Defining the Value of Interventional Radiology to Healthcare Stakeholders: Proceedings from a Society of Interventional Radiology Research Consensus Panel.

Interventional radiology (IR) has collectively struggled to articulate and prove its value to several external stakeholders. The goal of this research consensus panel was to provide a summary of the existing knowledge, identify current gaps in knowledge, identify the strengths and weaknesses in existing data, and prioritize research needs related to the value of IR. Panelists were asked to identify the critical relationships/alliances that should be fostered to advance the prioritized research and determine how the Society of Interventional Radiology and the Society of Interventional Radiology Foundation can further support these initiatives. Following presentations and discussions, it was determined that proving and quantifying how IR decreases the length of stay and prevents hospital admissions are the most salient, value-related research topics to pursue for the specialty.

Distance-Based Estimation Methods for Models for Discrete and Mixed-Scale Data.

Pearson residuals aid the task of identifying model misspecification because they compare the estimated, using data, model with the model assumed under the null hypothesis. We present different formulations of the Pearson residual system that account for the measurement scale of the data and study their properties. We further concentrate on the case of mixed-scale data, that is, data measured in both categorical and interval scale. We study the asymptotic properties and the robustness of minimum disparity estimators obtained in the case of mixed-scale data and exemplify the performance of the methods via simulation.

Methadone concentrations in blood, plasma, and oral fluid determined by isotope-dilution gas chromatography-mass spectrometry.

Methadone (MTD) is widely used for detoxification of heroin addicts and also in pain management programs. Information about the distribution of methadone between blood, plasma, and alternative specimens, such as oral fluid (OF), is needed in clinical, forensic, and traffic medicine when analytical results are interpreted. We determined MTD and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in blood, plasma, blood cells, and OF by gas chromatography-mass spectrometry (GC-MS) after adding deuterium-labeled internal standards. The analytical limits of quantitation for MTD and EDDP by this method were 20 and 3 ng/mL, respectively. The amounts of MTD and EDDP were higher in plasma (80.4 % and 76.5 %) compared with blood cells (19.6 % and 23.5 %) and we found that repeated washing of blood cells with phosphate-buffered saline increased the amounts in plasma (93.6 % and 88.6 %). Mean plasma/blood concentration ratios of MTD and EDDP in spiked samples (N = 5) were 1.27 and 1.21, respectively. In clinical samples from patients (N = 46), the concentrations of MTD in plasma and whole blood were highly correlated (r = 0.92, p < 0.001) and mean (median) plasma/blood distribution ratios were 1.43 (1.41). The correlations between MTD in OF and plasma (r = 0.46) and OF and blood (r = 0.52) were also statistically significant (p < 0.001) and the mean OF/plasma and OF/blood distribution ratios were 0.55 and 0.77, respectively. The MTD concentration in OF decreased as salivary pH increased (more basic). These results will prove useful in clinical and forensic medicine when MTD concentrations in alternative specimens are compared and contrasted.

Simultaneous Quantitation of Seven Phenethylamine-Type Drugs in Forensic Blood and Urine Samples by UHPLC-MS-MS.

