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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.)

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.

Purpose: To determine to what extent local anesthetic reduces postoperative pain after pediatric strabismus surgery., Methods: In this double-masked, randomized clinical trial of 50 children 13-91 months of age undergoing strabismus surgery, subjects were randomly assigned to one of three treatments given at the conclusion of surgery: topical lidocaine gel and sub-Tenon's (balanced salt solution) placebo (n = 16), topical placebo (hypromellose) and sub-Tenon's bupivacaine 0.75% (n = 17), or topical and sub-Tenon's placebo (n = 17). Pain was otherwise managed systemically in the usual fashion by the masked anesthesia team and assessed at regular postoperative intervals by a masked observer using an objective, validated pain scale., Results: Average pain in the first 30 minutes was 6.57, 6.36, and 6.58 in the lidocaine, bupivacaine, and placebo groups, respectively, and was significantly lower (P = 0.016) for bupivacaine vs placebo. The bupivacaine group had significantly lower scores for pain after 30 minutes, total pain, and peak pain versus the lidocaine group., Conclusions: Sub-Tenon's bupivacaine may reduce postoperative pain in children undergoing strabismus surgery., (Copyright © 2017 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Background: The cause of emergence agitation (EA) in children is unknown. Rapid emergence from inhaled anesthesia has been implicated because EA is more common with sevoflurane than with halothane. A dose-dependent effect of sevoflurane, which increases seizure-like electroencephalogram activity, has also been proposed., Methods: To determine whether depth of anesthesia as measured by bispectral index (BIS) affects EA, 40 ASA physical status I to II children aged 2 to 8 years undergoing ophthalmic surgery were enrolled in a blinded randomized controlled trial of low-normal (40-45, deep) versus high-normal (55-60, light) anesthesia. To distinguish transient irritability from severe EA, the primary outcome was first-stage postanesthesia care unit (PACU I) peak Pediatric Assessment of Emergence Delirium (PAED) score, with secondary outcomes of PAED and Face, Legs, Activity, Cry, and Consolability scores at emergence, postoperative fentanyl dose, emergence time, and discharge time. Subjects received a standard anesthesia protocol with oral midazolam followed by mask induction with sevoflurane 8%, fentanyl 1 to 1.5 μg/kg IV (then as needed), neuromuscular blockade, and endotracheal intubation. Providers titrated expired sevoflurane (in N2O 67%) from 0.5% to 3% to maintain BIS range. PAED, Richmond Agitation Sedation Scale, and Face, Legs, Activity, Cry, and Consolability scores were measured at emergence, at PACU I arrival, and during PACU I stay., Results: There was little difference between the groups in the primary outcome, peak PACU I PAED score (light: 7.7 ± 4.6; deep: 8.6 ± 5.3; mean difference, 0.9; 95% confidence interval, 4.1 to -2.3; effect size, 0.18). Discharge times were similar between groups. Treatment for severe EA was rare., Conclusions: There was no significant effect of BIS-guided deep versus light anesthesia on severe EA.

Purpose: To elucidate long-term outcomes in 65 consecutive patients meeting a uniform definition of mandibular osteoradionecrosis (ORN) treated with multimodality therapy including hyperbaric oxygen (HBO)., Methods and Materials: Pretreatment, post-treatment and long-term follow-up of mandibular lesions with exposed bone were ranked by a systematic review of medical records and patient telephone calls. The ranking system was based on lesion diameter and number plus disease progression. Changes from pretreatment to post-treatment and follow-up were analyzed by Wilcoxon signed-rank tests. Improved wound survival, measured by time to relapse, defined as any less favorable rank after HBO treatment, was assessed by Kaplan-Meier analysis., Results: In all, 57 cases (88%) resolved or improved by lesion grade or progression and evolution criteria after HBO (p < 0.001). Four patients healed before surgery after HBO alone. Of 57 patients who experienced improvement, 41 had failed previous nonmultimodality therapy for 3 months and 26 for 6 months or more. A total of 43 patients were eligible for time-to-relapse survival analysis. Healing or improvement lasted a mean duration of 86.1 months (95% confidence interval [95% CI], 64.0-108.2) in nonsmokers (n = 20) vs. 15.8 months (95% CI, 8.4-23.2) in smokers (n = 14) versus 24.2 months (95% CI, 15.2-33.2) in patients with recurrent cancer (n = 9) (p = 0.002 by the log-rank method)., Conclusions: Multimodality therapy using HBO is effective for ORN when less intensive therapies have failed. Although the healing rate in similarly affected patients not treated with HBO is unknown, the improvements seen with peri-operative HBO were durable provided that the patients remained cancer free and abstained from smoking.

