Upfront vascular imaging in acute stroke: Impact on thrombectomy transfer time at a primary stroke center.

OBJECTIVES: Early cerebral arterial imaging is currently only recommended in the subgroup of acute ischemic stroke (AIS) patients suspected of having large vessel occlusion (LVO). There is limited data on the impact of early cerebrovascular imaging in all suspected AIS patients presenting within 24 h of symptom onset and the impact on door in-door out (DIDO) time. MATERIALS AND METHODS: In January 2020, our Primary Stroke Center implemented a protocol to perform upfront head and neck CT angiography (CTA) with initial non-contrast CT head for all suspected ischemic stroke patients screening positive for BE-FAST stroke symptoms within 24 h from last known normal time. We retrospectively reviewed IV alteplase and thrombectomy-eligible patients before (January 1-December 31, 2019) and after protocol implementation (January 1, 2020-June 30, 2022). RESULTS: Of 86 patients meeting study criteria, up-front CTA was associated with significant reductions in door-to-CTA start (median 37 vs 15 min, p = 0.003), door-to-CTA result (median 83 vs 52 min, p = 0.023) and DIDO times (median 150 vs 106 min, p = 0.023). There was no significant difference in door-to-needle time before and after protocol implementation (median 48 vs 43 min, p = 0.450). CONCLUSION: Up-front cerebrovascular imaging with CTA in suspected AIS patients presenting within 24 h resulted in shorter DIDO times without delaying door-to-needle times. Primary Stroke Centers should consider this approach to detect LVO early and expedite patient transport to thrombectomy capable centers.

Different Vinculin Binding Sites Use the Same Mechanism to Regulate Directional Force Transduction.

Vinculin is a universal adaptor protein that transiently reinforces the mechanical stability of adhesion complexes. It stabilizes mechanical connections that cells establish between the actomyosin cytoskeleton and the extracellular matrix via integrins or to neighboring cells via cadherins, yet little is known regarding its mechanical design. Vinculin binding sites (VBSs) from different nonhomologous actin-binding proteins use conserved helical motifs to associate with the vinculin head domain. We studied the mechanical stability of such complexes by pulling VBS peptides derived from talin, α-actinin, and Shigella IpaA out of the vinculin head domain. Experimental data from atomic force microscopy single-molecule force spectroscopy and steered molecular dynamics (SMD) simulations both revealed greater mechanical stability of the complex for shear-like than for zipper-like pulling configurations. This suggests that reinforcement occurs along preferential force directions, thus stabilizing those cytoskeletal filament architectures that result in shear-like pulling geometries. Large force-induced conformational changes in the vinculin head domain, as well as protein-specific fine-tuning of the VBS sequence, including sequence inversion, allow for an even more nuanced force response.

Evaluation of Plot-Scale Methods for Assessing and Monitoring Salt Marsh Vegetation Composition and Cover.

Vegetation is a key component of salt marsh monitoring programs, but different methods can make comparing datasets difficult. We compared data on vegetation composition and cover collected with 3 methods (point-intercept, Braun-Blanquet visual, and floristic quality assessment [FQA]) in 3 Rhode Island salt marshes. No significant differences in plant community composition were found among the methods, and differences in individual species cover in a marsh never exceeded 6% between methods. All methods were highly repeatable, with no differences in data collected by different people. However, FQA was less effective at identifying temporal changes at the plot scale. If data are collected from many plots in a marsh, any of the methods are appropriate, but if plot-scale patterns are of interest, we recommend point-intercept.

Immunotherapy in Lung Cancer: A New Age in Cancer Treatment.

The management of Non-Small Cell Lung Cancer (NSCLC) has changed dramatically in the last 10 years with an increase in the understanding of the biology and with the development of new and multiple treatments. Chemotherapy being the first systemic treatment used in the setting of advanced disease, proving benefit for patients over palliative care. With the identification of oncogenic drivers, innovative targeted therapies were developed and tested, leading to important changes in the management of certain patients and giving to some of them the possibility to be treated in first line with oral inhibitors. Immunotherapy was then explored as a potential option, with promising results, and data of impact in important endpoints in lung cancer treatments. This chapter explores the different CTLA-4 inhibitors that have been investigated in NSCLC: ipilimumab and tremelimumab, as well as the different immune checkpoint inhibitors: anti PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab, avelumab, BMS-936559) medications. It also analyzes the different studies that have been developed for NSCLC with these medications, the evidence obtained, and the possible role in the management of patients. Immunotherapy has definitely changed the paradigm on NSCLC treatment, and the future is promising for the benefit of patients.

