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Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib

The catalytic hyperpolarisation of pyridine, 3-hydroxypyridine and oxazole by the Signal Amplification By Reversible Exchange (SABRE) process is achieved by a series of water soluble iridium phosphine and N-heterocyclic carbene dihydride complexes. While the efficiency of the SABRE process in methanol-d4 solution or ethanol-d6 solution is high, with over 400-fold 1H polarisation of pyridine being produced by [Ir(H)2(NCMe)(py)(IMes)(monosulfonated-triphenylphosphine)]BF4, changing to a D2O or a D2O–ethanol solvent mixture leads to dramatically reduced activity which is rationalised in terms of low H2 solubility. [ABSTRACT FROM AUTHOR]

The metabolism of radiolabelled alosetron was studied in rat, dog, rabbit, mouse and human. The metabolism in rat and dog was studied at a low and an elevated dose designed to generate sufficient quantities of metabolite for definitive identification. A strategy for the characterization of metabolites in cases of extensive metabolism was developed and demonstrated for alosetron. Semi–preparative high–performance liquid chromatography (HPLC), liquid chromatography–mass spectrometry (LC–MS), nuclear magnetic resonance (NMR) and liquid chromatography–nuclear magnetic resonance (HPLC–NMR) enabled the isolation and characterization of 28 metabolites of alosetron. The characterization of the metabolites in animal excreta facilitated the identification of human systemic metabolites. [ABSTRACT FROM AUTHOR]

Explores the effects of age and exercise on physiological dead space (VDS) during stimulated dives at 2.8 atmosphere absolute (ATA). Analysis of VDS at a relatively shallow depth of 18.3 of sea water equivalent to 2.8 ATA; Degree of hypercapnia experienced by both younger and older divers during moderate exercise at 2.8 ATA; Comparison of capnography and direct arterial measurement of carbon dioxide.

1. The urinary metabolites of the anti-convulsant compound 4-amino-1-(2,6-difluorobenzyl)-1H-1,2,3-triazolo[4,5-c]-pyridine hydrochloride (GI265080) obtained following a single oral dose to man have been detected and quantified relative to each other using [sup 19]F-NMR spectroscopy. 2. The human urinary metabolites of GI265080 were isolated using semipreparative HPLC and unequivocally characterized using [sup 1]H-NMR spectroscopy, two-dimensional heteronuclear NMR spectroscopy and mass spectrometry. The assignments of the N-(5)oxide and the N-(5)-O-glucuronide metabolites of GI265080 were further confirmed by independent synthesis. The urinary metabolites obtained following single oral doses to dog and rat have also been isolated and characterized. 3. The human urinary metabolites of GI265080 comprise the N-(5)-oxide, the quaternary N[sup +]-(5)-glucuronide, the 7-hydroxy glucuronide and a glucuronide conjugate of the N-(5)-oxide. The N-(5)-O-glucuronide conjugate is a novel species in human metabolism and is a significant route of elimination of GI265080 in man. 4. The urinary metabolites of the potential anti-convulsant GW273293 (6-amino-3-(2,3,5-trichlorophenyl)pyrazin-2-ylamine) obtained following a single oral dose to man have also been isolated and characterized. The formation of a novel N-O-glucuronide was also observed and was shown to constitute a significant route of elimination of GW273293 in man. [ABSTRACT FROM AUTHOR]

Yufit and Bongar (1992) argued that a deficiency in coping skills is an important risk factor for suicidal behavior. Dear, Thomson, Hall, and Howells (1998) found that prisoners who had self-harmed in the past 3 days were less likely than a comparison group to have used problem-solving or active cognitive coping strategies to handle the most significant stressor of the past week, but it was not clear whether this represented a difference in the quality of coping responses used. In this study, three groups of blind raters (prisoners, prison officers, and forensic psychologists) rated the coping responses of the participants in Dear et al.'s study. The coping responses of self-harmers were judged less beneficial and more risky. Problem-solving strategies were most often cited as contributing to beneficial outcomes and the catharsis strategies employed by self-harmers were most often judged to be counterproductive. It remains unclear whether prisoners who self-harmed routinely employ poor quality coping strategies or if they simply used poor quality coping on this occasion. [ABSTRACT FROM AUTHOR]

