The Banner psychiatric center: a model for providing psychiatric crisis care to the community while easing behavioral health holds in emergency departments.

Banner Health in the Phoenix, AZ, metropolitan area provides individuals in a behavioral health crisis with an alternative to presenting to an Emergency Department (ED). By implementing a process to quickly move patients out of our ED, our health care system has been able to greatly reduce the hold time for behavioral health patients. Through access to psychiatric clinicians around the clock at the Banner Psychiatric Center, patients now receive the appropriate treatment and needed care in a timely manner. Finally, disposition of patients into appropriate levels of care has freed up acute care Level 1 beds to be available to patients who meet those criteria.

Guidance for understanding solubility as a limiting factor for selecting the upper test concentration in the OECD in vitro micronucleus assay test guideline no. 487.

The OECD guideline for the in vitro mammalian cell micronucleus test (OECD 487) was recently adopted in July 22, 2010. Since its publication, it has become apparent that the guidance for testing chemicals where solubility is a limiting factor can be interpreted in a variety of ways. In this communication, we provide clarification for testing insoluble chemicals. The intent of the OECD 487 guideline is for the high dose to be the lowest precipitating concentration even if toxicity occurs above the solubility limit in tissue culture medium. Examination of precipitation can be done by the unaided eye or microscopically. Precipitation is examined at the onset or end of treatment, with the intent to identify precipitate present during treatment.

Follow-up actions from positive results of in vitro genetic toxicity testing.

Appropriate follow-up actions and decisions are needed when evaluating and interpreting clear positive results obtained in the in vitro assays used in the initial genotoxicity screening battery (i.e., the battery of tests generally required by regulatory authorities) to assist in overall risk-based decision making concerning the potential effects of human exposure to the agent under test. Over the past few years, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing developed a decision process flow chart to be applied in case of clear positive results in vitro. It provides for a variety of different possibilities and allows flexibility in choosing follow-up action(s), depending on the results obtained in the initial battery of assays and available information. The intent of the Review Subgroup was not to provide a prescriptive testing strategy, but rather to reinforce the concept of weighing the totality of the evidence. The Review Subgroup of the IVGT committee highlighted the importance of properly analyzing the existing data, and considering potential confounding factors (e.g., possible interactions with the test systems, presence of impurities, irrelevant metabolism), and chemical modes of action when analyzing and interpreting positive results in the in vitro genotoxicity assays and determining appropriate follow-up testing. The Review Subgroup also examined the characteristics, strengths, and limitations of each of the existing in vitro and in vivo genotoxicity assays to determine their usefulness in any follow-up testing.

Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme.

Since the publication of the International Programme on Chemical Safety (IPCS) Harmonized Scheme for Mutagenicity Testing, there have been a number of publications addressing test strategies for mutagenicity. Safety assessments of substances with regard to genotoxicity are generally based on a combination of tests to assess effects on three major end points of genetic damage associated with human disease: gene mutation, clastogenicity and aneuploidy. It is now clear from the results of international collaborative studies and the large databases that are currently available for the assays evaluated that no single assay can detect all genotoxic substances. The World Health Organization therefore decided to update the IPCS Harmonized Scheme for Mutagenicity Testing as part of the IPCS project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. The approach presented in this paper focuses on the identification of mutagens and genotoxic carcinogens. Selection of appropriate in vitro and in vivo tests as well as a strategy for germ cell testing are described.

Current and future application of genetic toxicity assays: the role and value of in vitro mammalian assays.

