Mechanical thrombectomy (MT) has become standard for large vessel occlusions, but rates of complete recanalization are suboptimal. Previous reports correlated radiographic signs with clot composition ...and a better response to specific techniques. Therefore, understanding clot composition may allow improved outcomes.
Clinical, imaging, and clot data from patients enrolled in the STRIP Registry from September 2016 to September 2020 were analyzed. Samples were fixed in 10% phosphate-buffered formalin and stained with hematoxylin-eosin and Martius Scarlett Blue. Percent composition, richness, and gross appearance were evaluated. Outcome measures included the rate of first-pass effect (FPE, modified Thrombolysis in Cerebral Infarction 2c/3) and the number of passes.
A total of 1430 patients of mean±SD age 68.4±13.5 years (median (IQR) baseline National Institutes of Health Stroke Scale score 17.2 (10.5-23), IV-tPA use 36%, stent-retrievers (SR) 27%, contact aspiration (CA) 27%, combined SR+CA 43%) were included. The median (IQR) number of passes was 1 (1-2). FPE was achieved in 39.3% of the cases. There was no association between percent histological composition or clot richness and FPE in the overall population. However, the combined technique resulted in lower FPE rates for red blood cell (RBC)-rich (P<0.0001), platelet-rich (P=0.003), and mixed (P<0.0001) clots. Fibrin-rich and platelet-rich clots required a higher number of passes than RBC-rich and mixed clots (median 2 and 1.5 vs 1, respectively; P=0.02). CA showed a trend towards a higher number of passes with fibrin-rich clots (2 vs 1; P=0.12). By gross appearance, mixed/heterogeneous clots had lower FPE rates than red and white clots.
Despite the lack of correlation between clot histology and FPE, our study adds to the growing evidence supporting the notion that clot composition influences recanalization treatment strategy outcomes.
Abstract
Background
Achromobacter and Burkholderia species are opportunistic pathogens in individuals with an immunodeficiency, most notably cystic fibrosis. Cefiderocol (CFDC) is a ...siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria. In this study, the activity of CFDC and comparator agents was determined against isolates of Achromobacter and Burkholderia cepacia species complex, collected in 2020–2022 in Europe and the USA as part of the SENTRY antimicrobial surveillance program.
Activity of cefiderocol and comparator agents against Achromobacter and Burkholderia Isolates
Methods
Minimum inhibitory concentrations (MICs) were determined according to CLSI guidelines against 167 Achromobacter and 160 Burkholderia cepacia species complex isolates, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Comparator agents included β-lactam/β-lactamase inhibitor combinations ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, piperacillin-tazobactam, as well as meropenem, ceftazidime, levofloxacin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Susceptibility was assessed for agents with CLSI breakpoints. For agents without established CLSI breakpoints, only MIC50, MIC90 and MIC ranges were reported.
Results
CFDC was the most potent agent tested against Achromobacter, showing MIC50 and MIC90 values of 0.03 and 0.25 µg/mL and all isolates were inhibited at ≤4 µg/mL (Table). Isolates from cystic fibrosis patients (n=15) showed higher MIC50 and MIC90 values for most agents, but CFDC MIC50 and MIC90 values remained low (0.06 and 0.25 µg/mL, respectively). Against Burkholderia cepacia species complex, CFDC was the most potent agent tested, with MIC50 and MIC90 values of 0.06 and 0.5 µg/mL, and 156 out of 160 isolates inhibited at ≤4 µg/mL. None of the comparator agents showed >90% susceptibility against these isolates (Table).
Conclusion
CFDC showed potent activity against a set of contemporary clinical Achromobacter and Burkholderia cepacia species complex isolates. These in vitro data suggest that CFDC could be an important treatment option for infections caused by these opportunistic pathogens.
Disclosures
Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee
Abstract
Background
Cefiderocol (CFDC) is a siderophore cephalosporin with broad activity against Gram-negative bacteria including multi-drug resistant isolates. The in vitro activity of CFDC and ...comparator agents was evaluated against pediatric (0-17 years old) isolates collected in 2020–2022 as part of the SENTRY Antimicrobial Surveillance Program.
