SU-E-T-197: A Comprehensive Variance Reporting System and an Analysis of Variances Reported at Our Institution.

PURPOSE: It is essential for radiation oncology departments to have comprehensive patient safety and quality programs. Two years ago we undertook a systematic review of our safety/QA program. Existing policies were updated and new policies created where necessary. One crucial component of any safety/QA program is continually updating it based on current information, the 'check' and 'act' portions of the Deming Cycle. We accomplished this with a transparent variance reporting system and a safety/QA committee reviewing and acting on reported variances. METHODS: With 5 radiation oncology centers in our institution, we needed to devise a system that would allow anyone to report a variance and provide our QA committee the ability to review variances system-wide. We developed the system using web-based tools. The system allows individuals to report variances, anonymously or named, specify the nature of the variance and indicate the tools used to identify the variance. RESULTS: In 2011, 285 variances were reported, 102 were reported by physicists, 86 anonymously, 71 by therapists and 26 by dosimetrists. We realized the need to develop clear classifications for variances. We added a high priority category, defined as variances which resulted in or had the potential to result in harm to a patient or when a policy is purposely overridden. Of the 285 variances reported, 5 were high priority. We created a process variance category, defined as variances where a specific clinical process is not followed. Of the 285 reported variances 155 were process variances. CONCLUSIONS: Reporting of variances through a centralized database is central toward developing a robust patient safety/quality assurance program. Anonymous reporting fosters a non-punitive environment, and promotes the 'safety culture'. The goal of such a system is to review trends in clinical processes and ultimately to improve safety/quality by reducing variances associated with these processes.

Chimeric RNA-DNA molecular beacon assay for ribonuclease H activity.

Current methods to detect and assay ribonuclease H (RNase H) activity are indirect and time-consuming. Here we introduce a direct and sensitive method, based on the fluorescence quenching mechanism of molecular beacons, to assay RNA cleavage in RNA:DNA hybrids. An RNA-DNA chimeric beacon assay for RNase H enzymatic activity was developed. The substrate is a single-stranded RNA-DNA chimeric oligonucleotide labeled with a 5'-fluorescein and a 3'-DABCYL. The fluorophore (fluorescein) of the probe is held in close proximity to the quencher (DABCYL) by the RNA:DNA stem-loop structure. When the RNA sequence of the RNA:DNA hybrid stem is cleaved, the fluorophore is separated from the quencher and fluorescence can be detected as a function of time. Chimeric beacons with different stem lengths and sequences have been surveyed for this assay with E. coli RNase H. We found that the beacon kinetic parameters are in qualitative agreement with previously reported values using more cumbersome assays. This method permits real-time detection of RNase H activity and a convenient approach to RNase H kinetic and mechanistic study.

Conceptual models for implementing biopsychosocial theory in clinical practice.

The integration of the biopsychosocial model into manual therapy practice is challenging for clinicians, especially for those who have not received formal training in biopsychosocial theory or its application. In this masterclass two contemporary models of health and disability are presented along with a model for organizing clinical knowledge, and a model of reasoning strategies that will assist clinicians in their understanding and application of biopsychosocial theory. All four models emphasise the importance of understanding and managing both the psychosocial and the biomedical aspects of patients' problems. Facilitating change in patients' (and clinicians') perspectives on pain and its biopsychosocial influences requires them to reflect on their underlying assumptions and the basis of those beliefs. Through this reflective process perspectives will be transformed, and for clinicians, in time, different management practices will emerge.

Acute low cervical nerve root conditions: symptom presentations and pathobiological reasoning.

Acute low cervical nerve root conditions may be easily misdiagnosed. The perspective presented is that their symptom presentation is not as straightforward as the classic descriptions of brachialgia would have us believe. This clinical commentary presents a series of observations and reasoning models that are relevant to patient symptom presentations believed to be of cervical nerve root origin. Clinicians are urged to consider low cervical nerve root assessment in the light of our current understanding of neural sensitivity, pain science, nerve root biomechanics and the presence and effect of degenerative changes. This particularly relates to thoughts about cervical movements and postures being able to bring forces to bear on nerve roots via compressive as well as elongation forces.