With the advent of new technologies (e.g., genomics, automated analyses, and in vivo monitoring), new regulations (e.g., the reduction of animal tests by the European REACH), and new approaches to toxicology (e.g., Toxicity Testing in the 21st Century, National Research Council), the field of regulatory genetic toxicology is undergoing a serious re-examination. Within this context, Toxicological Sciences has published a series of articles in its Forum Section on the theme, "Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation" (beginning with Goodman et al.). As a contribution to the Forum discussions, we present current methods for evaluating mutagenic/genotoxic risk using standard genotoxicity test batteries, and suggest ways to address and incorporate new technologies. We recognize that the occurrence of positive results in relation to cancer prediction has led to criticism of in vitro mammalian cell genetic toxicity assays. We address criticism of test results related to weak positives, associated only with considerable toxicity, only seen at high concentrations, not accompanied by positive results in the other tests of standard test batteries, and/or not correlating well with rodent carcinogenicity tests. We suggest that the problems pointed out by others with these assays already have been resolved, to a large extent, by international groups working to update assay protocols, and by changes in data interpretation at regulatory agencies. New guidances at the U.S. Environmental Protection Agency and the U.S. Food and Drug Administration improve data evaluation and help refocus risk assessment. We discuss the results of international groups working together to integrate new technologies and evaluate new tests, including human monitoring. We suggest that strategies for identifying human health risks should naturally change to integrate new technologies; however, changes should be made only when justified by strong scientific evidence of improvement in the risk assessment paradigm.

Patterns and changes in prescriber attitudes toward PDA prescription-assistive technology.

CONTEXT: Medication error prevention is a priority for the U.S. healthcare system in the 21st century. Use of technology is considered by some as critical to achieve this goal. Knowledge of the attitudinal barriers to such adoption, however, is limited. OBJECTIVE: To determine the attitudes of frontline prescriber clinicians towards technology in general, and PDAs specifically, before and after introduction of a PDA in the clinical setting of medication prescribing. DESIGN: A pre- and post-intervention web-based survey, 12-14 months apart. SETTING: Academic tertiary care children's hospital. PARTICIPANTS: Total of 244 prescriber clinicians. INTERVENTION: Distribution of a PDA with pediatric-specific medication prescribing information after completion of an on-line medication safety certification and other safety focused educational sessions. MAIN OUTCOME MEASURES: Ratings (5-point Likert scale) reflecting perceptions and attitudes towards technology in general and technology in medical settings along with self-reported usage of the PDA for Rx. RESULTS: Early Adopters and Late Adopters were identified statistically, and the group membership reflected their prior exposure to and ownership of other technologies. Early Adopters tended to be younger and less experienced clinically (e.g., residents) and more frequent owners and users of technology. Early Adopters expressed significantly more favorable attitudes toward technology and PDAs on both pre- to post-intervention survey occasions. They also utilized the PDA for Rx more often than LAs. Interestingly, PDA use for Early Adopters was based on its ease of use, while PDA use among later adopters was based on its clinical usefulness. CONCLUSIONS: Provision of point of care information using PDAs and a user-friendly, pediatric-specific medication information software package did not positively affect the attitudes of prescriber clinicians among those already favorable toward technology. However, a significant change was found among those with initially less favorable attitudes. Organizations need to understand the nature of both Early and Late Adopters and plan appropriately for managing the respective needs and expectations when potentially beneficial technologies are introduced. In order to ensure the success of an implementation, the training and supportive interventions need to be carefully designed and specifically catered to the personality-based outcome expectations of the prescriber.

An evaluation of the mode of action framework for mutagenic carcinogens case study: Cyclophosphamide.

In response to the 2005 revised US Environmental Protection Agency (EPA) Cancer Guidelines, a Risk Assessment Forum's Technical Panel has devised a strategy in which genetic toxicology data combined with other information are assessed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent adjustment factors (ADAFs) should be applied to the cancer risk assessment. A decision tree has been developed as a part of this approach and outlines the critical steps for analyzing a compound for carcinogenicity through a mutagenic MOA (e.g., data analysis, determination of mutagenicity in animals and in humans). Agents, showing mutagenicity in animals and humans, proceed through the Agency's framework analysis for MOAs. Cyclophosphamide (CP), an antineoplastic agent, which is carcinogenic in animals and humans and mutagenic in vitro and in vivo, was selected as a case study to illustrate how the framework analysis would be applied to prove that a carcinogen operates through a mutagenic MOA. Consistent positive results have been seen for mutagenic activity in numerous in vitro assays, in animals (mice, rats, and hamsters) and in humans. Accordingly, CP was processed through the framework analysis and key steps leading to tumor formation were identified as follows: metabolism of the parent compound to alkylating metabolites, DNA damage followed by induction of multiple adverse genetic events, cell proliferation, and bladder tumors. Genetic changes in rats (sister chromatid exchanges at 0.62 mg/kg) can commence within 30 min and in cancer patients, chromosome aberrations at 35 mg/kg are seen by 1 hr, well within the timeframe and tumorigenic dose range for early events. Supporting evidence is also found for cell proliferation, indicating that mutagenicity, associated with cytotoxicity, leads to a proliferative response, which occurs early (48 hr) in the process of tumor induction. Overall, the weight of evidence evaluation supports CP acting through a mutagenic MOA. In addition, no data were found that an alternative MOA might be operative. Therefore, the cancer guidelines recommend a linear extrapolation for the risk assessment. Additionally, data exist showing that CP induces mutagenicity in fetal blood and in the peripheral blood of pediatric patients; thus, the ADAFs would be applied.