1. The development of bio-analysis of drug molecules over the last 10 years is reviewed, focusing on advances in sample preparation, liquid chromatography and detection. 2. Developments have led to improvements in detection sensitivity, enhancements in specificity and increased capacity. 3. Emerging technologies such as monolithic column chromatography and miniaturized chip-based systems are discussed. [ABSTRACT FROM AUTHOR]

1. The urinary metabolites of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) have been investigated in samples obtained following oral administration to rabbit, mouse and human. GW420867X underwent extensive biotransformation to form hydroxylated metabolites and glucuronide conjugates on the aromatic ring, and on the ethyl and isopropyl side-chains in all species. In rabbit urine, a minor metabolite was detected and characterized as a cysteine adduct that was not observed in mouse or man. 2. The hydroxylated metabolites and corresponding glucuronide conjugates were isolated by semi-preparative HPLC and characterized using NMR, LC-NMR and LCMS/MS. The relative proportions of fluorine-containing metabolites were determined in animal species by [sup 19]F-NMR signal integration. 3. The fluorine atom of the aromatic ring underwent NIH shift rearrangement in the metabolites isolated and characterized in rabbit, mouse and human urine. 4. The characterization of the NIH shift metabolites in urine enabled the detection and confirmation of the presence of these metabolites in human plasma. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

1. The metabolism of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) has been investigated following oral administration to dog, cynomolgus monkey and mini-pig. 2. The urinary metabolites were isolated and characterized using semi-preparative HPLC, NMR and LC-MS MS. The relative proportions of fluorine-containing metabolites were determined for each species by F-NMR signal integration. 3. The metabolite profiles for each species were similar, although the proportion of individual components varied, suggesting that similar metabolic pathways are involved in the biotransformation of GW420867X in the species studied. 4. The urinary metabolites indicated that the major routes of biotransformation included hydroxylation and subsequent glucuronic acid conjugation on the aromatic ring, and on the ethyl and isopropyl side chains. A component was observed in mini-pig urine that corresponded to hydroxylation and glucuronidation accompanied by loss of the fluorine atom. [ABSTRACT FROM AUTHOR]

This article discusses that infectious pancreatic necrosis (IPN) virus Sp serotype in farmed Atlantic salmon, Salmo salar L., post-smolts is associated with mortality and clinical disease. IPN is a disease of salmonids which can cause losses of first feeding fry depending on the strain and serotype of virus. ln experimentally infected Atlantic salmon, Salmo salar L., the Sp serotype was virulent to sac fry and feeding fry with a mortality of 20% for sac fry, whereas the Te serotype was avirulent. There are increasing numbers of reports that IPN virus is also associated with losses around smoking both before and after transfer to sea water.

Gas exchange occurring in the abdominal cavity during laparoscopy, using carbon dioxide as the insufflating gas, was investigated in 25 female patients being ventilated with 66.6% nitrous oxide and 33.3% oxygen. The gas remaining in the abdomen at the end of the procedure was collected and measurements were made using an infrared spectrometer, a paramagnetic analyser and a mass spectrometer. The mean duration of the laparoscopy was 9.5 minutes and the mean volume of carbon dioxide delivered was 6.8 litres. Nitrous oxide concentration in the abdomen was found to increase significantly with the duration of the procedure, varying from 1.4% to 12.8% with a mean of 4.3% (s.d.±2.4). Oxygen concentration measured from 0.1 to 1.8% with a mean of 0.7% (s.d.±0.4). Nitrogen concentration varied from zero to 1.8%, having a mean concentration of 0.8% (s.d.±0.5). Carbon dioxide content was from 85.7 to 99.6% with a mean concentration of 94.2% (s.d. #x00B1;3.1). [ABSTRACT FROM AUTHOR]

Mr. Dear's article is based upon a study he made whilst attending the Senior Command Course at the Police College, Bramshill. It constitutes a general appreciation of the position regarding coloured immigrant communities with particular reference to problems presented to the police. [ABSTRACT FROM PUBLISHER]

This article focuses on a study related to histopathology of "Sekiten-byo" caused by Pseudomonas anguilliseptica in the European eel. "Sekiten-byo" has been described as a major disease of the Japanese eel. Externally the diseased fish were marked by petechial hemorrhages in the skin, particularly noticeable on the unpigmented ventrum. This characteristic lesion of red spots results from the vasodilatation and hemorrhage of the dermal and epidermal capillaries which ate a feature of eel skin. The epidermis of affected fish was sloughed over extensive areas.