Abuse of new psychoactive substances (NPS) has become a health and social issue of global concern. p-Methoxyamphetamine (PMA)/p-methoxymethamphetamine (PMMA) with fluoro- or chloro-derivatives of amphetamine and methamphetamine were among the most common drugs found in specimens from fatal cases in Taiwan during the January 2011 to December 2018 period. A liquid-liquid extraction sample preparation protocol with highly sensitive ultra-high performance liquid chromatography-tandem mass spectrometry approach was developed for the simultaneous analysis of seven phenethylamine-type drugs-PMA, PMMA, p-methoxyethylamphetamine, 4-fluoroamphetamine (4-FA), 4-fluoromethamphetamine (4-FMA), 4-chloroamphetamine (4-CA) and 4-chloromethamphetamine (4-CMA)-in postmortem blood and urine specimens. Separation by liquid chromatography was performed by Agilent Zorbax SB-Aq column. Tandem mass spectrometry was operated in Agilent Jet Stream Technology electrospray ionization in positive-ion multiple reaction monitoring mode. An analytical methodology was evaluated using drug-free blood and urine after fortification with 100-2,000 ng/mL of the seven target analytes. Average extraction recoveries were >80%; slightly higher ion suppression was observed for PMA and 4-CA; intra-/inter-day precision (% coefficient of variation) and accuracy were in the ranges of 0.52-12.3% and 85-110%, respectively. Limit of detection and lower limit of quantitation for these seven analytes were both in the 0.5-5 ng/mL range. Interference and carryover were not significant. This relatively simple methodology was found effective and reliable for routine identification and quantitation of these seven analytes in postmortem and antemortem blood and urine specimens received in 2018. Analytical data obtained from these actual cases indicated the following: (i) compared to findings reported during the 2007-2011 period, the use of substituted phenethylamine-type drugs decreased in 2018; (ii) ketamine and 7-aminonimetazepam (the main metabolite of nimetazepam) were the most common co-ingested substances in specimens containing PMA/PMMA, 4-FA/4-FMA, or 4-CA/4-CMA; and (iii) in drug fatalities, the concentration of PMA was significantly higher than the concentration of PMMA in both urine and blood, while the reverse was true in urine specimens from antemortem cases.

Interventional Radiology Workforce Shortages Affecting Small and Rural Practices: A Report of the SIR/ACR Joint Task Force on Recruitment and Retention of Interventional Radiologists to Small and Rural Practices.

Radiology practices characterized as small and rural are challenged to recruit and retain interventional radiologists. Lack of access to interventional radiologic services results in a failure to meet the needs of patients, hospitals, and other community stakeholders. Acknowledging this challenge, the ACR's Commission on General, Small, Emergency and/or Rural Practice and Commission on Interventional and Cardiovascular Imaging and the Society of Interventional Radiology partnered to establish a joint task force to study this issue and identify strategies the ACR and the Society of Interventional Radiology should take to improve small and rural practice recruitment and retention of interventional radiologists. This report describes the deliberations and recommendations of the task force.

Detector response and intensity cross-contribution as contributing factors to the observed non-linear calibration curves in mass spectrometric analysis.

It is a common knowledge that detector fatigue causes a calibration curve to deviate from the preferred linear relationship at the higher concentration end. With the adaptation of an isotopically labeled analog of the analyte as the internal standard (IS), cross-contribution (CC) of the intensities monitored for the ions designating the analyte and the IS can also result in a non-linear relationship at both ends. A novel approach developed to assess 'the extent and the effect of [CC]… in quantitative GC-MS analysis' can be extended (a) to examine whether a specific set of CC values is accurate; and (b) to differentiate whether the observed non-linear calibration curve is caused by detector fatigue or the CC phenomenon. Data derived from the exemplar secobarbital (SB)/SB-d(5) system (as di-butyl-derivatives) are used to illustrate this novel approach. Comparing the non-linear nature of calibration data that are empirically observed to that derived from theoretical calculation (with the incorporation of adjustment resulting from the ion CC phenomenon), supports the conclusions that (a) both CC and detector fatigue contribute significantly to the observed non-linear nature of the calibration curve based on ion-pair m/z 207/212; and (b) detector fatigue is the dominating contributor when the calibration curve is based on ion-pair m/z 263/268.

Increased per-patient imaging utilization in an emergency department setting during COVID-19.

INTRODUCTION: COVID-19 has resulted in decreases in absolute imaging volumes, however imaging utilization on a per-patient basis has not been reported. Here we compare per-patient imaging utilization, characterized by imaging studies and work relative value units (wRVUs), in an emergency department (ED) during a COVID-19 surge to the same period in 2019. METHODS: This retrospective study included patients presenting to the ED from April 1-May 1, 2020 and 2019. Patients were stratified into three primary subgroups: all patients (n = 9580, n = 5686), patients presenting with respiratory complaints (n = 1373, n = 2193), and patients presenting without respiratory complaints (n = 8207, n = 3493). The primary outcome was imaging studies/patient and wRVU/patient. Secondary analysis was by disposition and COVID status. Comparisons were via the Wilcoxon rank-sum or Chi-squared tests. RESULTS: The total patients, imaging exams, and wRVUs during the 2020 and 2019 periods were 5686 and 9580 (-41%), 6624 and 8765 (-24%), and 4988 and 7818 (-36%), respectively, and the percentage patients receiving any imaging was 67% and 51%, respectively (p < .0001). In 2020 there was a 170% relative increase in patients presenting with respiratory complaints. In 2020, patients without respiratory complaints generated 24% more wRVU/patient (p < .0001) and 33% more studies/patient (p < .0001), highlighted by 38% more CTs/patient. CONCLUSION: We report increased per-patient imaging utilization in an emergency department during COVID-19, particularly in patients without respiratory complaints.