In vitro Activity of Cefiderocol and Comparator Agents Against Pediatric Isolates
Methods
2,249 Enterobacterales (ENT), 707 P. aeruginosa, 194 Acinetobacter baumannii-calcoaceticus complex (ABC) and 220 S. maltophilia from the USA and Europe were tested for susceptibility (%S) by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB). Iron-depleted CAMHB was applied for CFDC. Comparators included newer β-lactam/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R) and meropenem-vaborbactam (MVB) as well as ampicillin/sulbactam (SAM) meropenem (MEM) and colistin (CST). %S was interpreted according to 2023 CLSI & EUCAST breakpoints. Carbapenem non-susceptible (CarbNS) was defined as non-susceptibility to imipenem and MEM.
Results
All agents displayed >96 %S for ENT while CFDC (MIC50/90, 2/4 mg/L; 91.7 %S) was the most active agent against CarbNS ENT. P. aeruginosa susceptibilities to CFDC and BL/BLI combinations were >97.0%. CFDC was the most potent agent against CarbNS P. aeruginosa with MIC50/90 values of 0.12/0.25 mg/L and 100 %S & 98.5 %S per CLSI & EUCAST breakpoints, respectively. ABC susceptibility to CFDC was >97% per CLSI & EUCAST while the susceptibility for MEM was 87.1% (CLSI & EUCAST) and SAM was 80.9% (CLSI). CFDC (MIC50/90, 0.25/1 mg/L; 95.7 %S) displayed better in vitro potency in CarbNS ABC as compared to SAM (MIC50/90, 32/ >64 mg/L; 17.4 %S CLSI) and CST (MIC50/90, 0.5/ >8 mg/L; 78.3%S EUCAST). Among pediatric S. maltophilia, CFDC was the most active agent with MIC50/90, 0.06/0.25 and 100 %S per CLSI & EUCAST breakpoints.
Conclusion
CFDC was a highly active β-lactam against contemporary pediatric isolates of Enterobacterales, P. aeruginosa, ABC, and S. maltophilia, including CarbNS subsets for which treatment options are limited. These data suggest CFDC may be a valuable treatment for serious Gram-negative infections in pediatric patients.
Disclosures
Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Anne Henriksen, PhD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee
Abstract
Background
Difficult to Treat Resistant (DTR) Gram-negative isolates show treatment-limiting resistance to all first-line agents; β-lactams and fluoroquinolones. Cefiderocol (CFDC) is a ...siderophore-conjugated cephalosporin with a unique mode of entry into bacteria, showing good activity against Gram-negative bacteria. Here, susceptibility of CFDC and comparator agents was determined against DTR isolates of Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus species complex (ABC).
Activity of Cefiderocol and Comparator Agents Against Difficult to Treat Resistance (DTR) Gram-negative Isolates
Methods
Minimum inhibitory concentrations were determined according to CLSI guidelines against 24,084 Enterobacterales, 7,310 P. aeruginosa, and 2,479 ABC isolates, collected in 2020–2022 in Europe and the USA as part of the SENTRY program, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Susceptibility was assessed according to CLSI, EUCAST and FDA breakpoints (BPs). DTR was defined as being non-susceptible, using CLSI BPs, to fluoroquinolones and β-lactams, except for CFDC and β-lactam/β-lactamase inhibitor (BL/BLI) combinations.
Results
1.6% (n=387) of the Enterobacterales isolates showed the DTR phenotype, the majority being K. pneumoniae (n=332; 85.8%). The isolates showed high susceptibility to CFDC (95.3% and 81.1% using CLSI/FDA or EUCAST BPs, respectively). Comparator agents, including novel BL/BLI combinations, showed susceptibility of < 80%, except for tigecycline (94.1%, FDA BPs). For P. aeruginosa 4.1% (n=299) showed the DTR phenotype, of which 98.3%, 97.7%, and 89.6% were susceptible to CFDC, according to CLSI, EUCAST and FDA BPs respectively. Colistin was also active (99.7% susceptible, EUCAST BPs) whereas other agents, including novel BL/BLI combinations, had susceptibility of < 65%. Amongst ABC, 47.1% (n=1167) showed the DTR phenotype, and 96.2%, 93.8%, and 89% were susceptible to CFDC according to CLSI, EUCAST and FDA BPs, respectively. Susceptibility to comparator agents was < 40%, except for colistin (81.2%, EUCAST BPs).