This article presents a study related to an outbreak of "Sekiten-byo" among cultured European eels. Adult eels had been kept with few health problems in this system since 1980s. Bacterial analyses had been made every week on both the circulating water and the eel slime. Adult eels and elvers began to die within 3 weeks of the introduction of the elvers. Microbiological examination of the muscle tissue below the red spots, and of the liver, spleen, kidneys and heart yielded large numbers of a slow-growing, motile Gram-negative bacillus in pure culture.

Psychologists who treat children are often asked by a parent or lawyers to disclose information or prepare reports for the Family Court, or they may have their clinical notes subpoenaed. This has important implications in respect of how psychologists record information and deal with confidential information. It also highlights the risk that psychologists may be forced into a dual relationship, namely that of therapist and forensic expert. This paper examines potential problems that may occur in this regard, and presents a set of guidelines in an attempt to avoid potential legal and ethical problems and reduce the anxiety that accompany situations of this nature. [ABSTRACT FROM AUTHOR]

Operating rooms (ORs) use energy-intensive equipment such as anesthesia gas machines, patient monitors, and lights. They are major contributors to an institution's carbon footprint; yet ORs are unoccupied 40% of the time. Implementing an initiative to power down electrical devices can reduce energy consumption, equipment failure, and financial outlay. This quality improvement project developed and implemented a power down initiative for anesthesia staff to use in ORs. The initiative included turning off anesthesia gas machines, patient monitors, auxiliary oxygen delivery, and room lights at the end of scheduled cases in ORs that were not used for emergencies. Convenience audits were conducted. Pre- and postimplementation compliance outcomes showed that there was an increase in powering down the anesthesia gas machine, patient monitor, auxiliary oxygen, and room lights. Powering down unnecessary equipment at this facility has the potential to save approximately $50,000 and prevent the emission of over 80 metric tons of CO2 per year. Other facilities can implement a similar quality improvement project aimed at fiscal and ecological conservation., Competing Interests: Name: Christine Parilli-Johnson, DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Jessica Szydlowski Pitman, DNP, CRNA, ACNP, CHSE Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Kristal Barbee, MSN, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Adam Flowe, MSN, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Nicolette Hooge, DNP, MBA, CRNA Contribution: This author made significant contributions to the conception and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Julie A. Thompson, PhD Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Guy Dear, MA, MB, BChir, FRCA, FUHM Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Emily M. Funk DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author; she is the corresponding author for this article. Disclosures: None. Disclosure statements are available upon request., (Copyright © by the American Association of Nurse Anesthetists.)