Methylglyoxal-mediated anxiolysis involves increased protein modification and elevated expression of glyoxalase 1 in the brain.

Methylglyoxal (MG) is a highly reactive metabolite that forms adducts with basic amino acid side chains in proteins. MG is degraded by glyoxalase1 (GLO1), an enzyme shown to be differentially expressed in several mouse models of anxiety-related behavior. As yet, molecular mechanisms by which altered GLO1 expression influences emotionality have not been elucidated. Here we report that both MG concentration and protein modification are altered in brain tissue of a mouse model for trait anxiety, with elevated levels in low anxiety-related behavior relative to high anxiety-related behavior animals. Accordingly, repeated intracerebroventricular injections of MG mediated anxiolysis in inbred high anxiety-related behavior and outbred CD1 mice. We found that anxiolytic-like properties of MG were independent of GLO1 expression. In contrast, antidepressant-like properties of intracerebroventricular MG were suppressed in CD1 mice carrying extra copies of the GLO1 gene. Moreover, MG treatment increased expression of GLO1 only in CD1 mice that did not have extra copies of GLO1. Taken together, these results suggest that the MG levels in brain are negatively correlated with anxiety. Thereby, we identified a novel molecular mechanism for anxiety-related behavior in mice that may help to elucidate genesis of psychiatric disorders in humans.

Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies.

The objective of this work was to further investigate the reasons for disconcordant clinical digoxin drug interactions (DDIs) particularly for false negative where in vitro data suggests no P-glycoprotein (P-gp) related DDI but a clinically relevant DDI is evident. Applying statistical analyses of binary classification and receiver operating characteristic (ROC), revised cutoff values for ratio of [I]/IC(50) < 0.1 and [I(2)]/IC(50) < 5 were identified to minimize the error rate, a reduction of false negative rate to 9% from 36% (based on individual ratios). The steady state total C(max) at highest dose of the inhibitor is defined as [I] and the ratio of the nominal maximal gastrointestinal concentration determined for highest dose per 250 mL volume defined [I(2)](.) We also investigated the reliability of the clinical data to see if recommendations can be made on values that would allow predictions of 25% change in digoxin exposure. The literature derived clinical digoxin interaction studies were statistically powered to detect relevant changes in exposure associated with digitalis toxicities. Our analysis identified that many co-meds administered with digoxin are cardiovascular (CV) agents. Moreover, our investigations also suggest that the presence of CV agents may alter cardiac output and/or kidney function that may act alone or are additional components to enhance digoxin exposure along with P-gp interaction. While we recommend digoxin as the probe substrate to define P-gp inhibitory potency for clinical assessment, we observed high concordance in P-gp inhibitory potency for calcein AM as a probe substrate.

Rapid screening and confirmation of drugs and toxic compounds in biological specimens using liquid chromatography/ion trap tandem mass spectrometry and automated library search.

