as a measure of non-evoked pain. In this model, MPEP, as morphine, showed dose-dependent effects and full efficacy after systemic administration (ED 50 =15 mg/kg, i.p. for MPEP, ED 50 =1.3 mg/kg, s.c. for morphine). In addition, intrathecal (i.t.) and intracerebroventricular (i.c.v.) MPEP reduced WB difference (ED 50 =65 μg/rat i.t. and ED 50 =200 μg/rat i.c.v.). Interestingly, intraplantar (i.pl.) injection of MPEP either before or after surgery induced a similar reduction in WB difference (ED 50 =90 μg/rat, i.pl.) while contralateral i.pl. MPEP injection did not produce any effect. These results demonstrate that both peripheral and central mGluR5 receptors play a role in nociceptive transmission observed during post-operative pain. In addition, the data suggest that mGluR5 antagonists could offer a new therapeutic approach to the treatment of post-operative pain.

ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.