Evaluation of genetic toxicity of 6-diazo-5-oxo-l-norleucine (DON).

DON (6-diazo-5-oxo-l-norleucine), a glutamine antagonist, was demonstrated to exhibit analgesic, antibacterial, antiviral and anticancer properties. The study was performed to characterize its in vitro and in vivo genetic toxicity potential. DON was tested in the bacterial reverse mutation assay (Ames test) using Salmonella typhimurium tester strains (TA98, TA100, TA1535 and TA1537) and Escherichia coli tester strain (WP2 uvrA) with and without S9 and also with reductive S9. In addition, DON was tested for the chromosome aberrations in Chinese hamster ovary (CHO) cells with or without S9 to evaluate the clastogenic potential. Furthermore, DON was also evaluated for its in vivo clastogenic activity by detecting micronuclei in polychromatic erythrocyte (PCE) cells in bone marrow collected from the male mice dosed intravenously with 500, 100, 10, 1 and 0.1 mg/kg at 24 and 48-h post-dose. The Ames mutagenicity assay showed no positive mutagenic responses. However, the in vitro chromosome aberration assay demonstrated dose dependent statistically positive increase in structural aberrations at 4 and 20-h exposure without S9 and also at 4-h exposure with S9. The in vivo micronucleus assay also revealed a statistically positive response for micronucleus formation at 500, 100 and 10 mg/kg at 24 and 48-h post-dose. Thus, DON appears to be negative in the Ames test but positive in the in vitro chromosome aberration assay and in the in vivo micronucleus assay. In conclusion, the results indicate DON is a genotoxic compound with a plausible epigenetic mechanism.

Organization of a United States county system for comprehensive acute stroke care.

BACKGROUND AND PURPOSE: Organized systems of care have the potential to improve acute stroke care delivery. The current report describes the experience of implementing a county-wide system of spoke-and-hub stroke neurology receiving centers (SNRC) that incorporated several comprehensive stroke center recommendations. METHODS: Observational study of patients with suspected stroke of <5 hours duration transported by emergency medical system personnel to an SNRC during the first year of this system. RESULTS: A total of 1360 patients with suspected stroke were evaluated at 9 hub SNRC, of which 553 (40.7%) had a discharge diagnosis of ischemic stroke. Of these 553, intravenous tissue-type plasminogen activator was administered to 110 patients (19.9% of ischemic strokes). Care at the 6 neurointerventional-ready SNRC was a major focus in which 25.1% (99/395) of the patients with ischemic stroke received acute intravenous or intra-arterial reperfusion therapy, and in which provision of such therapies was less common with milder stroke, older age, and Hispanic origin. The door-to-needle time for intravenous tissue-type plasminogen activator met the <60-minute target in only 25% of patients and was 37% longer (P=0.0001) when SNRC were neurointerventional-ready. CONCLUSIONS: A stroke system that incorporates features of comprehensive stroke centers can be effectively implemented with substantial rates of acute reperfusion therapy administration. Experiences potentially useful to broader implementation of comprehensive stroke centers are considered.

The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome.

The MM500 meta-study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well-annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein-coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease.

The human melanoma proteome atlas-Defining the molecular pathology.

The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.

A global benchmark study using affinity-based biosensors.

To explore the variability in biosensor studies, 150 participants from 20 countries were given the same protein samples and asked to determine kinetic rate constants for the interaction. We chose a protein system that was amenable to analysis using different biosensor platforms as well as by users of different expertise levels. The two proteins (a 50-kDa Fab and a 60-kDa glutathione S-transferase [GST] antigen) form a relatively high-affinity complex, so participants needed to optimize several experimental parameters, including ligand immobilization and regeneration conditions as well as analyte concentrations and injection/dissociation times. Although most participants collected binding responses that could be fit to yield kinetic parameters, the quality of a few data sets could have been improved by optimizing the assay design. Once these outliers were removed, the average reported affinity across the remaining panel of participants was 620 pM with a standard deviation of 980 pM. These results demonstrate that when this biosensor assay was designed and executed appropriately, the reported rate constants were consistent, and independent of which protein was immobilized and which biosensor was used.

Does START triage work? An outcomes assessment after a disaster.