The intent of this perspective is to share the recommendations of the International Consortium for Innovation and Quality in Pharmaceutical Development Metabolite Bioanalysis Working Group on the fit-for-purpose metabolite bioanalysis in support of drug development and registration. This report summarizes the considerations for the trigger, timing, and rigor of bioanalysis in the various assessments to address unique challenges due to metabolites, with respect to efficacy and safety, which may arise during drug development from investigational new drug (IND) enabling studies, and phase I, phase II, and phase III clinical trials to regulatory submission. The recommended approaches ensure that important drug metabolites are identified in a timely manner and properly characterized for efficient drug development., (© 2023 Novartis. AbbVie Inc. Incyte Corporation et al. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: The purpose of this project was to improve the consistency of verbal and written discharge instructions for women of childbearing age (13-55 years) taking hormonal contraceptives who receive aprepitant perioperatively, to address the need to use a secondary form of birth control for 28 days, as well as to increase the knowledge and confidence of Registered Nurses when providing discharge instructions., Design: This quality improvement project used a pre-/postdesign to evaluate two separate groups of patients and registered nurses., Methods: The patient sample consisted of 30 total women of childbearing age who received aprepitant during the perioperative period (15 pre and 15 post). The PACU nurse sample included 15 ambulatory surgery center nurses and 58 main hospital nurses for a combined sample of 73 PACU nurses. The PACU nurses were provided with educational in-service regarding information about aprepitant and its drug interactions. PACU nurses were additionally instructed to provide patient discharge instructions using both a written and verbal format. Patients were called postoperatively before and after both the written after visit summary (AVS) changes and the PACU nurse in-services, PACU nurses were evaluated on their knowledge, confidence, and frequency of discharge teaching before and after their educational in-service. The PACU nurses were surveyed 90 days after the intervention to assess their long-term knowledge retention., Findings: There was a significant increase in nurse knowledge about aprepitant from preimplementation to postimplementation (61.39% vs 81.95%, P < .001). Nursing knowledge showed a nonsignificant decline at 90-days postimplementation (81.95% vs 73.68%, P = .096) although remained significantly higher than preimplementation scores (73.68% vs 61.39%, P = .003). There was an overall 33.3% increase in the percentage of patients who were able to recall receiving aprepitant and the need to use a secondary form of birth control when comparing the preintervention group to the postintervention group (26.7% vs 60%, P = .123)., Conclusions: The findings suggest that providing a standardized presentation about aprepitant may improve the PACU nurses' ability to verbalize key information about aprepitant, including the need for patients to use a secondary form of birth control. This increase in nursing knowledge and confidence, along with improved written discharge instructions, may have led to improved patient comprehension of aprepitant discharge education. Additionally, there was an increase in the percentage of patients who were able to recall the need to use a secondary form birth control for 28 days, to reduce the likelihood of an unintentional pregnancy., (Copyright © 2022 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

For decades, preclinical toxicology was essentially a descriptive discipline in which treatment-related effects were carefully reported and used as a basis to calculate safety margins for drug candidates. In recent years, however, technological advances have increasingly enabled researchers to gain insights into toxicity mechanisms, supporting greater understanding of species relevance and translatability to humans, prediction of safety events, mitigation of side effects and development of safety biomarkers. Consequently, investigative (or mechanistic) toxicology has been gaining momentum and is now a key capability in the pharmaceutical industry. Here, we provide an overview of the current status of the field using case studies and discuss the potential impact of ongoing technological developments, based on a survey of investigative toxicologists from 14 European-based medium-sized to large pharmaceutical companies., (© 2023. Springer Nature Limited.)

The following case report describes a 13-year-old child with alternating hemiplegia of childhood (AHC) who underwent magnetic resonance imaging MRI with general anesthesia and experienced a hemiplegic spell, seizure, apnea, and sudden cardiac arrest with successful resuscitation. AHC is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis affecting one or both sides of the body and multiple other neurologic problems. The challenges associated with this disorder include management of developmental delay, dystonia, hemiplegia, cerebrovascular dysfunction, apnea, and autonomic dysfunction. The current literature is extremely limited in describing the effects of general anesthesia for a patient with AHC. While the neurologic manifestations of AHC are well described, autonomic dysfunction and the potential for sudden cardiac arrest have not been widely reported. To our knowledge, this is the first case report to emphasize anesthetic considerations in a pediatric patient with AHC, specifically the unrecognized potential for cardiac arrhythmia and sudden cardiac arrest., Competing Interests: Name: Emily M. Funk, DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Mohamad A. Mikati, MD Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: This author has a pending patent for treatment of Alternating Hemiplegia of Childhood. Name: Andrew P. Landstrom, MD, PhD Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Mary E. Moya-Mendez, MS Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Keri R. Wallace, BS Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. Name: Milton O. Pratt, BS Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Matthew E. Heyes, DNP, CRNA Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None Name: Guy Dear, MA, MB, BChir, FRCA, FUHM Contribution: This author made significant contributions to the conception, synthesis, writing, and final editing and approval of the manuscript to justify inclusion as an author. Disclosures: None. The authors did not discuss off-label use within the article. Disclosure statements are available upon request., (Copyright © by the American Association of Nurse Anesthetists.)

