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Vascular damage, initiated by host inflammatory cells, is a component of the pathophysiology of many acute and chronic inflammatory disorders. Neutrophil-mediated tissue damage is mediated primarily hyproteinases, particularly elastase and cathepsin G. In this study we have identified endothelial binding of two key serine proteinase inhibitors (serpins), α1-antitrypsin, the inhibitor of elastase, and α1-antichymotrypsin, the inhibitor of cathepsin G. These serpins are shed from the endothelium into the supernatant when neutrophils adherent to the endothelium are activated. Endothelium activated by lipopolysaccharide (LPS) augments this process, Serpin-proteinase complexes activate neutrophils and induce further cytokine release, thereby amplifying inflammatory processes. Strategies aimed at preventing endothelial serpin depletion may help minimize vascular damage during inflammation. [ABSTRACT FROM AUTHOR]

Objective: Describe the screening, referral, and treatment delivery associated with an opt-out tobacco treatment program (TTP) implemented in six hospitals varying in size, rurality and patient populations., Methods: Between March 6, 2021 and December 17, 2021, adult patients (≥ 18 years) admitted to six hospitals affiliated with the Medical University of South Carolina were screened for smoking status. The hospitals ranged in size from 82 to 715 beds. Those currently smoking were automatically referred to one of two tobacco treatment options: 1) Enhanced care (EC) where patients could receive a bedside consult by a trained tobacco treatment specialist plus an automated post-discharge follow-up call designed to connect those smoking to the South Carolina Quitline (SCQL); or 2) Basic care (BC) consisting of the post-discharge follow-up call only. An attempt was made to survey patients at 6-weeks after hospitalization to assess smoking status., Results: Smoking prevalence ranged from 14 to 49% across the six hospitals; 6,000 patients were referred to the TTP.The delivery of the bedside consult varied across the hospitals with the lowest in the Charleston hospitals which had the highest caseload of referred patients per specialist. Among patients who received a consult visit during their hospitalization, 50% accepted the consult, 8% opted out, 3% claimed not to be current smokers, and 38% were unavailable at the time of the consult visit. Most of those enrolled in the TTP were long-term daily smokers.Forty-three percent of patients eligible for the automated post-discharge follow-up call answered the call, of those, 61% reported smoking in the past seven days, and of those, 34% accepted the referral to theSCQL. Among the 986 of patients surveyed at 6-weeks after hospitalization quit rates ranged from 20%-30% based on duration of reported cessation and were similar between hospitals and for patients assigned to EC versus BC intervention groups., Conclusion: Findings demonstrate the broad reach of an opt-out TTP. Elements of treatment delivery can be improved by addressing patient-to-staffing ratios, improving systems to prescribe stop smoking medications for patients at discharge and linking patients to stop smoking services after hospital discharge., (© 2024. The Author(s).)

Methods to measure cellular target engagement are increasingly being used in early drug discovery. The Cellular Thermal Shift Assay (CETSA) is one such method. CETSA can investigate target engagement by measuring changes in protein thermal stability upon compound binding within the intracellular environment. It can be performed in high-throughput, microplate-based formats to enable broader application to early drug discovery campaigns, though high-throughput forms of CETSA have only been reported for a limited number of targets. CETSA offers the advantage of investigating the target of interest in its physiological environment and native state, but it is not clear yet how well this technology correlates to more established and conventional cellular and biochemical approaches widely used in drug discovery. We report two novel high-throughput CETSA (CETSA HT) assays for B-Raf and PARP1, demonstrating the application of this technology to additional targets. By performing comparative analyses with other assays, we show that CETSA HT correlates well with other screening technologies and can be applied throughout various stages of hit identification and lead optimization. Our results support the use of CETSA HT as a broadly applicable and valuable methodology to help drive drug discovery campaigns to molecules that engage the intended target in cells.

Interactive voice response (IVR) systems are computer programs, which interact with people to provide a number of services from business to health care. We examined the ability of an IVR system to administer and score a verbal fluency task (fruits) and the digit span forward and backward in 158 community dwelling people aged between 65 and 92 years of age (full scale IQ of 68-134). Only six participants could not complete all tasks mostly due to early technical problems in the study. Participants were also administered the Wechsler Intelligence Scale fourth edition (WAIS-IV) and Wechsler Memory Scale fourth edition subtests. The IVR system correctly recognized 90% of the fruits in the verbal fluency task and 93-95% of the number sequences in the digit span. The IVR system typically underestimated the performance of participants because of voice recognition errors. In the digit span, these errors led to the erroneous discontinuation of the test: however the correlation between IVR scoring and clinical scoring was still high (93-95%). The correlation between the IVR verbal fluency and the WAIS-IV Similarities subtest was 0.31. The correlation between the IVR digit span forward and backward and the in-person administration was 0.46. We discuss how valid and useful IVR systems are for neuropsychological testing in the elderly.

Glucocorticoids are very effective inhibitors of both the acute and chronic inflammatory response. In this study the hypothesis that glucocorticoids inhibit an early component of the inflammatory response, neutrophil adhesion to endothelium, by down-regulation of adhesion molecules on neutrophils or endothelium was examined. No effect of dexamethasone on neutrophil adhesion to endothelium or of antigen expression by neutrophils or endothelium was found. The mechanism of action of glucocorticoids in the inflammatory response is probably not mediated by alterations in adhesion molecules.