STUDY OBJECTIVE: The mass casualty triage system known as simple triage and rapid treatment (START) has been widely used in the United States since the 1980s. However, no outcomes assessment has been conducted after a disaster to determine whether assigned triage levels match patients' actual clinical status. Researchers hypothesize that START achieves at least 90% sensitivity and specificity for each triage level and ensures that the most critical patients are transported first to area hospitals. METHODS: The performance of START was evaluated at a train crash disaster in 2003. Patient field triage categories and scene times were obtained from county reports. Patient medical records were then reviewed at all receiving hospitals. Victim arrival times were obtained and correct triage categories determined a priori using a combination of the modified Baxt criteria and hospital admission. Field and outcomes-based triage categories were compared, defining the appropriateness of each triage assignment. RESULTS: Investigators reviewed 148 records at 14 receiving hospitals. Field triage designations comprised 22 red (immediate), 68 yellow (delayed), and 58 green (minor) patients. Outcomes-based designations found 2 red, 26 yellow, and 120 green patients. Seventy-nine patients were overtriaged, 3 were undertriaged, and 66 patients' outcomes matched their triage level. No triage level met both the 90% sensitivity and 90% specificity requirement set forth in the hypothesis, although red was 100% sensitive (95% confidence interval [CI] 16% to 100%) and green was 89.3% specific (95% CI 72% to 98%). The Obuchowski statistic was 0.81, meaning that victims from a higher-acuity outcome group had an 81% chance of assignment to a higher-acuity triage category. The median arrival time for red patients was more than 1 hour earlier than the other patients. CONCLUSION: This analysis demonstrates poor agreement between triage levels assigned by START at a train crash and a priori outcomes criteria for each level. START ensured acceptable levels of undertriage (100% red sensitivity and 89% green specificity) but incorporated a substantial amount of overtriage. START proved useful in prioritizing transport of the most critical patients to area hospitals first.

Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care.

STUDY OBJECTIVE: We developed recommendations for antidote stocking at hospitals that provide emergency care. METHODS: An expert panel representing diverse perspectives (clinical pharmacology, clinical toxicology, critical care medicine, clinical pharmacy, emergency medicine, internal medicine, pediatrics, poison centers, pulmonary medicine, and hospital accreditation) was formed to create recommendations for antidote stocking. Using a standardized summary of the medical literature, the primary reviewer for each antidote proposed guidelines for antidote stocking to the full panel. The panel used a formal iterative process to reach their recommendation for the quantity of an antidote that should be stocked and the acceptable period for delivery of each antidote. RESULTS: The panel recommended consideration of 24 antidotes for stocking. The panel recommended that 12 of the antidotes be available for immediate administration on patient arrival. In most hospitals, this period requires that the antidote be stocked in the emergency department. Another 9 antidotes were recommended for availability within 1 hour of the decision to administer, allowing the antidote to be stocked in the hospital pharmacy if the hospital has a mechanism for prompt delivery of antidotes. The panel identified additional antidotes that should be stocked by the hospital but are not usually needed within the first hour of treatment. The panel recommended that each hospital perform a formal antidote hazard vulnerability assessment to determine the need for antidote stocking in that hospital. CONCLUSION: The antidote expert recommendations provide a tool to be used in creating practices for appropriate and adequate antidote stocking in hospitals that provide emergency care.

Label-free global serum proteomic profiling reveals novel celecoxib-modulated proteins in familial adenomatous polyposis patients.

Celecoxib, a selective inhibitor of cyclooxygenase-2 (Cox-2), was efficacious in clinical prevention trials of patients with familial adenomatous polyposis (FAP) and sporadic colorectal cancer. To identify as yet poorly defined molecular determinants of celecoxib efficacy, a multidimensional serum fractionation approach was used coupled with nanospray tandem mass spectrometry to perform label-free global proteomic profiling of serum samples from the FAP/celecoxib prevention trial. Subsequently, the application of an algorithm for large-scale biomarker discovery on comparative serum proteomic profiles of pre- and post-celecoxib treatment samples identified 83 potentially celecoxib-responsive proteins from various cellular compartments, biological processes and molecular functions. Celecoxib modulation of some of these proteins was confirmed in serum samples of FAP patients and colorectal cancer cell lines by Western blotting. Thus, using a shotgun procedure to rapidly identify important celecoxib-modulated proteins, this pilot study has uncovered novel systemic changes some of which are highly relevant for carcinogenesis and vascular biology. Validation of selected markers, especially those involved in key signaling networks and those considered molecular indicators of cardiovascular pathology, in larger celecoxib clinical trials is expected to provide insights into the molecular mechanisms of celecoxib and the efficacy/toxicity issues related to its use as a chemopreventive agent.

Pharm. D. pathways to biomedical research: the National Institutes of Health special conference on pharmacy research.