Background: Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications., Goals: Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications., Methods: Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency)., Statistics: Fisher Exact test, Spearman correlations., Results: These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation., Conclusions: During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Introduction: Calls to provide sanctioned drug-checking (pill testing) at Australian music festivals have been met with resistance from most governments due to concerns that such services would increase use of ecstasy and other drugs. We investigated that concern and used the Theory of Planned Behaviour to examine the determinants of intention to use a drug-checking service., Methods: Data were collected over a 3-day period at a music festival in Western Australia. Participants (n = 247; 50% male; 52% aged 25-34 years) were presented with three hypothetical pill testing scenarios: no testing provided, onsite testing provided and fixed offsite testing provided., Results: Neither ecstasy users (n = 212) nor participants who had never used ecstasy (n = 35) reported an increased intention to use ecstasy in scenarios in which drug checking was provided. The combination of attitudes, subjective norms and perceived behavioural control predicted intention to use a fixed site drug-checking service, while only subjective norms predicted intention to use an onsite service., Discussion and Conclusions: These data do not support the view that offering a drug-checking service at a festival will result in ecstasy use by people who have never used ecstasy or lead to increased use among people who use ecstasy., (© 2021 Australasian Professional Society on Alcohol and other Drugs.)

Purpose: The purpose of this quality improvement project was to improve consistency of discharge teaching in women who used progesterone-containing hormonal contraceptive medications and received sugammadex during general anesthesia, as there is a risk of unintended pregnancy for 1 week after administration of sugammadex., Design: This project used a predesign and postdesign using two separate sample groups of patients and postanesthesia care unit (PACU) nurses., Methods: The sample consisted of 31 total women of childbearing age and 59 PACU nurses. Simplification of sugammadex discharge instructions was achieved by incorporating evidence-based recommendations for electronic discharge instructions and nursing education. PACU nurses were educated and surveyed before and after regarding frequency of discharge teaching, clarity, and comprehension of the after-visit summary and knowledge of sugammadex. Patients were called via telephone postoperatively to assess recall of sugammadex discharge teaching., Findings: Postoperative patient phone calls identified a small increase in patient recall of discharge instructions from 5 of 14 patients (35.7%) before implementation to 7 of 17 after implementation (41.2%). PACU nurse surveys indicated an increase in self-reported frequency of sugammadex discharge teaching (34.8% vs 64.2%, P = .024) and that new discharge instructions contained more clear, comprehensive information as compared with previous instructions (29.4% vs 75.5%, P = .001)., Conclusions: This quality improvement project successfully implemented more consistent and comprehensive discharge instructions for women who receive sugammadex intraoperatively. Limitations of the project included a small sample size and short implementation intervals. As a result of switching to uniform discharge instructions, more patients received important discharge teaching from PACU nurses, and the percentage of patients who recalled this information increased., (Copyright © 2020 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Objectives: The operating room is a specialized, complex environment with many factors that can impede effective communication during transitions of care between anesthesia clinicians. We postulated that an efficient, accessible, standardized tool for intraoperative handoffs built into standard workflow would improve communication and handoff safety. Most institutions now use an electronic health record (EHR) system for patient care and have independently designed intraoperative handoff tools, but these home-grown tools are not scalable to other organizations and lack vendor-supported features. The goal of this project was to create a standardized, intraoperative handoff tool supported by EHR functionality., Methods: The Multicenter Handoff Collaborative, with support from the Anesthesia Patient Safety Foundation, created a working group of frontline anesthesia experts to collaborate with a development team from the EHR vendor (Epic Systems) to design a standardized intraoperative handoff tool. Over 2 years, the working group identified the critical elements for the tool and software usability, and the EHR team designed a standardized intraoperative handoff tool that is accessible to any institution using this EHR., Results: The first iteration of the intraoperative handoff tool was released in August 2019, with a second version in February 2020. The tool is standardized but customizable by individual institutions., Conclusion: We demonstrate that work on complex health care processes critical to patient safety, such as handoffs, can be performed on a national scale through cross-industry collaboration. Frontline experts can partner with health care industry vendors to design, build, and release a product on an accelerated timeline., Competing Interests: Author F.L.'s work documented in this manuscript was performed as part of his employment at Epic Systems. All other authors report no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Amoxicillin-clavulanate is the most common cause of idiosyncratic drug-induced liver injury (DILI). Drug-specific CD4+ T cells have been detected in patients with DILI, suggestive of an immune etiology. Furthermore, genetic associations including the human leucocyte antigen (HLA) DRB1*15:01-DQB1*06:02 haplotype influence susceptibility. Amoxicillin forms protein adducts that are postulated to activate T cells, by conjugating with lysine residues. However, a role for such adducts has not been described. This study aimed to (1) investigate whether amoxicillin-modified HLA-DRB1*15:01-DQB1*06:02 binding peptides selectively activate DILI patient T cells and (2) define the nature of the T-cell response with respective to antigen structure. Peptides carrying lysine residues for amoxicillin binding in positions (KP) 2-6 and anchors for the HLA-DRB1*15:01-DQB1*06:02 haplotype were designed. The amoxicillin-modified peptides were characterized by mass spectrometry prior to culturing with patient peripheral blood mononuclear cell. T-cell clones were then tested for specificity with amoxicillin, unmodified- and amoxicillin-modified peptides, and structural variants. Amoxicillin-modified KP-2 and KP-3 peptide-specific CD4+ clones proliferated and secreted interferon gamma (IFN-γ), interleukin (IL)-10, perforin and/or IL-17/IL-22 in a dose-dependent manner and displayed no cross-reactivity with amoxicillin, unmodified peptide or with positional derivatives. The T cells response was HLA class II restricted and the amoxicillin-modified peptides bound selectively to HLA-DRB1*15:01 and/or DQB1*06:02. To conclude, we show that amoxicillin-modified peptides bind to both components of the risk haplotype to stimulate DILI patient T cells and describe the importance of the position of nucleophilic lysine residue in the HLA binding peptide sequence., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3K δ ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers ( n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen., (Copyright © 2019 The Author(s).)