Conclusion
DTR isolates remained susceptible to CFDC, indicative of a low degree of cross resistance with β-lactams, including BL/BLI combinations, and fluoroquinolones.
Disclosures
Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee
The study of the metabolite complement of biological samples, known as metabolomics, is creating large amounts of data, and support for handling these data sets is required to facilitate meaningful ...analyses that will answer biological questions. We present a data model for plant metabolomics known as ArMet (architecture for metabolomics). It encompasses the entire experimental time line from experiment definition and description of biological source material, through sample growth and preparation to the results of chemical analysis. Such formal data descriptions, which specify the full experimental context, enable principled comparison of data sets, allow proper interpretation of experimental results, permit the repetition of experiments and provide a basis for the design of systems for data storage and transmission. The current design and example implementations are freely available (http://www.armet.org/). We seek to advance discussion and community adoption of a standard for metabolomics, which would promote principled collection, storage and transmission of experiment data.
Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing ...populations of many individual neurons over time. In contrast, current methods for recording the nervous system’s actual motor output – the activation of muscle fibers by motor neurons – typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices (‘Myomatrix arrays’) that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a ‘motor unit,’ during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system’s motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.
ABSTRACT The Interface Region Imaging Spectrograph (IRIS) reveals small-scale rapid brightenings in the form of bright grains all over coronal holes and the quiet Sun. These bright grains are seen ...with the IRIS 1330, 1400, and 2796 slit-jaw filters. We combine coordinated observations with IRIS and from the ground with the Swedish 1 m Solar Telescope (SST) which allows us to have chromospheric (Ca ii 8542 , Ca ii H 3968 , H , and Mg ii k 2796 ) and transition region (C ii 1334 , Si iv 1403 ) spectral imaging, and single-wavelength Stokes maps in Fe i 6302 at high spatial ( ), temporal, and spectral resolution. We conclude that the IRIS slit-jaw grains are the counterpart of so-called acoustic grains, i.e., resulting from chromospheric acoustic waves in a non-magnetic environment. We compare slit-jaw images (SJIs) with spectra from the IRIS spectrograph. We conclude that the grain intensity in the 2796 slit-jaw filter comes from both the Mg ii k core and wings. The signal in the C ii and Si iv lines is too weak to explain the presence of grains in the 1300 and 1400 SJIs and we conclude that the grain signal in these passbands comes mostly from the continuum. Although weak, the characteristic shock signatures of acoustic grains can often be detected in IRIS C ii spectra. For some grains, a spectral signature can be found in IRIS Si iv. This suggests that upward propagating acoustic waves sometimes reach all the way up to the transition region.
We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients to study the association between histological composition and stroke etiology METHODS: Consecutive ...patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using martius scarlet blue (MSB) staining, and quantification for red blood cells (RBCs), white blood cells (WBCs), fibrin and platelets was performed using Orbit Image Software. A Wilcoxon test was used for continuous variables and χ
test for categorical variables.
1350 patients were included in this study. The overall rate of Thrombolysis In Cerebral Infarction (TICI) 2c/3 was 68%. 501 patients received tissue plasminogen activator (tPA) (37%). 267 patients (20%) had a large artery atherosclerosis (LAA) source, 662 (49%) a cardioembolic (CE) source, 301 (22%) were cryptogenic, and the remainder had other identifiable sources including hypercoagulable state or dissection. LAA thrombi had a higher mean RBC density (46±23% vs 42±22%, p=0.01) and a lower platelet density (24±18% vs 27±18%, p=0.03) than CE thrombi. Clots from dissection patients had the highest mean RBC density (50±24%) while clots from patients with a hypercoagulable state had the lowest mean RBC density (26±21%).
Our study found statistically significant but clinically insignificant differences between clots of CE and LAA etiologies. Future studies should emphasize molecular, proteomic and immunohistochemical characteristics to determine links between clot composition and etiology.
The 2018 12
Workshop on Recent Issues in Bioanalysis took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical ...companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for PK, PD and ADA assays by hybrid LBA/LCMS and regulatory agencies' input. Part 1 (LCMS for small molecules, peptides, oligonucleotides and small molecule biomarkers) and Part 3 (LBA/cell-based assays: immunogenicity, biomarkers and PK assays) are published in volume 10 of
, issues 22 and 24 (2018), respectively.
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