Development of a "treatment program" descriptor: the addiction treatment inventory.

This paper reviews the current literature on the definition and classification of drug and alcohol user treatment "programs," and provides a rationale for our approach to measuring the treatment programs in the Drug Evaluation Network System (DENS). The DENS gathers extensive background and recent status data on patients' drug, alcohol, psychiatric, medical, employment, legal, and family problems as they enter a sample of treatment programs throughout the country. The DENS recognized the need for descriptive information on important structural, organizational, and service delivery aspects of the programs in which those patients were treated. To this end, we present our efforts thus far in characterizing and monitoring "service delivery units" or "programs" that are sampled in the DENS system. Specifically, we present development of the Addiction Treatment Inventory (ATI), a standardized measurement instrument to characterize these service delivery units and their services.

A medico-legal report to a solicitor.

This is an example of the influence that modern pain science can have on medico-legal reporting. The report has been reproduced with minor changes. These changes have been made so as to protect the identities of those involved and to assist the reader.

Designing interdisciplinary documentation for the continuum of care.

An increased emphasis on integrated care delivery and the need to access information across the care continuum led to an assessment and modification of the current documentation system at Summa Health System in Akron, Ohio. The goal was to achieve more complete and concise interdisciplinary charting. This article describes the process the two-hospital system developed to achieve integrated documentation reflecting the patient's progress toward team-defined outcomes. Steps in the evaluation and modification of the old system, lessons learned, and results/implications for quality improvement are shared.

Developing a national addiction treatment information system. An introduction to the Drug Evaluation Network System.

The purpose of this article is to test the applicability and utility of the Drug Evaluation Network Study (DENS), a timely electronic information system that tracks trends in substance abuse treatment. This article examines existing large-scale data collection efforts, discusses the rationale and design of the DENS system, and presents results of the DENS pilot phase. Clinical staff from more than 40 service delivery units in five cities were trained to conduct intake assessments on laptop computers with the computerized Addiction Severity Index (ASI). The DENS computer system also included an automatic data transfer protocol to allow regular transmission of ASIs and other data to a central server at Treatment Research Institute. Descriptive information and discharge status were also collected. Several problems were encountered during the early stages of the pilot phase, including obtaining consecutive cases from treatment programs, computerization and software application, treatment staff turnover, and assuring quality of data. Data is presented on 4,300 adults entering drug and/or alcohol treatment at the nonrandomly selected DENS pilot programs between June 1996, and April 6, 1998. Various examples of how DENS data can be used are presented.

Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides.

Animal models are frequently used to aid prediction of intestinal absorption in humans. However, there is little comparative quantitative information on species differences in paracellular permeation, which is an important route for oral absorption of small to medium-sized hydrophilic drug molecules. This study addresses this issue by comparing the molecular mass (MM) dependency in oral bioavailability between rat and dog of poly(ethylene glycol) (PEG), a polydispersed model mixture commonly used to characterize paracellular absorption, and of a series of eight D-peptides (based on D-phenylalanine). Fasted rats and dogs received PEG (400/900) and the D-peptides (MM 236-406 Da), orally and intravenously, with total 24-48 h urine collection to estimate oral bioavailability. After HPLC separation, the individual PEG oligomers and D-peptides were determined using radiometric detection, for radiolabeled material, and LC-MS, for unlabeled (PEG) material. All compounds were predominantly excreted unchanged following intravenous administration. After oral administration, the predominant peak in the radiochromatogram was unchanged material, indicating stability of the compounds in the gastrointestinal tract. A clear molecular mass dependency in oral bioavailability was seen with both series, but with absorption much greater in dog than rat. Thus, for PEG in rat, bioavailability decreased sharply from 79 to around 2% with increasing MM between 282 and 591 Da, and then tapered to around 1. 5% up to 1295 Da. Whereas in dog, bioavailability remained around 100% for oligomers up to 600 Da and then decreased quite sharply with increasing MM, tending to plateau around 13% beyond 900 Da. Likewise, for the d-peptides in rat, bioavailability decreased from 30 to 1% with increasing MM between 236 and 406 Da, whereas in dog it was 100%, declining to 16% over the same molecular range. This species difference appears to be due to a larger pore size and greater frequency of pores in the paracellular pathway of dog compared to rat. Furthermore, on the basis of comparison with literature data for PEG and selected drugs, rat would appear to be a better predictor than dog of absorption of hydrophilic compounds in human.