Risk reduction for adverse drug events through sequential implementation of patient safety initiatives in a children's hospital.

BACKGROUND: Medication management is a complex, multifaceted system. Prescribing errors occur upstream in the process, and as such, their effects can be perpetuated, and sometimes even exacerbated, in subsequent steps. These errors place patients at risk of adverse drug events. Children, especially young infants, are at particular risk because of their size, unique physiology, and immature ability to metabolize drugs. OBJECTIVE: The purpose of this study was to reduce the risk of harm to children resulting from prescribing errors. METHODS: We sequentially implemented patient safety initiatives over a 1-year time frame at a pediatric tertiary care academic facility. The initiatives included an educational Web site with competency examination, distribution of a personal digital assistant-based standardized dosing reference, a zero-tolerance policy for incomplete or incorrect medication orders, prescriber performance feedback, and presentation of outcome data at citywide grand rounds. A total of 8718 orders were collected and analyzed to assess the impact of these initiatives. RESULTS: The absolute risk reduction from prescribing errors was 38 per 100 orders, with a relative risk reduction of 49%. Web-based education with point-of-care drug references and a zero-tolerance policy for incomplete or incorrect orders were most effective in decreasing potential adverse drug events. Documentation of appropriate weight-based dosing and indication for therapy increased by 24% and 42%, respectively. CONCLUSIONS: Process-improvement initiatives focusing on prescriber education and behavior modification can reduce the risk of harm to pediatric patients from prescribing errors.

Comparative overview of current international strategies and guidelines for genetic toxicology testing for regulatory purposes.

National and international regulatory agencies historically have used genotoxicity information as part of a weight-of-evidence approach to evaluate potential human carcinogenicity. Additionally, some agencies consider heritable mutation a regulatory endpoint. Furthermore, genotoxicity has the potential to contribute to other adverse health conditions. This article provides a comparative overview of the testing strategies used by regulatory agencies throughout the world. Despite minor variations in details, the genotoxicity test schemes for most regulatory entities generally comprise three tests: a bacterial gene mutation assay, an in vitro mammalian cell assay for gene mutation and/or chromosome aberrations, and often an in vivo assay for chromosomal effects. In some cases, fewer than these three tests are required. In other cases, when exposure data, structure-activity considerations, or other factors warrant, even chemicals negative in the three baseline tests may be subject to additional testing. If genotoxicity is identified by the baseline screening tests, assessment of the ability of the chemical to interact with DNA in the gonad may be required. This may apply regardless of whether or not a cancer bioassay has been triggered. Mutagens positive in second stage gonadal assay(s) may be tested in third stage in vivo rodent tests to provide data for a quantitative risk assessment. In all testing, theutilization of internationally-recognized protocols, where they exist, is advisable, although not in all instances required. When testing for regulatory purposes, it is advisable to verify the testing program with the specific regulatory body or bodies responsible forregulatory oversight before beginning testing.

An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints.