Recent advances in liquid chromatography/tandem mass spectrometry (LC/MS/MS) technology have provided an opportunity for the development of more specific approaches to achieve the 'screen' and 'confirmation' goals in a single analytical step. For this purpose, this study adapts the electrospray ionization ion trap LC/MS/MS instrumentation (LC/ESI-MS/MS) for the screening and confirmation of over 800 drugs and toxic compounds in biological specimens. Liquid-liquid and solid-phase extraction protocols were coupled to LC/ESI-MS/MS using a 1.8-microm particle size analytical column operated at 50 degrees C. Gradient elution of the analytes was conducted using a solvent system composed of methanol and water containing 0.1% formic acid. Positive-ion ESI-MS/MS spectra and retention times for each of the 800 drugs and toxic compounds were first established using 1-10 microg/mL standard solutions. This spectra and retention time information was then transferred to the library and searched by the identification algorithm for the confirmation of compounds found in test specimens - based on retention time matches and scores of fit, reverse fit, and purity resulting from the searching process. The established method was found highly effective when applied to the analyses of postmortem specimens (blood, urine, and hair) and external proficiency test samples provided by the College of American Pathology (CAP). The development of this approach has significantly improved the efficiency of our routine laboratory operation that was based on a two-step (immunoassay and GC/MS) approach in the past.

Development of an information-rich LC-MS/MS database for the analysis of drugs in postmortem specimens.

With several instrument configurations available from various manufacturers, liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology is currently intensively studied for comprehensive drug screen and confirmation. An LC-MS/MS database, including 780 drug and toxic compounds, has been constructed, featuring information-rich MS/MS spectra derived from a novel fragmentation approach incorporating voltage ramping and broadened mass window for activation. The resulting spectra are rich in high- and low-mass fragment ions, highly effective for matching and proven reproducible over a 6 month test period. Coupled to effective sample preparation protocols, the database-searching process greatly improved the identification of drugs in postmortem specimens by the LC-electrospray ionization (ESI)-MS/MS technology. This method has significantly improved the efficiency of our routine laboratory operation that was based on a two-step [fluorescence polarization immunoassay (FPIA) and gas chromatography/mass spectrometry (GC/MS)] approach in the past.

An empirical study on the selection of analytes and corresponding cutoffs for immunoassay and GC-MS in a two-step test strategy--buprenorphine example.

(i) Standard solutions of buprenorphine (B) and three metabolites; (ii) immunoassay (IA) reagents designed for the analysis of B and/or its metabolites; and (iii) clinical urine specimens collected from patients (under B-treatment), constitute the B-System for fundamental study of parameters critical to the two-step test strategy, an analytical approach designed for a high-volume testing environment. The cross-reacting characteristics of IA reagents were examined using standard solutions of B and its metabolites. Resulting data were used as the basis for selecting target analytes suitable for the preliminary and the confirmatory test steps. Test data derived from IA and GC-MS analysis of clinical urine specimens (with natural distribution of B and its metabolites) were quantitatively correlated. Correlation parameters were examined: (i) to verify whether the analyte-pair targeted by the IA and GC-MS test steps has been properly selected; and (ii) to decide on appropriate cutoffs for the two test steps. In conclusion, this study has demonstrated that the most effective analyte(s) that should be targeted in the GC-MS determination step vary with the IA selected in the preliminary test step. All analytes that generate significant responses to the IA reagent should be targeted in the GC-MS test step.

Methylenedioxymethamphetamine-related deaths in Taiwan: 2001-2008.

Methylenedioxymethamphetamine (MDMA) has been one of most popular drugs in the "club" scene in Taiwan. This epidemic was studied through the examination of toxicological data obtained from the 59 fatalities tested positive for MDMA during the period of January 2001 to December 2008. Ketamine was found in 28 of these cases, signifying the popularity of this drug in Taiwan. The annual number of deaths in each of the 8 years in this period was 4, 7, 9, 14, 8, 9, 2, and 6, respectively. Among these 59 deaths, 39 (66.1%) were men, and the mean, median, and range of ages were 24.6, 23, and 14-46, respectively. Causes of death ruled by the attending pathologists and the distributions for these fatalities were acute intoxication, 40 and mechanical injury, 19, including 3 hanging and 2 drowning. The manners of death were ruled as accidental, 44; homicidal, 6; suicidal, 7; and undetermined, 2. In this study, postmortem whole blood was analyzed by gas chromatography-mass spectrometry with a limit of quantitation at 0.05 microg/mL for both MDMA and MDA. The mean, median, and range of MDMA concentrations in the cases, where MDMA acute intoxication was ruled as the cause of death, were 4.75, 2.60, and 0.12-40.41 microg/mL. MDA was found in 30 of these 40 cases with the following mean, median, and range data: 0.19, 0.13, and 0.05-1.81 microg/mL. The corresponding data of MDMA and MDA in the remaining 19 MDMA-related deaths were significantly lower: 1.25, 0.97, 0.08-3.05 and 0.11, 0.09, 0.06-0.24 microg/mL, respectively.

