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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.)