A retrospective analysis of standard genetic toxicity (genetox) tests, reproductive and developmental toxicity (reprotox) studies, and rodent carcinogenicity bioassays (rcbioassay) was performed to identify the genetox and reprotox endpoints whose results best correlate with rcbioassay observations. A database of 7205 chemicals with genetox (n = 4961), reprotox (n = 2173), and rcbioassay (n = 1442) toxicity data was constructed; 1112 of the chemicals have both genetox and rcbioassay data and 721 chemicals have both reprotox and rcbioassay data. This study differed from previous studies by using conservative weight of evidence criteria to classify chemical carcinogens, data from 63 genetox and reprotox toxicological endpoints, and a new statistical parameter of correlation indicator (CI, the average of specificity and positive predictivity) to identify good surrogate endpoints for predicting carcinogenicity. Among 63 endpoints, results revealed that carcinogenicity was well correlated with certain tests for gene mutation (n = 8), in vivo clastogenicity (n = 2), unscheduled DNA synthesis assay (n = 1), and reprotox (n = 3). The current FDA regulatory battery of four genetox tests used to predict carcinogenicity includes two tests with good correlation (gene mutation in Salmonella and in vivo micronucleus) and two tests with poor correlation (mouse lymphoma gene mutation and in vitro chromosome aberrations) by our criteria.

An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: II. Identification of genotoxicants, reprotoxicants, and carcinogens using in silico methods.

This study examined a novel method to identify carcinogens that employed expanded data sets composed of in silico data pooled with actual experimental genetic toxicity (genetox) and reproductive and developmental toxicity (reprotox) data. We constructed 21 modules using the MC4PC program including 13 of 14 (11 genetox and 3 reprotox) tests that we found correlated with results of rodent carcinogenicity bioassays (rcbioassays) [Matthews, E.J., Kruhlak, N.L., Cimino, M.C., Benz, R.D., Contrera, J.F., 2005b. An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints. Regul. Toxicol. Pharmacol.]. Each of the 21 modules was evaluated by cross-validation experiments and those with high specificity (SP) and positive predictivity (PPV) were used to predict activities of the 1442 chemicals tested for carcinogenicity for which actual genetox or reprotox data were missing. The expanded data sets had approximately 70% in silico data pooled with approximately 30% experimental data. Based upon SP and PPV, the expanded data sets showed good correlation with carcinogenicity testing results and had correlation indicator (CI, the average of SP and PPV) values of 75.5-88.7%. Conversely, expanded data sets for 9 non-correlated test endpoints were shown not to correlate with carcinogenicity results (CI values <75%). Results also showed that when Salmonella mutagenic carcinogens were removed from the 12 correlated, expanded data sets, only 7 endpoints showed added value by detecting significantly more additional carcinogens than non-carcinogens.

Assessing medication prescribing errors in pediatric intensive care units.

OBJECTIVE: To evaluate a matrix for determining the predominant type, cause category, and rate of medication prescribing errors, and to explore the effectiveness of hospital-based improvement initiatives among pediatric intensive care units (PICUs). DESIGN: This study involved the prospective identification of medication errors for categorization and evaluation by using a matrix methodology. A pretest-posttest design without a control group was used to explore the impact of initiatives employed to reduce medication error rates and severity. SETTING: PICUs in nine freestanding, collaborating tertiary care children's hospitals that participated in both baseline and postintervention analyses. METHODS: We evaluated 12,026 PICU medication orders at baseline and 9,187 orders postintervention for prescribing errors, excluding resuscitation orders. A standardized tool and process captured error type, cause category, and severity for 2 wks before and after intervention. Three levels of error detection were used and included pharmacy order entry, PICU nurse order transcription, and team-based overview. Site-specific interventions were implemented, which included predominantly provider education as well as informational (47%) and dosing "assists" via preprinted orders, forcing functions, or prompts (39%). RESULTS: Of baseline orders, 11.1% had at least one prescribing error. The interception of prescribing errors improved 30.9% (1.6% of all orders at baseline, 2.0% post intervention). Preventable adverse drug events were uncommon (0.6% of all medication errors) and of low severity at baseline; most were wrong dose errors. The implementation of improvement initiatives, specific for each facility, resulted in a 31.6% reduction in prescribing errors from 11.1% to 7.6%. However, site results varied considerably. CONCLUSIONS: A benchmark for medication prescribing errors in the PICU was identified among nine children's hospitals. The methodology was successful in accounting for site-specific differences with regard to identifying and documenting errors as well as reporting results of improvement initiatives. Furthermore, the methodology employed was generalizable in the identification of predominant prescribing error types, which helped to track individual hospital improvement initiative development and implementation. Overall improvement in prescribing error rates was noted; however, considerable variation in the success of improvement initiatives was noted and bears further attention.