A novel approach to evaluate the extent and the effect of cross-contribution to the intensity of ions designating the analyte and the internal standard in quantitative GC-MS analysis.

In gas chromatography-mass spectrometry methods of analysis adopting the analyte's isotopic analog as the internal standard (IS), the cross-contribution (CC) phenomenon -- contribution of IS to the intensities of the ions designating the analyte, and vice versa -- has been demonstrated to affect the quantitation data. A novel approach based on the deviations of the empirically observed concentrations of a set of standards was developed to assess the accuracy of the empirically derived CC data. This approach demonstrated that normalization of ion intensities derived from the analyte and the IS generates reliable CC data. It further demonstrated that an ion-pair (designating the analyte and the IS) with approximately 5% or higher CC will result in a very limited linear calibration range.

Evaluation of various derivatization approaches for gas chromatography-mass spectrometry analysis of buprenorphine and norbuprenorphine.

Various chemical derivatization approaches have been adapted for the analysis of buprenorphine and its major metabolite (norbuprenorphine) by GC-MS based methodologies. These approaches included alkylation, acylation, and silylation resulting in the formation of methyl, acetyl, trifluoroacetyl, pentafluoropropionyl, heptafluorobutyryl, and trimethylsilyl derivatives. This study conducted a comprehensive evaluation on the merits of these approaches based on the following criteria: reaction yields and ionization efficiency of the derivatization products; chromatographic characteristics; and cross-contributions to the intensities of ions designating the analytes and the internal standards. Under acidic derivatization conditions, the analytes could form three artifact products. Overall, derivatization by acetyl anhydride resulted in best performance characteristics.

A novel derivatization approach for simultaneous determination of glyoxal, methylglyoxal, and 3-deoxyglucosone in plasma by gas chromatography-mass spectrometry.

A two-step derivatization approach has been developed to enable the simultaneous analysis of glyoxal, methylglyoxal, and 3-deoxyglucosone by the most efficient and widely applied GC-MS methodology. These three analytes are reactive carbonyl compounds associated with the formation of advanced glycation and lipoxidation end products, a process thought to contribute to uremic toxicity and referred to as "carbonyl stress". Effective analysis of these compounds would facilitate understanding these compounds' role in diabetes-related complications. Plasma samples were deproteinized by acetonitrile, followed by a two-step derivatization approach. Pooled plasma samples from healthy individuals were used as the "blank" for preparing calibration standards. The concentrations of the analytes in the "blank" were first determined by standard addition method. Calibration parameters were accordingly established and used to analyze these compounds in plasma samples collected from healthy individuals and diabetic patients. Analytical findings are comparable with those reported in the literature. Quantitation data can be further improved by making available and using isotopically labeled analogs of these analytes as the internal standards.

GC-MS analysis of multiply derivatized opioids in urine.

Opiates such as hydrocodone, hydromorphone, oxycodone, noroxycodone, and oxymorphone reportedly may interfere with the analysis of morphine and codeine. The analysis of these compounds themselves also is an important issue. Thus, double derivatization approaches utilizing methoxyamine and hydroxylamine to first form oxime products with keto-opiates, followed by the derivatization with trimethylsilyl (TMS) or propionyl groups, have been developed for the simultaneous analysis of these compounds. However, these studies have not included all compounds of interest and resulted in inadequate chromatographic resolution or significant intensity cross-contribution between the ions designating the analyte and its deuterated internal standard for certain compounds. By exploring three-step derivatization approaches with the combination of various derivatization groups and orders, this study concluded that application of methoxyimino/propionyl/TMS groups, in the order listed, facilitated the simultaneous analysis of eight opiates (morphine, 6-acetylmorphine, hydromorphone, oxymorphone, codeine, hydrocodone, oxycodone and noroxycodone) in urine samples, achieving satisfactory limits of quantitation and detection. In addition, the adapted approach resulted in two usable products for morphine and codeine providing alternatives, should interferences render any of these products non-usable.