Investigative Toxicology describes the de-risking and mechanistic elucidation of toxicities, supporting early safety decisions in the pharmaceutical industry. Recently, Investigative Toxicology has contributed to a shift in pharmaceutical toxicology, from a descriptive to an evidence-based, mechanistic discipline. This was triggered by high costs and low throughput of Good Laboratory Practice in vivo studies, and increasing demands for adhering to the 3R (Replacement, Reduction and Refinement) principles of animal welfare. Outside the boundaries of regulatory toxicology, Investigative Toxicology has the flexibility to embrace new technologies, enhancing translational steps from in silico, in vitro to in vivo mechanistic understanding to eventually predict human response. One major goal of Investigative Toxicology is improving preclinical decisions, which coincides with the concept of animal-free safety testing. Currently, compounds under preclinical development are being discarded due to the use of inappropriate animal models. Progress in Investigative Toxicology could lead to humanized in vitro test systems and the development of medicines less reliant on animal tests. To advance this field a group of 14 European-based leaders from the pharmaceutical industry founded the Investigative Toxicology Leaders Forum (ITLF), an open, non-exclusive and pre-competitive group that shares knowledge and experience. The ITLF collaborated with the Centre for Alternatives to Animal Testing Europe (CAAT-Europe) to organize an "Investigative Toxicology Think-Tank", which aimed to enhance the interaction with experts from academia and regulatory bodies in the field. Summarizing the topics and discussion of the workshop, this article highlights Investigative Toxicology's position by identifying key challenges and perspectives.

1. In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702. PBPK models were populated with the in vitro parameters and DDI simulations conducted and compared to the observed data from a clinical study with DM and GSK1034702. 3. GSK1034702 was a potent direct and metabolism-dependent inhibitor of human CYP2D6, with inhibition parameters of: IC 50  =   1.6 μM, K inact  = 3.7 h -1 and K I  = 0.8 μM. Incorporating these data into PBPK models predicted a DDI after repeat, but not single, 5 mg doses of GSK1034702. 4. The DDI observed with repeat administration of GSK1034702 (5 mg) can be attributed to metabolism-dependent inhibition of CYP2D6. Further, in vitro data were generated and several potential mechanisms proposed to explain the interaction observed following a single dose of GSK1034702.