Definitive information on the metabolism of a drug candidate in humans is achieved through dosing radiolabelled drug as part of a clinical study, and is typically conducted post-proof of concept in Phase III of the clinical development plan. Here we describe a novel approach, using preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy, to determine the human systemic exposure to a drug and its metabolites using samples derived from Phase I clinical studies. Using the described methodology, novel human plasma metabolites, as low as 10 ng/ml can be detected and quantified. This provides an opportunity, early in the development process to understand the potential role of metabolites in the safety and efficacy of drugs in humans.

Diving fatalities causes were investigated in 947 recreational open-circuit scuba diving deaths from 1992-2003. Where possible, cases were classified at each step of a four step sequence: trigger, disabling agent, disabling injury, cause of death (COD). The most frequent adverse events within each step were: (a) triggers 41% insufficient gas, 20% entrapment, 15% equipment problems; (b) disabling agents--55% emergency ascent, 27% insufficient gas, 13% buoyancy trouble; (c) disabling injuries--33% asphyxia, 29% arterial gas embolism (AGE), 26% cardiac incidents; and (d) COD--70% drowning, 14% AGE, 13% cardiac incidents. We concluded that disabling injuries were more relevant than COD as drowning was often secondary to a disabling injury. Frequencies and/ or associations with risk factors were investigated for each disabling injury by logistic regression. (The reference group for each injury was all other injuries.) Frequencies and/or associations included: (a) asphyxia--40% entrapment (Odds Ratio, OR > or = 30), 32% insufficient gas (OR = 15.9), 17% buoyancy trouble, 15% equipment trouble (OR = 4.5), 11% rough water, drysuit (OR = 4.1), female gender (OR = 2.1); (b) AGE--96% emergency ascent (OR > or = 30), 63% insufficient gas, 17% equipment trouble, 9% entrapment; (c) cardiac incidents--cardiovascular disease (OR = 10.5), age > 40 (OR = 5.9). Minimizing the frequent adverse events would have the greatest impact on reducing diving deaths.

The recent commercial availability of small particle packed columns (<2 microm) and associated instrumentation capable of withstanding the high pressures of such columns, has lead to an increase in the application of so called ultra-performance liquid chromatography. The improved efficiency, resolution and peak capacity of these columns, when coupled to mass spectrometry, provides particular benefit for the identification of drug metabolites in complex biological samples. In this work, the ability of ViewLux, a microplate imager, to act as a suitable radiodetection system for ultra-performance liquid chromatography methods is assessed. The system demonstrates robustness and sensitivity comparable to a microplate scintillation counter (TopCount) more typically used for off-line metabolite radiodetection. The ViewLux is also used here to undertake successful metabolite profiling of actual samples, for two investigational drug candidates, using both 96- and 384-well yttrium silicate microplates.

A growing number of individuals with insulin-requiring diabetes mellitus (IRDM) dive, but data on plasma glucose (PG) response to diving are limited, particularly for adolescents. We report on seven 16-17 year old novice divers with IRDM participating in a tropical diving camp who had recent at least moderate PG control (HbA1c 7.3 +/- 1.1%) (mean +/- SD). PG was measured at 60, 30 and 10 min pre-dive and immediately following 42 dives. Maximum depth (17 +/- 6 msw) and total underwater times (44 +/- 14 min) were not extreme. Pre-dive PG exceeded 16.7 mmol x L(-1) (300 mg x dL(-1)) in 22% of dives. Males had significantly higher pre-dive levels (15.4 +/- 5.6 mmol x L(-1) [277 +/- 100 mg x dL(-1)] vs. 12.8 +/- 2.9 mmol x L(-1) [230 +/- 52 mg x dL(-1)], respectively) and greater pre-post-dive changes (-4.3 +/- 4.4 mmol x L(-1) [-78 +/- 79 mg x dL(-1)] vs. -0.5 +/- 4.3 mmol x L(-1) [-9 +/- 77 mg x dL(-1)], respectively). Post-dive PG was < 4.4 mmol x L(-1) [< 80 mg x dL(-1)] in two dives by two different males (3.4 and 3.9 mmol x L(-1) [61 and 70 mg x dL(-1)]). No symptoms or complications of hypoglycemia were reported. These data show that in a closely monitored situation, and with benign diving conditions, some diabetic adolescents with good control and no secondary complications may be able to dive safely. The impact of purposeful elevation of PG to protect against hypoglycemia during diving remains to be determined.