Performance characteristics of ELISAs for monitoring ketamine exposure.

BACKGROUND: Growing misuse of ketamine necessitates the development of high throughput testing approaches. Two commercial enzyme-linked immunosorbent assays (ELISA) for ketamine have recently become available and were adapted for this development. METHOD: The newly available ketamine ELISA reagents were examined to better understand their cross-reacting, calibration and other performance characteristics. ELISA apparent analyte concentrations were also correlated against ketamine concentrations as determined by GC-MS to examine the relationship between these 2 parameters. RESULT: Both adapting ketamine as the targeted analyte, reagent from International Diagnostic Systems (IDS) also responded very significantly to the metabolites of ketamine (norketamine and dehydronorketamine), while the NEOGEN reagent responded very specifically to ketamine. CONCLUSION: NEOGEN ELISA test data exhibit better correlation with the ketamine concentration as determined by GC-MS. It can be more reliably used as the preliminary test method in the 2-step approach now routinely adapted in workplace drug testing programs. Using 100 ng/ml ketamine as the GC-MS cutoff, the corresponding ELISA cutoff value is approximately 110-120 ng/ml. With significantly higher responses to ketamine metabolites, IDS reagent can detect specimens with much lower ketamine/metabolites concentrations and can better meet other testing requirements.

Gas chromatography-mass spectrometry analysis of ketamine and its metabolites--a comparative study on the utilization of different derivatization groups.

Method of chemical derivatization is the main difference among the GC-MS based methodologies reported for the analysis of ketamine and its major metabolites (norketamine and dehydronorketamine). These approaches included acylation and silylation resulting in the formation of acetyl, trifluoroacetyl, heptafluorobutyryl, and pentafluorobenzoyl (for acylation); and possibly trimethylsilyl and t-butyldimethylsilyl (for silylation) derivatives. This study evaluates the merits of these approaches based on the following criteria: reaction yields and ionization efficiency of the derivatization products; chromatographic characteristics; and cross-contributions to the intensities of ions designating the analyte and the internal standard. Pentafluorobenzoyl-derivatives were found to provide the best performance characteristics.

6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism.

Mahlavu cells, poorly differentiated and p53 mutants of a human hepatoma subline, are known to be highly refractory to a number of chemotherapeutic agents and radiotherapy due to their high expressions of multidrug resistance gene-1 (MDR-1) and Bcl-2 proteins. Thus, it is desirable to search for an alternative strategy for effective eradication of this type of cancer cells. We present evidence here for the first time that 6-shogaol (6-SG), an alkanone isolated from the rhizomes of ginger, can effectively induce apoptotic cell death of Mahlavu cells via an oxidative stress-mediated caspase-dependent mechanism. The cascade of events in 6-SG-induced apoptosis of these cells involved an initial overproduction of reactive oxygen species (ROS) followed by a severe depletion of intracellular glutathione (GSH) contents. Both events consequently entailed a significant drop in mitochondrial transmembrane potential (DeltaPsim), which ultimately activated the activities of caspases 3/7 resulting in the DNA fragmentation. Interestingly, we also found that N-acetylcysteine (NAC), an antioxidant and a precursor of GSH biosynthesis, could offer a near complete protection of apoptotic cell death exerted by 6-SG. Similarly, exogenously added GSH could also provide protection with an equal efficacy. However, it was paradoxical that both Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporin A (an mitochondrial permeability transition opening inhibitor) could only partially protect these cells from 6-SG-induced apoptosis. Taking these data into consideration, it is obvious that GSH depletion is the major contributing factor in arbitrating 6-SG-induced apoptosis of Mahlavu cells. In conclusion, we provide here a novel modality that can help to eradicate a p53 mutant of human hepatoma cells by using a natural consistent isolated form of ginger. These data also provide evidence to reaffirm the notion that consumption of certain foodstuffs can be beneficial to health because some of the constituents contained in them may be anticarcinogenic.