Methadone dosage for prevention of opioid withdrawal in children.

BACKGROUND: Opioids are frequently used for sedation in the Paediatric Intensive Care Unit (PICU). With time the dosing often increases because of tolerance. On cessation of the sedation there is a risk of the opioid withdrawal syndrome. The aim of our study was to evaluate methadone dosing as a risk factor for opioid withdrawal and to determine optimal dose and efficacy of methadone to prevent withdrawal. METHOD: We undertook a clinical, retrospective, chart review study. Data were analysed from the quality improvement initiative database of a tertiary-care 18 bed PICU. RESULTS: Data from 30 children who received an opioid infusion for >/=7 days and subsequently received methadone for opioid withdrawal (between January 2000 and July 2001) were analysed. Nurses documented the presence or absence of withdrawal signs daily. Our unit protocol has recommended converting the patient's opioid dose into fentanyl equivalents and a dose of methadone equal to the total daily dose of fentanyl to be given three times a day. Twenty patients had no or minimal withdrawal symptoms and 10 experienced significant withdrawal. Age, weight, PRISM score, lorazepam dose, muscle relaxant use and fentanyl dose were not statistically significantly between these groups. Receiver Operator Characteristics analysis showed that 80% of the suggested methadone dose was effective in minimizing withdrawal symptoms. The odds ratio for withdrawal with <80% of the predicted methadone dose was 21. CONCLUSIONS: Inadequate methadone is a risk factor for opioid withdrawal. A daily starting methadone dose equivalent to 2.5 times the daily fentanyl dose is effective in minimizing withdrawal symptoms.

Genotoxicity risk assessment: a proposed classification strategy.

Recent advances in genetic toxicity (mutagenicity) testing methods and in approaches to performing risk assessment are prompting a renewed effort to harmonize genotoxicity risk assessment across the world. The US Environmental Protection Agency (EPA) first published Guidelines for Mutagenicity Risk Assessment in 1986 that focused mainly on transmissible germ cell genetic risk. Somatic cell genetic risk has also been a risk consideration, usually in support of carcinogenicity assessments. EPA and other international regulatory bodies have published mutagenicity testing requirements for agents (pesticides, pharmaceuticals, etc.) to generate data for use in genotoxicity risk assessments. The scheme that follows provides a proposed harmonization approach in which genotoxicity assessments are fully developed within the risk assessment paradigm used by EPA, and sets out a process that integrates newer thinking in testing battery design with the risk assessment process. A classification strategy for agents based on inherent genotoxicity, dose-responses observed in the data, and an exposure analysis is proposed. The classification leads to an initial level of concern for genotoxic risk to humans. A total risk characterization is performed using all relevant toxicity data and a comprehensive exposure evaluation in association with the genotoxicity data. The result of this characterization is ultimately used to generate a final level of concern for genotoxic risk to humans. The final level of concern and characterized genotoxicity risk assessment are communicated to decision makers for possible regulatory action(s) and to the public.

Normal volume of distribution of tobramycin in a mother and daughter with a CFTR splice mutation (1717 - 1G --> A).

A mother and daughter pair with CF who shared a splice mutation (1717 - 1G --> A) had a normal volume of distribution of tobramycin. The literature on tobramycin pharmacokinetics, which was published before the genetic defect was identified, is discussed. The authors speculate on the role of CFTR in the distribution of aminoglycosides and recommend that CFTR mutations should be clarified in all future studies of tobramycin pharmacokinetics in patients with CF.