To address the shortage of research-trained pharmaceutical scientists (or doctor of pharmacy [Pharm.D.] scientists), a 2-day pharmacy research conference titled "Pharm.D. Pathways to Biomedical Research" was convened on December 13-14, 2006, at the National Institutes of Health (NIH) campus (Bethesda, MD). The workshop included invited speakers and participants from academia, industry, and government. Forty-two pharmacy schools were represented, including deans and clinical pharmaceutical scientists with current NIH funding. In addition, several pharmacy professional organizations were represented--American Association of Colleges of Pharmacy, American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and the Accreditation Council on Pharmaceutical Education. The workshop was divided into three sessions followed by breakout discussion groups: the first session focused on presentations by leading pharmaceutical scientists who described their path to success; the second session examined the NIH grant system, particularly as it relates to training opportunities in biomedical research and funding mechanisms; and the third session addressed biomedical research education and training from the perspective of scientific societies and academia. We summarize the discussions and findings from the workshop and highlight some important considerations for the future of research in the pharmacy community. This report also puts forth recommendations for educating future pharmaceutical scientists.

Bioaccumulation and effects of dietary exposure to the alternative flame retardant, bis(2-ethylhexyl) tetrabromophthalate (TBPH), in the Atlantic killifish, Fundulus heteroclitus.

Bis(2-ethylhexyl) tetrabromophthalate (TBPH), a high production volume flame retardant chemical used as a replacement for banned flame retardants, has been detected in media and human and wildlife tissues globally. We describe bioaccumulation and biological effects from dietary exposure of TBPH to an estuarine fish, Atlantic killifish, Fundulus heteroclitus. Briefly, adult fish were fed carrier control or chemically amended diets for 28 d, followed by 14 d of control diet feeding. Diets were amended with TBPH (TBPH_LO diet, 139 µg/g dry wt, or TBPH_HI diet, 4360 µg/g dry wt) or a polychlorinated biphenyl congener (PCB153 diet, 13 µg/g dry wt), which was included as a positive control for bioaccumulation. Although bioaccumulation of either chemical correlated with fish size, only a small proportion of the TBPH offered (<0.5% total TBPH) had bioaccumulated into TBPH-treated fish by 28 d. In contrast, 24.5% of the PCB153 offered was accounted for in 28-d PCB-treated fish. Although 28-d bioaccumulated concentrations of TBPH differed by sex and treatment, sexes did not differ in their rates of TBPH bioaccumulation, and the time to achieve 50% of 28 d concentration (T1/2 ) was estimated to be 13 d. Depuration rates of TBPH did not differ by sex or treatment, and the time after exposure to achieve T1/2 was estimated to be 22 d. Independent of treatment, male fish grew faster than female fish, but for both sexes reproductive condition (gonadal somatic index) declined unexpectedly over the experimental period. Across treatments, only the TBPH_LO treatment affected growth, reducing male but increasing female growth rates by small amounts relative to respective controls. In summary, our study used very high concentrations of dietary TBPH to contaminate fish tissues above the highest levels reported to date in wild biota, yet we observed few adverse biological effects. Environ Toxicol Chem 2018;37:2350-2360. © 2018 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Convenient care clinics: the future of accessible health care.

The need for accessible, affordable, quality health care in the United States has never been greater. In response to this need, convenient care clinics (CCCs) are being launched across the country to help provide care to meet the basic health needs of the public. In CCCs, highly qualified health care providers diagnose and treat common health problems, triage patients to the appropriate level of care, advocate for a medical home for all patients, and reduce unnecessary visits to emergency rooms and Urgent Care Clinics. CCCs have been called a "disruptive innovation" because they are consumer driven. They serve as a response to many patients who are unhappy with the current conventional health care delivery system--a system that is challenged to provide access to basic health care services when people need it the most. CCCs are based in retail stores and pharmacies. They are primarily staffed by nurse practitioners (NPs). Some CCCs are staffed by physician assistants (PAs) and physicians. The authors acknowledge the important roles of both PAs and physicians in CCCs; however, this paper primarily provides education about the role of NPs in CCCs. CCCs have evolved at a time when our health care system is floundering, and the need for accessible, affordable health care is at its greatest. The CCC model provides an accessible, affordable entry point into the health care system for those who previously were restricted access.

Success and complication rates with prehospital placement of an esophageal-tracheal combitube as a rescue airway.