The integration of pain sciences into clinical practice.

In the past three decades, a scientific revolution has occurred in the understanding of the experience of pain. However, a clinical revolution based on the new science is yet to occur. Pain is a multidimensional experience with many contributing and interacting biological/pathobiological mechanisms. These mechanisms may be nociceptive, peripheral neurogenic, central, affective/cognitive or relate to output systems such as the motor and autonomic nervous system. With a better understanding of pain-related neurobiology and some clinical decision making skills, reasoned attempts at a diagnosis of pain can be made. The essential question and first step related to clinical integration is to ask, "what is (are) the predominant mechanism(s) in a given patient's pain state?" This paper provides the underlying clinical biology of pain mechanisms and proposes pain patterns related to the mechanisms.

Domain organization of calbindin D28k as determined from the association of six synthetic EF-hand fragments.

Calbindin D28k is an intracellular Ca(2+)-binding protein containing six subdomains of EF-hand type. The number and identity of the globular domains within this protein have been elucidated using six synthetic peptide fragments, each corresponding to one EF-hand subdomain. All six peptides were mixed in equimolar amounts in the presence of 10 mM Ca2+ to allow for the reconstitution of domains. The mixture was compared to native calbindin D28k and to the sum of the properties of the individual peptides using circular dichroism (CD), fluorescence, and 1H NMR spectroscopy, as well as gel filtration and ion-exchange chromatography. It was anticipated that if the peptides associate to form native-like domains, the properties would be similar to those of the intact protein, whereas if they did not interact, they would be the same as the properties of the isolated peptides. The results show that the peptides in the mixture interact with one another. For example, the CD and fluorescence spectra for the mixture are very similar to those of the intact calbindin D28k, suggesting that the mixed EF-hand fragments associate to form a native-like structure. To determine the number of domains and the subdomain composition of each domain in calbindin D28k, a variety of peptide combinations containing two to five EF-hand fragments were studied. The spectral and chromatographic properties of all the mixtures containing less than six peptides were closer to the sum of the properties of the relevant individual peptides than to the mixture of the six peptides. The results strongly suggest that all six EF-hands are packed into one globular domain. The association of the peptide fragments is observed to drive the folding of the individual subdomains. For example, one of the fragments, EF2, which is largely unstructured in isolation even in the presence of high concentrations of Ca2+, is considerably more structured in the presence of the other peptides, as judged by CD difference spectroscopy. The CD data also suggest that the packing between the individual subdomains is specific.

Oral absorption of D-oligopeptides in rats via the paracellular route.

PURPOSE: This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers. METHODS: The study series comprised eleven D-oligopeptides, designed not to be recognised by peptidases or transport proteins, and to have molecular weights between 222 and 406 daltons with different net electrical charges and composition of D-amino acids. All the peptides were [3H]-radiolabelled and analyzed by HPLC with radiometric detection. Bioavailability was estimated based on 24-hr urinary excretion of unchanged peptide after oral and intravenous administrations. RESULTS: As expected, the series proved metabolically stable. Bioavailability was independent of oral dose when varied by a factor of 10,000, suggesting passive absorption. Whereas bioavailability decreased sharply from 30% to 1% with increasing molecular weight, net charge showed little, if any, effect on bioavailability. CONCLUSIONS: This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.