Insulin-requiring diabetes mellitus (IRDM) is commonly described as an absolute contraindication to scuba diving. A 1993 Divers Alert Network survey, however, identified many active IRDM divers. We report on the plasma glucose response to recreational diving in IRDM divers. Plasma glucose values were collected before and after diving in IRDM and healthy control divers. Time/depth profiles of 555 dives in IRDM divers were recorded. IRDM divers had been diving for a mean of almost nine years and had diabetes for a mean of over 15 years. No symptoms or complications related to hypoglycemia were reported (or observed). Post-dive plasma glucose fell below 70 mg x dL(-1) in 7% (37/555) of the IRDM group dives compared to 1% (6/504) of the controls (p<0.05). Moderate levels of hyperglycemia were also noted in 23 divers with IRDM on 84 occasions. While large plasma glucose swings from pre-dive to post-dive were noted, our observations indicate that plasma glucose levels, in moderately-controlled IRDM, can be managed to avoid hypoglycemia during routine recreational dives under ordinary environmental conditions and low risk decompression profiles.

Study Objective: To determine how much patients are willing to pay to avoid intraoperative awareness?, Design: Observational study, Setting: University-affiliated metropolitan hospital., Patients: 60 patients who completed a questionnaire (39 F, 21 M). The mean age was 43 years and the median household income range of 45,000-60,000 US dollars., Interventions: Patients completed an interactive computer-generated questionnaire on the value of preventing intraoperative awareness and their willingness to pay for a "depth of anesthesia" monitor. Their willingness to pay for the prevention of postoperative pain, nausea and vomiting, postoperative grogginess, and sleepiness was also determined as a means of comparison., Measurements and Main Results: Patients were willing to pay (WTP) 34 US dollars, 10 US dollars to 42 US dollars (median, interquartile range) for a monitor that would assist an anesthesia care provider assess the depth of anesthesia in an effort to avoid awareness. This increased to 43 US dollars, 20 US dollars to 77 US dollars (p < 0.0,001) (median, interquartile range), if the insurance company was making the payment and the WTP value only decreased minimally to 33 US dollars if the incidence of awareness was reduced 10-fold., Conclusion: The incidence of intraoperative awareness and WTP value for monitoring awareness have a nonlinear relationship (a risk averse utility function), which suggests that patients assign an intrinsic base value for a rare or very rare possibility of an event. Other healthcare economic analyses (such as cost effectiveness) do not take this factor into account and assume a linear value relationship (i.e., if something occurs ten times less frequently, it has ten times less value)., Implication: The median value for patients' WTP for a monitor that might prevent awareness under anesthesia was 34 US dollars given an incidence of 5/1,000 cases. The incidence of awareness and WTP value have a nonlinear relationship suggesting that patients assign an intrinsic base value for the possibility of awareness.

Background: Tracheal tube (TT) size selection in children is important to avoid complications. Formulae utilizing age and physical characteristics to predict appropriate tube size are not entirely predictive., Methods: Using an automated anaesthesia record keeper database, the anaesthetic records of 8504 children, aged up to 7 years, who required tracheal intubation, were reviewed. Age, height and weight data were related to TT size. The total number of patients whose age, height and weight were independently available was 8396, 3929 and 7823, respectively. The number having all three variables was 3814. A linear regression analysis was performed for patients with all three variables and for each variable individually., Results: Tracheal tube size is best predicted using multivariate analysis and, for any child aged up to 7 years, is represented by the formula: 2.44 + (age x 0.1) + (height x 0.02) + (weight x 0.016). Formulae utilizing these variables individually are also reviewed., Conclusions: Prediction of TT size is best accomplished using multiple variables. Further prospective study is suggested.

The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug for the potential treatment of HIV, has been studied with singly expressed human cytochromes P450 (CYP 450). No biotransformation of [14C]GW420867X was evident in the presence of any of the CYP 450 isoforms, with the exception of CYP 450 1A2, where a single metabolite was observed in the HPLC radiochromatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy and mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared that CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumably during formation of an arene oxide intermediate during aromatic hydroxylation.