INTRODUCTION: Previous studies have proven the success of the Esophageal-Tracheal Combitube (ETC) as a primary airway, but not as a rescue airway. OBJECTIVE: The object of this study was to observe success and complication rates of paramedic placement of an ETC as a rescue airway, and to compare success rates with endotracheal tube (ETT) intubation. The primary outcome indicator was placement with successful ventilation. Complication rates, esophageal placement, and return of spontaneous circulation (ROSC) were secondary measures. METHODS: A retrospective review of the records of patients who had ETC attempts by Emergency Medical Services (EMS) was conducted for a period of three years. Complications were defined a priori. The ETC is used primarily as rescue airway for a failed attempt at an endotracheal tube (ETT) intubation. A control group for ETT placements was drawn from the EMS quality assurance (QA) database for the same period. RESULTS: Esophageal-Tracheal Combitube insertion was attempted on 162 patients, of which, 113 (70%) were successful, 46 (28%) failed, and the outcome of three (2%) was not recorded. Inability to place the ETC occurred in 29 (18%) patients, and accounted for 48% (22/46) of failures. The use of the ETC caused dental trauma in one patient, and one placement of the ETC was related to the onset of subcutaneous emphysema. Blood in the ETC from active upper gatrointestinal bleeding occurred in nine patients (6%), and four tubes (3%) became dislodged en route to the hospital. The apriori complication rate was 44/162 (27%). Inability to determine placement of the ETC due to emesis from both ports occurred in 21 cases. Combining these problems with the apriori complications, the overall rate was 40% (65/162). Esophageal-Tracheal Combitube location was noted in a subset of 90 charts, of which, 76 (84%) were esophageal, and 14 (16%) were tracheal. Thirteen of 126 (10%) patients in cardiac arrest had return of spontaneous circulation (ROSC) in the field after placement of the ETC. An ETT was attempted in 128 control patients, of which, 107 (84%) were successful, 21 (16%) failed (odds ratio (OR) for ETT vs. ETC = 2.1; 95% CI = 1.12-3.86). CONCLUSION: Despite a low ROSC rate, the complication and success rates of ETC are acceptable for a rescue airway device. Tracheal placement of the Combitube is uncommon, but requires fail-safe discrimination. Similar to previous reports, the success ratio for ETT was greater than for the ETC.

Lessons learned in preparing to receive large numbers of contaminated individuals.

Traditionally, medical radiation emergency plans have provided for the receipt and care of a limited number of individuals, usually no more than two or three at any given time. Large numbers of contaminated, uninjured individuals cannot be effectively handled in the emergency departments (EDs) of hospitals as they present a risk of forcing the ED to close because of contamination and they divert ED personnel away from patients needing medical attention. Alternative locations and plans for handling large numbers of contaminated but otherwise uninjured patients must be considered. Such plans developed at the Penn State Hershey Medical Center (HMC) during the 1979 accident at the Three Mile Island Nuclear Power Plant (TMI) were resurrected post 9/11 and used there in developing and upgrading plans and capabilities for handling large numbers of contaminated, uninjured individuals.

Risk-informed, performance-based inspections at medical facilities.

During the past couple of years, radiation safety professionals have observed a significant change with regard to the inspection philosophy of regulators. The NRC and many Agreement State agencies have implemented a performance-based, risk-informed approach for inspecting medical Radiation Safety Programs. This new, less prescriptive approach originates from the necessity to produce safety benefits commensurate with their cost to the industry and still maintain health and safety performance. While compliance with regulatory requirements is important, regulatory agencies have been focusing on areas that provide greater safety benefit, such as protecting the radiation worker, members of the general public and the environment. This paper discusses simple and practical measures that may assist licensees in preparing for performance-based, risk informed inspections.

Acute inhalation injury.

The lungs can be an efficient means for the absorption of inhaled toxicants, resulting in airway and pulmonary injury or systemic toxicity. Although a few specific antidotes exist for inhaled toxicants, the syndrome of acute inhalation injury and clinical therapeutics are linked by common pathways of pathophysiology. Understanding the mechanisms of inhalation injury and occupation- or situation-specific toxicants can simplify the decision-making process for the out-of-hospital emergency responder and the emergency physician when confronted with a patient and the myriad of potential inhaled toxicants.

Health physics considerations in medical radiation emergencies.

Preplanning and organization can facilitate the health physics response in the event of a medical radiation emergency. Anticipating the needs will allow for advanced assembly of needed information and supplies that would be useful in effectively responding to such events. Annual training of emergency care providers and an easy to read and understand poster will be of great benefit in guiding personnel until health physics arrives. Major events also need consideration, in advance, as they will place additional demands on health physics.