We established a guinea pig model to investigate effects of in utero and neonatal exposure to sidestream cigarette smoke (SSCS) on bronchial reactivity during early life. Animals were divided into four groups: 1) room air/room air, 2) sham/sham, 3) SSCS/room air, and 4) SSCS/SSCS. Pregnant and neonatal animals of group 1 breathed room air and those of group 2 were sham treated. Pregnant animals of both groups 3 and 4 as well as neonates of group 4 were exposed to SSCS. SSCS exposure was limited to between days 28 and 55 of pregnancy and days 8 and 24 of the neonatal period. Bronchial response to acetylcholine (ACh) and substance P (SP) were determined in very young animals at 25 days of age. Maximal expiratory flow was used as an index of airway dimension. SP, but not ACh, induced a significantly larger decrease in peak maximal expiratory flow in group 4, indicating an important role of neonatal SSCS exposure in augmenting bronchial response to SP. To further investigate the role of tachykinins in cigarette smoke-induced changes in bronchial reactivity, four additional groups (the same as above) of neonates were pretreated with capsaicin to deplete tachykinins. In the SSCS/SSCS group, SP-induced airway hyperreactivity was abolished by capsaicin pretreatment. Furthermore, in all four groups, capsaicin pretreatment abolished the bronchial response to SP but not the response to ACh. In additional very young animals, acute SSCS caused a nonsignificant increase in bronchial response to SP. These results indicate that chronic neonatal SSCS exposure induces bronchial hyperreactivity to SP; this hyperreactivity is abolished by capsaicin pretreatment.
Concurrent Developments in Alignment and Science Education The Standards for Educational and Psychological Assessment recognize that evidence of validity based on test content is "at the heart of" alignment (AERA, APA, & NCME, 2014, p. 15). Alignment studies have traditionally focused on gathering specific evidence of the match between assessment items and performance expectations presented in the form of academic content standards (hereafter referred to as standards) by convening educators and content experts to review test forms in conjunction with content standards to determine the level of consistency between the two. Although such data serve as a good source of validity evidence, this content focus provides only a part of the picture of assessment alignment as envisioned over two decades ago. Alignment criteria, originally developed by a panel of experts and published in a monograph by Norman Webb (1997), included not only Content Focus, but also Articulation Across Grades and Ages, Equity and Fairness, Pedagogical Implications, and System Applicability. The Articulation Across Grades and Ages criterion addresses the extent to which standards and assessment reflect a common, research-based view of human development and how students move from basic to more complex understanding of concepts. The Equity and Fairness criterion addresses the extent to which both standards and assessment provide all students the opportunity to demonstrate high levels of learning. The Pedagogical Implications criterion addresses the classroom practices implied by the standards and assessment. Finally, the System Applicability criterion addresses the extent to which key stakeholder groups understand the standards and assessment and consider them to be acceptable and attainable (Webb, 1997). Early alignment studies that sought to apply these criteria focused on the Content Focus criterion (e.g., Webb, 1999), which set the stage for the Webb alignment benchmarks of categorical concurrence, depth of knowledge consistency, range of knowledge correspondence, and balance of representation to become what are arguably the most commonly known indicators of alignment. Lesser known components of the Content Focus criterion that were omitted from these early empirical studies included structure of knowledge comparability, which compared the relationships among ideas as suggested by the standards with those reflected in the test, and dispositional consonance, which focused on the extent to which broader expectations reflected in standards (e.g., attitudes) are also reflected in assessment practices. This narrowed focus was likely shaped by the fact that evidence of
Background An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814 (lufotrelvir) the prodrug and its active moiety (PF-00835231), is a potent inhibitor of the SARS-CoV-2 3CL protease. Methods Eligible participants were 18‒79 years and hospitalized with confirmed COVID-19. This first-in-human, phase 1b study was designed with single ascending dose (SAD) and multiple ascending dose (MAD) groups. Participants could receive local standard of care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results In SAD, participants were randomized to receive 250 mg lufotrelvir (n=2), 500 mg lufotrelvir (n=2), or placebo (n=4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n=7), 500 mg lufotrelvir (n=6), or placebo (n=4) by continuous 120-hour infusion. No AEs or SAEs were considered related to lufotrelvir. At doses of 250 mg and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250 mg and 500 mg doses, respectively. Conclusions These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. ClinicalTrials.gov, NCT04535167.
An animal study was carried out to evaluate the in vivo bronchodilator action of isoproterenol (Iso) from poly(glycolide-co-lactide) (PGL) microspheres. Microspheres with a mean diameter of 4.5 microns and a drug load of 7% were administered intratracheally to Long-Evans rats. The microspheres released about 70% of the incorporated drug in the instillation medium before administration, which provided immediate action, and the remaining 30% was available for sustained release. A total of 120 animals was anesthetized, paralyzed, artificially ventilated, and divided into 15 groups (n = 8): 3 groups each for saline, blank microspheres, free Iso, blank microspheres with free Iso, and microencapsulated Iso. All instillations were made in a volume of 1 ml/kg and the dose of all Iso preparations was 0.1 mg/kg. At 3, 6, or 12 hr after the intratracheal instillation, a serotonin challenge (40 micrograms/rat) was administered intravenously to constrict the airways. Airway function tests were performed at each time interval on one group of animals by a maximal expiratory flow-volume maneuver. The heart rate in animals receiving Iso formulations was similar to that in the saline control group, indicating minimal systemic effect of the dose administered. The systemic serum levels were below 2 ng/ml in all the groups. Animals receiving encapsulated Iso resisted the serotonin challenge for at least 12 hr after intratracheal instillation, indicating that the drug was still present over this period of time. On the other hand, the serotonin-induced airway constriction observed in the animals receiving blank microspheres, free Iso, or free Iso with blank microspheres was similar to that in saline controls at all time points. The results clearly show that only a small fraction of the free dose is required in sustained-release form for a prolonged pharmacological effect, resulting in a 50- to 100-fold reduction in the total dose administered.
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