Lack of interaction between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

1. The aim of the study was to examine the potential pharmacokinetic interaction between methotrexate and flucloxacillin. 2. Ten rheumatoid arthritis patients participated in the interaction study. Subjects were allocated to either methotrexate alone (5-15 mg per week) or methotrexate plus flucloxacillin (500 mg four times a day 48 h prior to sampling) in a random order. 3. There was a statistically, but not clinically, significant decrease in methotrexate AUC (1307 +/- 389 vs 1212 +/- 394 micrograms l-1 h) in the presence of flucloxacillin. Cmax and tmax parameters for methotrexate were not significantly altered in the presence of flucloxacillin. 4. Data from an additional 10 rheumatoid arthritis patients, starting on methotrexate, were added to the data from the placebo arm of the interaction study and a model dependent pharmacokinetic analysis was performed. The plasma concentration profiles were best described by a two-compartment model with a mean clearance of 11.9 (+/- 1.7) l h-1 and an initial volume of distribution of 31.2 (+/- 2.6) l. The pronounced intersubject variability in the pharmacokinetic parameters was not related to any of the available covariate information. 5. Our findings suggest that no important clinical interaction occurs between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

Regional drug delivery II: relationship between drug targeting index and pharmacokinetic parameters for three non-steroidal anti-inflammatory drugs using the rat air pouch model of inflammation.

PURPOSE: To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokinetic parameters of the target and systemic sites, and to compare predictions with observations. METHODS: DTI was calculated based on area under the concentration time curve at target (pouch) and systemic site (venous blood) following administration into and sampling from both sites. A model was derived relating DTI to systemic clearance, target permeability, plasma protein binding and fraction of the targeted dose that is systemically available. RESULTS: Both NSAIDs exhibited linear pharmacokinetics over the dose ranges studies. They differed primarily in total body clearance which was approximately 16 fold greater for diclofenac (213 ml hr-1 per 250 g) than piroxicam (13 ml hr-1 per 250 g). Observed DTIs (11, 114 and 276 for piroxicam, S[+]ibuprofen [studied previously] and diclofenac) were ranked in order of total body clearance but were approximately 7.5 fold lower than predicted (101, 700 and 2214 respectively). CONCLUSIONS: The discrepancy was explained by the influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammatory response. The originally derived equation for DTI, which assumed only unbound drug diffuses across the target site, was modified to take into account the simultaneous flux of bound drug.

Regional drug delivery I: permeability characteristics of the rat 6-day-old air pouch model of inflammation.

PURPOSE: To determine the permeability characteristics of the rat air pouch model of inflammation using permeability extremes within which the NSAIDs S[+] ibuprofen, piroxicam and diclofenac could be evaluated. METHODS: Permeability was calculated using concentration data obtained following intrapouch and intravenous administration of [3H]-water, [14C]-urea, [14C]-inulin and [125I]-albumin and compared to similar data obtained for the three NSAIDs. RESULTS: Similar permeability values (5-6.5 ml hr-1) were obtained for the three NSAIDS which fell between the permeability extremes of the molecular weight markers [3H]-water (9.7 ml hr-1), [14C]-urea (6.8 ml hr-1), [14C]-inulin (1.0 ml hr-1) and [125I]-albumin (0.6 ml hr-1). Coadministration of equipotent anti-inflammatory doses of the NSAIDs did not affect local blood flow to the air pouch (as assessed by urea kinetics) but did reduced vascular permeability (as assessed by albumin flux into the pouch). CONCLUSIONS: Comparison of the NSAIDs with the permeabilities of the molecular weight markers indicates that a perfusion rate limitation probably exists. Systemic absorption is complete over the first two hours following intrapouch administration of the NSAIDs, therefore albumin flux into the pouch is insufficient to materially affect the permeability of the NSAIDs. However, subsequently (post 5hr) albumin concentration in the pouch rises sufficiently to lower the effective flux of the NSAIDs.

Clinical safety of gadopentetate dimeglumine.