Postoperative nausea and vomiting (PONV) are unpleasant experiences. However, there is no drug that is completely effective in preventing PONV. Whereas cost effectiveness analyses rely on specific health outcomes (e.g., years of life saved), cost-benefit analyses assess the cost and benefit of medical therapy in terms of dollars. We hypothesized that patients were willing to pay for a hypothetical new drug that would eliminate PONV. Eighty elective day surgical patients using general anesthesia participated in the study. After their recovery in the postanesthetic care unit, they were asked to complete an interactive computer questionnaire on demographics, the value of avoiding PONV, and their willingness to pay for an antiemetic. Patients were willing to pay US$56 (US$26--US$97; median, 25%--75%) for an antiemetic that would completely prevent PONV. Patients who developed nausea (n = 21; 26%) and vomiting (n = 9; 11%) were willing to pay US$73 (US$44--US$110) and $100 (US$61--US$200; median, 25%--75%), respectively (P < 0.05). Seventy-six percent of patients considered avoiding postoperative nausea and 78% of patients considered avoiding vomiting as important (> or = 50 mm on a 0--100-mm visual analog scale). Nausea or vomiting in the postanesthetic care unit, greater patient income, previous history of PONV, more importance placed on avoiding nausea and vomiting, increasing age, and being married are independent covariates that increase the willingness to pay estimates. Patients associated a value with the avoidance of PONV and were willing to pay between US$56 and US$100 for a completely effective antiemetic.

Monolithic columns have been successfully used with steep gradient and high flow rates for the direct analysis of a candidate pharmaceutical compound in human plasma. The monolithic columns showed excellent robustness with nearly 300 20-microL injections of plasma (diluted 1:1 with water) being made onto one column without significant deterioration in performance. The system gave excellent sensitivity with a limit of quantification of 5 ng/mL being achieved. Unlike previous methods of direct analysis the monolithic columns showed excellent resolution even after nearly 300 plasma injections. The column performance was measured before and after the analysis of the plasma samples., (Copyright 2001 John Wiley & Sons, Ltd.)

The Holyoake Codependency Index is being developed to measure the extent to which a person endorses codependent beliefs and attributions. A 28-item pilot version was administered to 39 male and 268 female clients of a family counseling agency. Factor analysis, used to identify the shortest version with acceptable reliability, yielded a 13-item final version comprising three subscales (external focus, self-sacrifice, and reactivity). The subscales correspond to key themes within the literature on codependency. Scores on each subscale correlated significantly in the predicted direction with relevant measures of psychological functioning; providing initial evidence of construct validity. The 13-item scale was administered to a general community sample of 303 women and the factor structure was fully replicated. Internal consistency of the subscales ranged from .74 to .84 with the family counseling sample and from .73 to .83 with the general community sample.

Purpose: To describe neuromuscular effects of rapacuronium in pediatric patients during N2O-halothane anesthesia and compare them with mivacurium in children., Methods: 103 pediatric patients, seven days -12 yr, received rapacuronium or mivacurium during N2O-halothane anesthesia. Onset and recovery of block were measured using EMG (Datex). Block was compared between groups based on drug treatment and age. Children < two years received 1 or 2 mg x kg(-1) rapacuronium: 2-12 yr received either 2 mg x kg(-1) or 3 mg x kg(-1) rapacuronium, or 0.2 mg x kg(-1) mivacurium., Results: There were no differences in onset (1.7+/-1.8 min) or maximum block (T1 2.4+/-8%) among neonates, infants, and toddlers after either dose of rapacuronium. There was no difference between 1 and 2 mg x kg(-1) of rapacuronium block at 60 sec. Train-of-four ratio (T4/T1) >0.7 occurred later after 2 mg x kg(-1) than 1 mg x kg(-1) in these patients (P<0.05). There was no difference in T25 among neonates, infants and toddlers for 1 mg x kg(-1) or 2 mg x kg(-1) doses. Rapacuronium, 3 mg x kg(-1), produced maximum block 1.5 min earlier than did mivacurium, 0.2 mg x kg(-1) (P<0.001). There was no difference in block at 60 sec, maximum block or time to maximum block between 2 and 3 mg x kg(-1) rapacuronium for children > two years of age. Maximum block occurred 1.0+/-0.5 min after 2 or 3 mg x kg(-1) when T1 was 0.2+/-1.1% of baseline. T25 and T4/T1 >0.7 occurred 10 to 11 min later after this dose of rapacuronium than after mivacurium., Conclusion: Rapacuronium produces block earlier than mivacurium. Recovery from rapacuronium block is dose related and slower than that following mivacurium during halothane anesthesia.