PURPOSE: To quantify the rate of adverse reactions to gadopentetate dimeglumine. MATERIALS AND METHODS: Magnetic resonance (MR) imaging was performed in 15,496 patients in April-September 1992. Data were collected before and after intravenous administration of 0.1 mmol/kg gadopentetate dimeglumine. RESULTS: Adverse reactions occurred in 2.4% (n = 372) of patients. Symptoms abated the same or next day in 94.1% (n = 350). Whereas onset occurred within 30 minutes after injection in 49.7% (n = 185), onset occurred more than 1 hour after injection in 44.9% (n = 167). Two serious adverse reactions occurred and were attributed to underlying disease. The rate of adverse reaction was 3.7% in patients with a history of asthma (31 of 831 patients) or allergy (144 of 3,860 patients). Patients with previous reactions to an MR imaging or iodinated contrast agent had an adverse-reaction rate in this study of 21.3% (16 of 75) and 6.3% (54 of 857), respectively. The rate of adverse reaction was 2.2% when gadopentetate dimeglumine was administered slowly and 2.9% when it was administered rapidly. CONCLUSION: Findings confirm the safety of gadopentetate dimeglumine.

Affinity labeling of the membrane protein-binding component of human polymorphonuclear leukocyte receptors for leukotriene B4.

A radiolabeled N-(3-aminopropyl)-leukotriene B4 amide ([3H]LTB4-APA) analog of the potent leukocyte chemotactic factor leukotriene B4 (LTB4) binds to receptors for LTB4 in plasma membrane-enriched preparations from human blood polymorphonuclear leukocytes (PMNL) and intact PMNL with respective mean dissociation constants of 2.3 nM and 69 nM at 4 degrees C. The [3H]LTB4-APA bound to plasma membrane-enriched preparations from PMNL was covalently cross-linked to membrane proteins with disuccinimidyl suberate. Solubilization and resolution by SDS-PAGE of proteins from [3H]LTB4-APA-labeled PMNL membranes revealed predominant labeling of a 60-kDa protein. Labeling of the PMNL membrane protein was inhibited by LTB4 and its analogs at concentrations similar to those inhibiting the binding of [3H]LTB4 to its receptor, with an identical rank order of potency of LTB4 greater than 20-hydroxy-LTB4 greater than LTB4-APA = 5(S),12(R)-dihydroxy-eicosa-14-cis-6,8,10-trans-tetraenoic acid much greater than LTD4 = LTC4. GTP suppressed the labeling of the 60-kDa PMNL membrane protein to an extent consistent with the decrease in receptor affinity for LTB4 induced by GTP. The stereospecificity of the affinity cross-linking reaction and the regulation by GTP support the identification of an approximately 60-kDa protein as the binding component of the PMNL receptor for LTB4.

Robotic analysis of aflatoxin M1 in milk.

An automated aflatoxin M1 assay system capable of performing multiple unattended extractions and chromatographic analyses has been developed. A six-axis anthropomorphic laboratory robot and a flexible computer system are combined to operate a sample turntable, a multisolvent dispensing facility, a solid-phase extraction station, a vacuum manifold, an automatic HPLC sample preconcentration unit, an HPLC, a fluorescence detector and a computing integrator. The system is capable of handling bulk milk samples and can determine aflatoxins at the sub-micrograms/kg level with an accuracy and precision comparable to those of the manual methods of analysis. Time of analysis is reduced. The system can be run in an unattended mode of operation.

Assay of 1-hydroxy-3-aminopropylidene-1,1-bisphosphonate and related bisphosphonates in human urine and plasma by high-performance ion chromatography.

A method is described for the analysis of 1-hydroxy-3-aminopropylidene-1, 1-bisphosphonate and related bisphosphonates in human urine and plasma. Samples are spiked with 1-hydroxy-5-aminopentylidene-1,1-bisphosphonate as an internal standard and calcium chloride is added to precipitate the bisphosphonates. Following centrifugation the precipitate is redissolved in acetic acid, and the bisphosphonates are separated by high-performance ion chromatography on a Dionex AS7 column using nitric acid as mobile phase. The bisphosphonates are oxidised to orthophosphate using post-column addition of ammonium persulphate and this is followed by post-column reaction with molybdenum-ascorbate to yield the phosphomolybdate chromophore which is detected at 820 nm. A detection limit of 10 ng/ml is possible.